Carbon dioxide (CO2) emissions and adherence to Mediterranean diet in an adult population: the Mediterranean diet index as a pollution level index.

BACKGROUND: Research related to sustainable diets is is highly relevant to provide better understanding of the impact of dietary intake on the health and the environment. AIM: To assess the association between the adherence to an energy-restricted Mediterranean diet and the amount of CO2 emitted in an older adult population. DESIGN AND POPULATION: Using a cross-sectional design, the association between the adherence to an energy-reduced Mediterranean Diet (erMedDiet) score and dietary CO2 emissions in 6646 participants was assessed. METHODS: Food intake and adherence to the erMedDiet was assessed using validated food frequency questionnaire and 17-item Mediterranean questionnaire. Sociodemographic characteristics were documented. Environmental impact was calculated through greenhouse gas emissions estimations, specifically CO2 emissions of each participant diet per day, using a European database. Participants were distributed in quartiles according to their estimated CO2 emissions expressed in kg/day: Q1 (≤2.01 kg CO2), Q2 (2.02-2.34 kg CO2), Q3 (2.35-2.79 kg CO2) and Q4 (≥2.80 kg CO2). RESULTS: More men than women induced higher dietary levels of CO2 emissions. Participants reporting higher consumption of vegetables, fruits, legumes, nuts, whole cereals, preferring white meat, and having less consumption of red meat were mostly emitting less kg of CO2 through diet. Participants with higher adherence to the Mediterranean Diet showed lower odds for dietary CO2 emissions: Q2 (OR 0.87; 95%CI: 0.76-1.00), Q3 (OR 0.69; 95%CI: 0.69-0.79) and Q4 (OR 0.48; 95%CI: 0.42-0.55) vs Q1 (reference). CONCLUSIONS: The Mediterranean diet can be environmentally protective since the higher the adherence to the Mediterranean diet, the lower total dietary CO2 emissions. Mediterranean Diet index may be used as a pollution level index.

Treatment patterns and outcomes of palliative systemic therapy in patients with salivary duct carcinoma and adenocarcinoma, not otherwise specified.

BACKGROUND: Salivary duct carcinoma (SDC) and adenocarcinoma, not otherwise specified (adeno-NOS), are rare salivary gland cancers. Data on the efficacy of systemic therapy for these diseases are limited. METHODS: Data were retrospectively collected from patients seen at The University of Texas MD Anderson Cancer Center during 1990 to 2020. Objective response rate (ORR) was assessed per RECIST v1.1. Recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were assessed by Kaplan-Meier method. Cox regression model was performed to identify predictors of survival. RESULTS: The analysis included 200 patients (110 with SDC and 90 with adeno-NOS); 77% had androgen-receptor-positive tumors and 47% had HER2-positive (2+-3+) tumors. Most patients without metastasis at diagnosis underwent surgery (98%) and postoperative radiotherapy (87%). Recurrence rate was 55%, and the median RFS was 2 years. Nodal involvement and positive surgical margins were associated with recurrence (P < .005). Among patients with stage IVA-B disease, addition of systemic therapy to local therapy increased OS (P = .049). The most-used palliative-systemic-therapy regimen was platinum doublet ± trastuzumab. For first-line therapy, the ORR and median PFS were 33% and 5.76 months, respectively, and for second-line therapy the ORR and median PFS were 25% and 5.3 months, respectively. ORR and PFS were higher with HER2-targeting agents. Median OS was 5 years overall and 2 years for metastatic disease. Older age and higher stage were associated with worse OS. CONCLUSION: Adding systemic therapy to local therapy may improve outcomes of patients with locoregionally advanced SDC or adeno-NOS. Except for HER2-targeted therapy, response to palliative systemic therapy is limited. These findings may be used as a benchmark for future drug development.

Clinical Validation of a 3-Dimensional Ultrafast Cardiac Magnetic Resonance Protocol Including Single Breath-Hold 3-Dimensional Sequences.

