Omission of Completion Lymph Node Dissection in Sentinel Node Biopsy Positive Head and Neck Cutaneous Melanoma Patients.

BACKGROUND: Recent studies evaluating patients with a positive sentinel lymph node biopsy (SLNB+) show no melanoma-specific survival difference between patients undergoing lymph node basin surveillance and completion lymph node dissection (CLND). This has been broadly applied, despite underrepresentation of head and neck (HN) cutaneous melanoma patients. We evaluated whether this was upheld in the HN melanoma cohort. METHODS: Patients with HN melanoma with a SLNB+ were selected from the National Cancer Database (NCDB) from 2012 to 2019. Overall survival (OS) of patients who underwent SLNB only versus SLNB + CLND were compared. Subgroup analyses were performed based on pathologic N (pN) and receipt of immunotherapy. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were calculated. RESULTS: Analysis of 634 patients with multivariable Cox regression showed no difference in OS in SLNB only versus SLNB + CLND cohorts (hazard ratio [HR] 1.13; 95% confidence interval [CI] 0.71-1.81; p = 0.610). Charlson-Deyo score (CDS) 1 versus 0 (HR 1.70; 95% CI 1.10-2.63; p = 0.016), pN2+ versus pN1 (HR 1.74; 95% CI 1.23-2.45; p = 0.002), and lymphovascular invasion (LVI) versus no (HR 2.07; 95% CI 1.34-3.19; p = 0.001) were associated with worse prognosis. Subgroup analysis by pN showed no OS benefit for CLND in either pN1 (HR 1.04; 95% CI 0.51-2.10; p = 0.922) or pN2+ (HR 1.31; 95% CI 0.67-2.57; p = 0.427) patients or in patients who received immunotherapy (HR 1.32; 95% CI 0.54-3.22; p = 0.549). CONCLUSIONS: This study of SLNB + HN melanoma patients showed no OS difference in SLNB only versus SLNB + CLND. Further studies need to be performed to better define the role of CLND.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

Impact of genomic assays on treatment and outcomes in locally advanced breast cancer.

PURPOSE: Genomic profiling in early-stage breast cancer provides prognostic and predictive information. Genomic profiling assays have not been validated in locally advanced breast cancer (LABC). We examined a large cancer registry to evaluate genomic profiling in LABC and its effect on treatment decisions and survival. METHODS: Females with ER+/HER2- LABC who did not receive neoadjuvant therapy were selected from the National Cancer Database 2004-2017. We compared characteristics between patients with and without genomic profiling and with low genomic risk, 21-gene recurrence score ≤ 25 or low-risk 70-gene signature, treated with endocrine therapy ± chemotherapy. Propensity score methods were utilized to account for covariates that may have predicted treatment. Univariable and multivariable survival analyses were performed. RESULTS: Of 18,437 patients with LABC, 1258 (7%) had genomic profiling and 1022 (81%) had low genomic risk results. 562 patients (55%) with low genomic risk received chemotherapy and endocrine therapy (chemoendocrine). Patients who received chemoendocrine therapy were younger, had fewer comorbidities, presented with higher stage disease, had higher grade tumors, more frequently had partial mastectomy, and more often received radiation than those who received endocrine therapy alone. On multivariable analysis, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy (HR 1.77, 95% CI 1.13-2.78, p = 0.013). CONCLUSION: In women with LABC and low genomic risk, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy. This suggests that genomic profiling is not predictive in LABC. Accordingly, genomic profiling should not be routinely utilized to make adjuvant treatment decisions in LABC in the absence of further data which shows a benefit.

Neoantigen Identification and Response to Adoptive Cell Transfer in Anti-PD-1 Naïve and Experienced Patients with Metastatic Melanoma.

PURPOSE: Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the NCI demonstrated decreased responses in patients previously treated with anti-PD-1 agents. We aimed to find a basis for the difference in response rates between anti-PD-1 naïve and experienced patients. PATIENTS AND METHODS: We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti-PD-1 naïve and 69 anti-PD-1 experienced patients. RESULTS: Anti-PD-1 naïve patients were found to possess tumors with higher TMBs (352.0 vs. 213.5, P = 0.005) and received TIL reactive with more neoantigens (2 vs. 1, P = 0.003) compared with anti-PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT nonresponders in both anti-PD-1 naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, treatment products administered to anti-PD-1 naïve patients were more likely to contain T cells reactive against neoantigens than treatment products for anti-PD-1 experienced patients (2.5 vs. 1, P = 0.02). CONCLUSIONS: These results indicate that decreases in TMB and targeted neoantigens partially account for the difference in response to ACT and that additional factors likely influence responses in these patients. See related commentary by Blass and Ott, p. 2980.

Treatment and Survivorship Interventions to Prevent Poor Body Image Outcomes in Breast Cancer Survivors.