OBJECTIVES: This study sought to clinically validate a novel 3-dimensional (3D) ultrafast cardiac magnetic resonance (CMR) protocol including cine (anatomy and function) and late gadolinium enhancement (LGE), each in a single breath-hold. BACKGROUND: CMR is the reference tool for cardiac imaging but is time-consuming. METHODS: A protocol comprising isotropic 3D cine (Enhanced sensitivity encoding [SENSE] by Static Outer volume Subtraction [ESSOS]) and isotropic 3D LGE sequences was compared with a standard cine+LGE protocol in a prospective study of 107 patients (age 58 ± 11 years; 24% female). Left ventricular (LV) mass, volumes, and LV and right ventricular (RV) ejection fraction (LVEF, RVEF) were assessed by 3D ESSOS and 2D cine CMR. LGE (% LV) was assessed using 3D and 2D sequences. RESULTS: Three-dimensional and LGE acquisitions lasted 24 and 22 s, respectively. Three-dimensional and LGE images were of good quality and allowed quantification in all cases. Mean LVEF by 3D and 2D CMR were 51 ± 12% and 52 ± 12%, respectively, with excellent intermethod agreement (intraclass correlation coefficient [ICC]: 0.96; 95% confidence interval [CI]: 0.94 to 0.97) and insignificant bias. Mean RVEF 3D and 2D CMR were 60.4 ± 5.4% and 59.7 ± 5.2%, respectively, with acceptable intermethod agreement (ICC: 0.73; 95% CI: 0.63 to 0.81) and insignificant bias. Both 2D and 3D LGE showed excellent agreement, and intraobserver and interobserver agreement were excellent for 3D LGE. CONCLUSIONS: ESSOS single breath-hold 3D CMR allows accurate assessment of heart anatomy and function. Combining ESSOS with 3D LGE allows complete cardiac examination in <1 min of acquisition time. This protocol expands the indication for CMR, reduces costs, and increases patient comfort.

The tumor immune contexture of salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy. Recently, biomarker studies found promising targetable alterations. In this study, we provide a descriptive analysis of tumor and immune biomarkers and survival associations. METHODS: We extracted clinical data and performed immunohistochemistry for AR, AR-V7, HER-2, PD-L1, LAG-3, and tumor-infiltrating immune cells. RESULTS: We included 17 patients. Age ranged from 42 to 85 years old; HER-2 was overexpressed or amplified in 65%. AR was positive in 88% of patients, while AR-V7 was positive in 13% by IHC. We found low scores of immune infiltration and a PD-L1 expression in 53%. We found no clinically significant association between biomarkers and survival outcomes. CONCLUSION: In this small series of SDC, biomarkers do not seem to correlate with disease biology, although they provide additional treatment options. SDC may harbor a different immune profile compared to other subtypes, with an indication of T-cell dysfunction.

Prognostic Factors for Orbital Exenteration, Local Recurrence, Metastasis, and Death From Disease in Conjunctival Squamous Cell Carcinoma.

PURPOSE: Information regarding risk of metastasis and disease-related death (DD) from conjunctival squamous cell carcinoma (SCC) is relatively scarce. We explored prognostic factors for orbital exenteration, local recurrence, nodal metastasis, and DD in patients with conjunctival SCC. DESIGN: Retrospective cross-sectional study. METHODS: All consecutive patients with conjunctival SCC treated by the senior author at MD Anderson Cancer Center during1999-2018 were included. Survival curves were estimated using the Kaplan-Meier method, and survival differences were assessed using 2-sided log-rank tests. RESULTS: The study included 44 patients (24 men, 20 women); median age was 64 years (range, 40-90). T categories at presentation were as follows: Tis, 20 patients; T2, 8; T3, 9; and T4, 7. Eighteen patients (41%) had tumors exclusively in the bulbar conjunctiva; 26(59%) had nonbulbar conjunctival involvement. The median follow-up time was 29.2 months (95% CI: 21.8-44.3). Orbital exenteration was performed in 10 cases (23%) and was associated with T3 or more advanced disease at presentation (p < 0.001). Seven patients developed local recurrence during follow up. History of organ transplant correlated with local recurrence and orbital exenteration (p < 0.01). Nodal metastasis was present in 1 patient at presentation and occurred in 3 patients during follow up, for an overall nodal metastasis rate of 9% (4/44). By end of follow up, 2 patients had died of disease, 4 had died of other causes, and 38 were alive with no evidence of disease. The results suggest that both orbital exenteration and nodal metastasis are independent variables associated with DD. CONCLUSIONS: In patients with conjunctival SCC, orbital exenteration and nodal metastasis are associated with DD and organ transplantation is associated with orbital exenteration.

Prognostic factors for local recurrence and survival and impact of local treatments on survival in lacrimal gland carcinoma.

BACKGROUND/AIMS: To identify prognostic factors for local recurrence, distant metastasis and disease-specific survival (DSS) for lacrimal gland carcinoma. METHODS: All consecutive patients with lacrimal gland carcinoma treated from January 1998 through December 2018 were included. Log-rank tests and univariate Cox proportional hazards regression models were used to study risk factors and survival. RESULTS: Overall, 55 patients were included in this study, and 5 patients were excluded from the survival analysis. Median age was 46 years (range: 10-76). 43 patients (78%) had adenoid cystic carcinoma (ACC). 31 patients (56%) had T2 disease at presentation. 28 patients (51%) underwent orbital exenteration with or without adjuvant radiotherapy or chemoradiation, 26 (47%) underwent eye-sparing surgery with or without adjuvant radiotherapy or chemoradiation, and 1 received palliative chemoradiation. 11 patients (22%) experienced local recurrence; 14 (29%) experienced distant metastasis. Five- and 10-year local-recurrence-free survival rates were 0.71 (95% CI 0.58 to 0.88), and 5- and 10-year distant-metastasis-free survival rates were 0.67 (95% CI 0.53 to 0.85) and 0.49 (95% CI 0.30 to 0.81), respectively. There was no significant difference in risks of local recurrence, distant metastasis or DSS between ACC patients who had orbital exenteration and those who had eye-sparing surgery. Perineural invasion was negatively associated with local-recurrence-free survival (p=0.02). Among patients with ACC, basaloid/solid histologic type was associated with significantly worse DSS than non-basaloid/solid histologic type (p<0.01). CONCLUSIONS: For lacrimal gland carcinoma, orbital exenteration with adjuvant therapy and eye-sparing surgery with adjuvant therapy are associated with similar recurrence outcomes. Eye-sparing surgery is associated with better DSS. Perineural invasion is a risk factor for local recurrence. ACC with basaloid/solid subtype correlates with worse DSS.

Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ Tumor Lymphocyte Density, Safety, and Efficacy in Patients with Oropharynx Cancer: CIAO Trial Results.

PURPOSE: In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC. PATIENTS AND METHODS: Patients with newly diagnosed stage II-IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes. RESULTS: Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: -1.07-2.28). In each group, 6 patients (43%, 95% CI: 17.66-71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: -0.33-3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence. CONCLUSIONS: Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.

Association of T and N Categories of the American Joint Commission on Cancer, 8th Edition, With Metastasis and Survival in Patients With Orbital Sarcoma.