Body image concerns often arise during and after treatment and are a major concern in up to 67% of breast cancer survivors. Negative changes in body image are a predictor of worse satisfaction with appearance and poor quality of life outcomes. Opportunities to mitigate the negative impact of cancer treatment on a patient's body image present during preoperative education or in the neoadjuvant setting, or during surgical management, adjuvant therapy delivery, and survivorship. The surgical management of breast cancer has evolved from breast amputations to procedures that provide improved cosmesis without compromising the oncologic outcome. The advent of the sentinel lymph node biopsy and lymphatic reconstruction techniques has led to decreased axillary morbidity. Modified radiation techniques and systemic therapies tailored to subtype limit unnecessary exposure to skin and systemic toxicities. Finally, incorporating prehabilitation and survivorship support optimizes the physical and psychosocial well-being of these patients. Setting expectations, treatment de-escalation when appropriate, morbidity risk reduction and improved screening and management of psychological sequelae during survivorship can decrease breast cancer treatment's negative impact on body image. The following review synthesizes interventions during preoperative planning, local and systemic treatment, and survivorship to prevent poor body image outcomes without compromising oncologic success.

Clinical Outcomes for Primary and Radiation-Associated Angiosarcoma of the Breast with Multimodal Treatment: Long-Term Survival Is Achievable.

BACKGROUND: The optimal management of primary angiosarcoma (PAS) and radiation-associated angiosarcoma (RAAS) of the breast remains undefined. Available data show persistently poor survival outcomes following treatment with surgery or chemotherapy alone. The objective of this study was to evaluate long-term outcomes in patients treated with multimodality therapy. METHODS: Patients diagnosed with stage I-III PAS or RAAS of the breast were identified from our local tumor registry (2010-2020). Patient demographics, tumor characteristics, and treatment were collected. Primary outcomes were local recurrence (LR), distant recurrence (DR), and median overall survival (OS). A secondary outcome was pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC). Mann-Whitney U, chi-squared, or Fisher exact tests were used to analyze data. Kaplan-Meier curves compared OS for PAS and RAAS. RESULTS: Twenty-two patients met inclusion criteria, including 11 (50%) with RAAS and 11 (50%) with PAS. Compared to PAS patients, RAAS patients were older and had more comorbidities. For RAAS patients, median time from radiation to diagnosis was 6 years (IQR: 5-11). RAAS patients were more likely to have a pCR to NAC (40% vs. 20%, p = 0.72). RAAS patients had a higher LR rate (43% vs. 38%, p = 0.83), and PAS patients were more likely to develop a DR (38% vs. 0%, p = 0.07). Median OS was 81 months in PAS patients and 90 months in RAAS patients (p = 1.00). DISCUSSION: Long-term survival can be achieved in patients with PAS and RAAS who undergo multimodality treatment. NAC can result in pCR. The long-term clinical implications of pCR warrant further investigation.

Adjuvant endocrine therapy is associated with improved overall survival in elderly hormone receptor-positive breast cancer patients.

PURPOSE: There is controversy regarding the survival benefit of endocrine therapy (ET) in elderly patients with early invasive hormone receptor-positive (HR+) breast cancer. In this study, we characterize a single institution's practice patterns using adjuvant ET for these patients and evaluated the effect of ET on outcomes. METHODS: A review of a prospectively maintained database identified 483 women ≥ 70 years old who underwent breast -conserving surgery (BCS) for stage I-III HR+ tumors from 2004-2013. We compared clinicopathologic characteristics, overall survival (OS), disease-free survival (DFS), locoregional recurrence (LRR), and breast cancer-specific survival (BCSS) in patients who did and did not receive ET. RESULTS: Compared to patients who did not get ET, patients who received ET were younger (median age 76 vs 78 years, p = 0.006), had larger tumors (median size 15 vs 14 mm, p = 0.016), underwent sentinel lymph node (LN) biopsy (83.7 vs 67.8%, p < 0.001), had positive LNs (25.5 vs 9.8%, p = 0.008), and received radiation (XRT, 76 vs 43%, p < 0.001). After adjusting for ASA score, age, LN status, tumor grade, and XRT, receipt of ET was associated with improved OS (HR 0.44; 95% CI 0.25-0.77; p = 0.004) and DFS (HR 0.42; 95% CI 0.28-0.64; p < 0.01). Receipt of ET was associated with improved LRR on univariate analysis (HR 0.25; 95% CI 0.09-0.70; p = 0.008); however, after adjusting for grade and XRT, this was not statistically significant on multivariable analysis (HR 0.38; 95% CI 0.13-1.08; p = 0.069) and was not associated with BCSS (HR 0.59; 95% CI 0.16-2.16; p = 0.43). CONCLUSIONS: ET was associated with significant improvements in OS and DFS, regardless of clinicopathological features; however, receipt of ET did not impact LRR and BCSS.