Importance: No previous studies to date have validated the American Joint Committee on Cancer (AJCC) 8th edition of the TNM classification for orbital sarcoma. Objectives: To determine the prognostic performance of the most recent TNM classification for orbital sarcoma and to identify other prognostic factors for local recurrence, lymph node metastasis, distant metastasis, and death due to disease. Design, Setting, and Participants: This single-center retrospective cohort study included 73 consecutive patients treated for orbital sarcoma from March 1, 2003, through June 30, 2018. Data were analyzed from November 1 to December 31, 2018. Main Outcomes and Measures: T and N categories at presentation and disease-related outcomes, including local recurrence, lymph node metastasis, distant metastasis (DM), and death due to disease (DD). Results: The 73 participants included 43 men (59%), and the median age was 21 (range, 0-77) years. The common histologic types were rhabdomyosarcoma (RMS) (35 [48%]), solitary fibrous tumor/hemangiopericytoma (10 [14%]), and Ewing sarcoma (8 [11%]). The most common TNM designations were T2 N0 M0 (26 [36%]) and T4 N0 M0 (24 [33%]). T category was associated with the risk of all disease-related outcomes, including local recurrence (hazard ratio [HR] for T2 vs T4, 0.22 [95% CI, 0.06-0.81]; HR for T3 vs T4, 0.59 [95% CI, 0.13-2.65]; P = .03), lymph node metastasis by the last follow-up (T1, 1 [14%]; T2, 0; T3, 0; T4, 12 [35%]; P = .001), DM (HR for T2 vs T4, 0.29 [95% CI, 0.08-1.07]; P = .04), and DD (HR of T2 vs T4, 0.16 [95% CI, 0.04-0.73]; HR of T3 vs T4, 0.30 [95% CI, 0.04-2.34]; P = .02). Higher risk of DM and higher risk of DD were associated with disease category of at least T3 (HR for DM, 3.24 [95% CI, 0.89-11.72; P = .06]; HR for DD, 6.32 [95% CI, 1.43-27.95; P = .005]), N1 disease (HR for DM, 13.33 [95% CI, 4.07-43.65; P < .001]; HR for DD, 7.07 [95% CI, 2.45-20.44; P < .001]), tumor size larger than 3 cm (HR for DM, 2.72 [95% CI, 0.92-8.05; P = .06]; HR for DD, 5.79 [95% CI, 1.85-18.14; P < .001]), and age of patient with RMS younger than 1 year or 10 years or older (HR for DM, 6.85 [95% CI, 0.83-56.53; P = .04]; HR for DD, 7.03 [95% CI, 0.85-57.83; P = .04]). Higher risk of local recurrence was associated with disease category of at least T3 (HR for3 cm, 0.27 [95% CI, 0.09-0.77]; P = .009). Higher risk of lymph node metastasis was associated with disease category of at least T3 (odds ratio [OR], 13.33 [95% CI, 1.77-602.30]; P = .004), alveolar RMS (OR, 9.98 [95% CI, 2.13-51.55]; P = .001), and age of patient with RMS younger than 1 year or 10 years or older (OR, 9.20 [95% CI, 1.01-458.29] P = .03). Conclusions and Relevance: In patients with orbital sarcoma, T and N categories at presentation (defined by the AJCC 8th edition classification) correlate with metastasis and survival. These findings appear to support consideration of strict surveillance testing for regional nodal and systemic metastases in patients with orbital sarcoma with disease category of at least T3 and/or N1 disease.

Whole-exome sequencing for ocular adnexal sebaceous carcinoma suggests PCDH15 as a novel mutation associated with metastasis.

Ocular adnexal sebaceous carcinoma (OASeC) is an aggressive eyelid carcinoma. Analysis of molecular-genetic drivers of this disease could reveal new prognostic markers and actionable targets for treatment. To identify somatically acquired genomic mutations in OASeC and explore their associations with metastasis, whole-exome sequencing on DNA extracted from retrospectively collected tumor samples was performed. Thirty-one patients in two orbital oncology centers with OASeC were included. Sequencing results were analyzed to detect mutations and explore their possible association with metastasis. The median patient age was 64 years. A total of 1780 candidate somatic mutations were identified with median mutation rate of 1.0/Mb (range, 0.2-13.6). The five most commonly mutated genes (as determined by MutSig; q value < 0.25) were TP53 (mutated in 22 cases), ZNF750 (13 cases), RB1 (12 cases), NOTCH1 (8 cases), and PCDH15 (5 cases). Mutations in ZNF750 or NOTCH1 pathway genes were present in 24 (77%) of the 31 cases; there was a trend toward mutual exclusivity of ZNF750 and NOTCH1 mutations. All eight tumors with NOTCH1 mutations also had TP53 and/or RB1 mutations. Four of the five PCDH15 mutations and all four PCDH15 missense mutations were identified in patients with metastatic disease, including one patient with distant metastasis and three with nodal metastasis. PCDH15 was significantly associated with metastasis (P = 0.01). We identified the most commonly mutated genes in a series of OASeCs and found a previously unreported mutation in OASeC, PCDH15 mutation, that was significantly associated with metastasis. NOTCH1 mutation is an actionable mutation; clinical trials targeting this mutation are available throughout the US and could be considered for patients with metastatic NOTCH1-mutant OASeC. TP53, ZNF750, RB1, and PCDH15 mutations are most likely loss-of-function mutations and may have diagnostic and prognostic importance.

Response rates and survival to systemic therapy after immune checkpoint inhibitor failure in recurrent/metastatic head and neck squamous cell carcinoma.

OBJECTIVES: Prior reports have demonstrated a potential enhancement in overall response rate (ORR) to chemotherapy after exposure to immunotherapy. The goal of this study was to evaluate the ORR and survival to chemotherapy and/or targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients who progressed on immune checkpoint inhibitors (ICI). MATERIALS AND METHODS: We retrospectively collected clinical and pathologic data from patients with recurrent/metastatic HNSCC who progressed on ICI and subsequently received chemotherapy or targeted therapy. ORR was assessed by RECIST version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 43 patients met criteria for inclusion. The majority were male (91%) and former smokers (60%). Most patients received ICI as first-line (58.14%); the vast majority was platinum exposed (90.7%). The ORR to ICI was 21%. The ORR to systemic therapy before ICI was 47%, and the ORR after ICI failure was 42%. After progression on ICI, the median PFS and OS on the subsequent line of therapy were 4.2 and 8.4 months respectively. CONCLUSION: In our cohort of recurrent/metastatic HNSCC patients, the ORR and OS to systemic therapy after progression on ICI were higher than historical controls for second-line or beyond. Further investigations are warranted to better characterize optimal sequencing and combination strategies.

Greater Tumor Thickness, Ulceration, and Positive Sentinel Lymph Node Are Associated With Worse Prognosis in Patients With Conjunctival Melanoma: Implications for Future AJCC Classifications.

Identifying tumor characteristics that correlate with metastasis and survival in patients with conjunctival melanoma can potentially lead to better outcomes through a better selection of patients for adjuvant treatments including potentially life-saving new melanoma therapy. The objective of this study was to validate the conjunctival melanoma staging criteria in the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (8th edition) and explore the prognostic importance of tumor thickness, histologic ulceration, and sentinel lymph node biopsy (SLNB) findings in patients with conjunctival melanoma. This is a case series of 88 consecutive patients with conjunctival melanoma. Clinicopathologic characteristics were analyzed. Associations between pathologic characteristics and outcomes were studied using Kaplan-Meier survival analysis. Local recurrence, lymph node metastasis, distant metastasis, and disease-specific survival (DSS) were the main outcome measures. The study included 56 women and 32 men; the median age was 62 years. At presentation, 41 patients had T1 disease, 23 had T2 disease, 23 had T3, and 1 had T4 disease. Sixty-six patients had invasive conjunctival melanoma (median thickness, 1.56 mm), 17 had conjunctival melanoma in situ, and in 5 patients, tumor thickness could not be determined. Overall, 22 patients had ulceration. In total, 31 patients underwent SLNB, and 4 had a positive sentinel lymph node (SLN). The median follow-up time was 46.6 months. Overall, 12 patients had nodal metastasis at presentation or during follow-up, 19 patients had distant metastasis at last follow-up, and 14 patients died of the disease. Tumor thickness and ulceration were associated with increased risks of nodal metastasis, distant metastasis, and death from the disease. Overall, greater clinical T category at presentation was associated with increased risks of distant metastasis and disease-related death; however, the risks of distant metastasis and disease-related death did not differ between T1 (bulbar) and T2 (nonbulbar) tumors or between T2c,d (caruncular) and T1-T2a,b (noncaruncular) tumors. In patients who underwent SLNB, a positive SLN was associated with worse distant metastasis free survival and DSS. Consideration should be given to adding ulceration and emphasizing tumor thickness as the main determinants of pathologic T category for conjunctival melanoma in future AJCC classifications. The significant association between a positive SLN and worse DSS highlights the importance of SLNB for prognosis in patients with conjunctival melanoma and selecting high-risk patients for adjuvant drug treatment.