Sentinel Lymph Node Biopsy: Indications and Technique.

Sentinel lymph node biopsy is a key tool in the care of many patients with melanoma. The indications for the procedure have gradually become clearer over the 3 decades since the technique was developed. For appropriately selected patients, it carries enormous significance. Although it is a minimally invasive procedure, it does carry some risk. It is also a multidisciplinary procedure, requiring knowledge and experience from several specialties including nuclear medicine, surgery, and pathology.

Midgut Neuroendocrine Tumors with Liver-only Metastases: Benefit of Primary Tumor Resection.

BACKGROUND: Management of metastatic midgut neuroendocrine tumors (MNET) remains controversial. The benefits of resecting the primary tumor are not clear and advocated only for select patients. This study aimed to determine whether resection of the primary MNET in patients with untreated liver-only metastases has an impact on survival. METHODS: This retrospective study reviewed data of the National Cancer Database from 2004 to 2015 for patients with liver-only metastatic MNETs and compared those who received resection of their primary MNET with those who did not. Patient demographics, tumor characteristics, and clinical outcomes were compared between the groups. The primary outcome was overall survival (OS) after adjustment for patient, demographic, and tumor-related factors. RESULTS: The study identified 1952 patients with a median age of 63 years (range, 18-90 years). The median primary tumor size was 2.4 cm (range, 0.1-20 cm). Of these patients, 1295 (66%) underwent resection of the primary tumor and 667 (34%) did not. The patients who underwent resection were younger (median age, 63 vs 65 years; p < 0.001) and had smaller primary tumors (median, 2.3 vs 3.0 cm; p < 0.001). The patients with clinical T1 or T2 tumors were significantly less likely to undergo resection than those with stage T3 or T4 tumors (58.5% vs 89.7%; p < 0.001). The median follow-up period was 43 months (range, 1-83 months). In the entire cohort, 483 deaths occurred, with a 5-year OS of 61%. The 5-year OS rate was 49% for the patients who underwent resection and 66% for those who did not (p < 0.001). When the patients were grouped according to T stage, no OS difference between resection and no resection for stages T1 (p = 0.07) and T2 (p = 0.40) was identified. However, the 5-year OS rate was significantly better for the resected patient cohort with T3 (67.5% vs 37.2%; p < 0.001) or T4 (59.8% vs 21.5%; p < 0.001) tumors. CONCLUSIONS: The patients with treatment-naïve liver-only metastatic MNET had improved OS when the primary tumor was resected, particularly those with clinical stage T3 or T4 tumors. These patients may benefit from surgical resection of their primary tumor.

Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers.

Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers. SIGNIFICANCE: TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.This article is highlighted in the In This Issue feature, p. 983.

Primary Leiomyosarcoma of the Colon: A Report of Two Cases, Review of the Literature, and Association with Immunosuppression for IBD and Rheumatoid Arthritis.

Primary leiomyosarcomas (LMS) of the colon are rare and aggressive neoplasms and have been infrequently reported in the literature. These tumors are more aggressive and have poorer prognoses than adenocarcinoma of the colon and are often mistaken as such on initial evaluation. While the former has a clear association with inflammatory bowel disease (IBD), this correlation is not known to exist with LMS and IBD. Nor is there a known link between LMS and the immunosuppression for IBD, despite the known association between malignancy and immunosuppression for other diseases. Due to the low prevalence of this disease entity, there is limited knowledge and literature on the approach to diagnosing and treating these neoplasms, especially in the setting of the aforementioned comorbidities. Here, we describe two cases of this rare entity, presenting in two different circumstances: one in the setting of immunosuppression for IBD and arthritis, with a synchronous urothelial carcinoma, and the second appearing as the source of an acute abdomen. Both diagnoses were established following pathologic analysis.

Injury patterns and outcomes in late middle age (55-65): The intersecting comorbidity with high-risk activity - A retrospective cohort study.

BACKGROUND: Late middle age (LMA), is a watershed between youth and old age, with unique physical and social changes and declines in vitality, but a desire to remain active despite increasing comorbidity. While post-injury outcomes in the elderly are well studied, little is known regarding LMA patients. We analyzed the injured LMA population admitted to a rural, regional Level 1 Trauma Center relative to outcomes for both younger and older patients. MATERIALS AND METHODS: Our registry was queried retrospectively for patients admitted 7/2008- 12/2015; they were divided into three cohorts: 18-54, 55-65, and >65 years. Demographics, injury details, comorbidities, and outcomes were compiled and compared using ANOVA and Chi-square; p < 0.05 was significant. RESULTS: During the study period, 10,543 were admitted; 1419 (14%) were LMA who experienced overall injury mechanisms, severities and patterns that mirrored the younger cohort. However comorbidity rates were high (56.4%) and comparable to the elderly. LMA patients had the highest rates of alcohol abuse, morbid obesity, and psychiatric illness (p < 0.0001) and suffered the poorest outcomes: highest complications and hospital charges, and longest ICU and hospital LOS. LMA mortality (4.1%) was 41% higher than younger patients (2.9%; p < 0.02) and similar to the older cohort (4.7%; p = 0.32). CONCLUSIONS: The LMA population has similar mechanisms and injury patterns to younger patients, while exhibiting comorbidity rates similar to the elderly. High-energy injuries exact a greater toll in LMA with poorer outcomes and greater resource utilization. Targeted outreach for injury prevention, and future studies, are needed to address high-risk behavior, substance abuse, and societal contributors.

Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer.

Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer.Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized.Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1*1501-restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples.Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer. Clin Cancer Res; 23(15); 4347-53. ©2017 AACR.

Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression.

Purpose: The adoptive transfer of lymphocytes genetically modified to express tumor reactive T-cell receptors (TCR) can mediate tumor regression. Some tumor-infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TILs target tumor-specific neoantigens. Here we attempted to isolate neoantigen-reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs.Experimental Design: Mutations expressed by tumors were identified using whole-exome and RNA sequencing. Tandem minigene (TMG) constructs encoding 12-24 mutated gene products were synthesized, each encoding the mutated amino acid flanked by 12 amino acids of the normal protein sequence. TILs were cultured with autologous dendritic cells (DC) transfected with in vitro transcribed (IVT) mRNAs encoding TMGs and were evaluated for IFNγ secretion and CD137 expression. Neoantigen-reactive T cells were enriched from TILs by sorting for CD137+ CD8+ T cells and expanded in vitro Dominant TCR α and ß chains were identified in the enriched populations using a combination of 5' rapid amplification of cDNA ends, deep sequencing of genomic DNA, PairSeq analysis, and single-cell RT-PCR analysis. Human PBL retrovirally transduced to express the TCRs were evaluated for recognition of relevant neoantigens.Results: We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells.Conclusions: This strategy provides the means to generate T cells expressing neoantigen-reactive TCRs for use in future adoptive cell transfer immunotherapy trials for patients with cancer. Clin Cancer Res; 23(10); 2491-505. ©2016 AACR.

A comparison of initial lactate and initial base deficit as predictors of mortality after severe blunt trauma.

BACKGROUND: After injury, base deficit (BD) and lactate are common measures of shock. Lactate directly measures anaerobic byproducts, whereas BD is calculated and multifactorial. Although recent studies suggest superiority for lactate in predicting mortality, most were small or analyzed populations with heterogeneous injury severity. Our objective was to compare initial BD with lactate as predictors of inhospital mortality in a large cohort of blunt trauma patients all presenting with hemorrhagic shock. MATERIALS AND METHODS: The Glue Grant multicenter prospective cohort database was queried; demographic, injury, and physiologic parameters were compiled. Survivors, early deaths (≤24 h), and late deaths were compared. Profound shock (lactate ≥ 4 mmol/L) and severe traumatic brain injury subgroups were identified a priori. Chi-square, t-test, and analysis of variance were used as appropriate for analysis. Multivariable logistic regression and area under the receiver operating characteristic curve analysis assessed survival predictors. P < 0.05 was significant. RESULTS: A total of 1829 patients met inclusion; 289 (15.8%) died. Both BD and lactate were higher for nonsurvivors (P < 0.00001). After multivariable regression, both lactate (odds ratio [OR] 1.17; 95% confidence interval [CI]: 1.12-1.23; P < 0.00001) and BD (OR 1.04; 95% CI: 1.01-1.07; P < 0.005) predicted overall mortality. However, when excluding early deaths (n = 77), only lactate (OR 1.12 95% CI: 1.06-1.19; P < 0.0001) remained predictive but not BD (OR 1.00 95% CI: 0.97-1.04; P = 0.89). For the shock subgroup, (n = 915), results were similar with lactate, but not BD, predicting both early and late deaths. Findings also appear independent of traumatic brain injury severity. CONCLUSIONS: After severe blunt trauma, initial lactate better predicts inhospital mortality than initial BD. Initial BD does not predict mortality for patients who survive >24 h.

Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens.

Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. Cancer Immunol Res; 4(8); 669-78. ©2016 AACR.

Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor.

Adoptive transfer of T cells with engineered T-cell receptor (TCR) genes that target tumor-specific antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8(+)PD-1(+) T-cell subset, matching of TCRA-TCRB pairs by pairSEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes, which included reactivity against neoantigens. These data show the feasibility of developing a rapid, personalized TCR-gene therapy approach that targets the unique set of antigens presented by the autologous tumor without the need to identify their immunologic reactivity. Cancer Immunol Res; 4(9); 734-43. ©2016 AACR.