Validation Study of the AJCC Cancer Staging Manual, Eighth Edition, Staging System for Eyelid and Periocular Squamous Cell Carcinoma.

Importance: To our knowledge, there are no validation studies to date of the prognostic value of the AJCC Cancer Staging Manual, eighth edition (AJCC 8), criteria for eyelid and periocular squamous cell carcinoma. Objective: To determine the association of tumor (T) category in AJCC 8 with local recurrence, nodal metastasis, distant metastasis, and disease-specific survival (DSS) for eyelid and periocular squamous cell carcinoma. Design, Setting, and Participants: In this retrospective, single-center cohort study, 109 consecutive patients with eyelid and periocular squamous cell carcinoma treated from January 1999 to April 2018 were included. Patients with secondary involvement of the periocular region were excluded. Main Outcomes and Measures: Local recurrence, nodal metastasis, distance metastasis, and DSS. Results: Of the 109 included patients, 81 (74.3%) were male, and the median (range) age was 66 (40-91) years. At presentation, 43 patients (39.4%) had recurrent tumor, 4 (3.7%) had nodal metastasis, and 1 (0.9%) had distant metastasis. The median (range) follow-up was 23 (1-161) months. During follow-up, 11 patients (10.1%) developed local recurrence, 7 (6.4%) developed nodal metastasis, 2 (1.8%) developed distant metastasis, and 9 (8.3%) died of disease. The 5-year DSS rate was 87.7% (95% CI, 79.5-96.9). Chronic immunosuppression (hazard ratio, 47.24; 95% CI, 7.33-304.30; P < .001) and presentation with recurrent squamous cell carcinoma (hazard ratio, 5.22; 95% CI, 1.12-24.31; P = .04) were associated with local recurrence during follow-up. Of the 11 patients with local recurrence during follow-up, 7 (64%) had perineural invasion. T category was associated with nodal metastasis; clinical stage of T2c or worse at presentation was associated with higher risk of nodal metastasis and death of disease but not with a higher risk of local recurrence. Distant metastasis was associated with nodal metastasis at presentation (hazard ratio, 32.50; 95% CI, 1.97-536.40; P = .02) and during follow-up. A total of 33 patients (30.3%) had different T categories depending on whether disease was staged according to the seventh or eighth edition of the AJCC Cancer Staging Manual. Compared with AJCC 7, AJCC 8 showed a better predictive value in terms of local recurrence (T3, 17% vs 14%; T4, 11% vs 16%) and DSS. Conclusions and Relevance: These findings suggest that T category in AJCC 8 is associated with nodal metastasis and DSS. Immunosuppression and presentation with recurrent disease are associated with increased risk of future local recurrence. Patients with tumors of clinical stage T2c or worse at presentation are at increased risk of nodal metastasis and worse DSS and should undergo surveillance for nodal metastasis. Future studies, ideally prospective in design, could provide greater confidence in these findings.

PD-L1 Expression, Tumor Mutational Burden, and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non-Small Cell Lung Cancer.

INTRODUCTION: Immune checkpoint blockade (ICB) has revolutionized the treatment of NSCLC, but only approximately 15% of patients achieve durable benefit. Understanding mechanisms of resistance to ICB is pivotal in developing more effective treatment strategies. Recent studies showed that human leukocyte antigen (HLA) class I heterozygosity might be important in mediating benefit from ICB. We aimed to investigate the impact of HLA class I genotype on outcomes of patients with NSCLC treated with ICB. METHODS: We collected HLA typing, genomic, and clinical data from patients with advanced NSCLC treated with ICB at M. D. Anderson Cancer Center. We compared HLA class I-heterozygous and HLA class I-homozygous patients for progression-free survival (PFS) and overall survival (OS). HLA I supertype/alleles were also analyzed. To validate our findings, we also analyzed two previously published independent cohorts of patients with NSCLC (the CheckMate-012 and Chowell cohorts). RESULTS: No significant correlations were observed for HLA class I zygosity and PFS or OS in the M. D. Anderson Cancer Center (n = 200), CheckMate-012 (n = 75), or Chowell (n = 371) cohorts. No HLA class I supertype/allele was consistently shown to be correlated with PFS or OS. Predictors of worse outcome across the three cohorts included presence of targetable driver mutation, serine/threonine kinase 11 gene (STK11) mutation, negative programmed death ligand 1 expression, and low tumor mutational burden. CONCLUSIONS: HLA class I genotype is not correlated with survival in advanced NSCLC treated with ICB. This suggests that the impact of HLA class I diversity may be disease specific and that tumor genomic and immune markers are more impactful in predicting benefit from ICB in NSCLC.

Prognostic factors for local recurrence, metastasis and survival for sebaceous carcinoma of the eyelid: observations in 100 patients.

BACKGROUND/AIMS: To validate the predictive value of the American Joint Committee on Cancer (AJCC) 8th-edition classification for local recurrence, metastasis and survival in patients with eyelid sebaceous carcinoma. METHODS: We performed a retrospective review of 100 consecutive patients with eyelid sebaceous carcinoma. Eyelid carcinomas were staged according to the AJCC 7th-edition and 8th-edition criteria. Associations between T and N categories and disease-related outcomes including local recurrence, lymph node metastasis, distant metastasis and survival were evaluated. RESULTS: 60 women and 40 men had a median age of 67 years (range, 41-94 years). The proportions of patients who experienced local recurrence, lymph node metastasis, distant metastasis and death from disease were 6%, 21%, 7% and 6%, respectively. Two-year and 5-year disease-specific survival (DSS) rates were 93.8% and 92.0%, respectively. There were significant correlations between (1) T2c or worse category and lymph node metastasis (p=0.04) and distant metastasis (p=0.01), (2) T3b or worse category and local recurrence (p=0.01) and death from disease (p=0.01) and (3) N1 category at presentation and distant metastasis (p<0.01) and death from disease (p<0.01). The AJCC 8th-edition classification showed a better homogeneity of the T-category distribution (p<0.01) and a slightly higher discrimination ability for lymph node metastasis (C=0.734 vs C=0.728) than the 7th-edition. CONCLUSIONS: T and N categories per AJCC 8th-edition classification are predictive of local recurrence, metastasis and DSS outcomes for eyelid sebaceous carcinoma. Surgeons should perform strict surveillance testing for nodal and systemic metastases in patients with T2c or worse T category and/or N1 disease at presentation.

A joint logistic regression and covariate-adjusted continuous-time Markov chain model.

The use of longitudinal measurements to predict a categorical outcome is an increasingly common goal in research studies. Joint models are commonly used to describe two or more models simultaneously by considering the correlated nature of their outcomes and the random error present in the longitudinal measurements. However, there is limited research on joint models with longitudinal predictors and categorical cross-sectional outcomes. Perhaps the most challenging task is how to model the longitudinal predictor process such that it represents the true biological mechanism that dictates the association with the categorical response. We propose a joint logistic regression and Markov chain model to describe a binary cross-sectional response, where the unobserved transition rates of a two-state continuous-time Markov chain are included as covariates. We use the method of maximum likelihood to estimate the parameters of our model. In a simulation study, coverage probabilities of about 95%, standard deviations close to standard errors, and low biases for the parameter values show that our estimation method is adequate. We apply the proposed joint model to a dataset of patients with traumatic brain injury to describe and predict a 6-month outcome based on physiological data collected post-injury and admission characteristics. Our analysis indicates that the information provided by physiological changes over time may help improve prediction of long-term functional status of these severely ill subjects. Copyright © 2017 John Wiley & Sons, Ltd.

Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds.

OBJECT There is limited literature available to guide transfusion practices for patients with severe traumatic brain injury (TBI). Recent studies have shown that maintaining a higher hemoglobin threshold after severe TBI offers no clinical benefit. The present study aimed to determine if a higher transfusion threshold was independently associated with an increased risk of progressive hemorrhagic injury (PHI), thereby contributing to higher rates of morbidity and mortality. METHODS The authors performed a secondary analysis of data obtained from a recently performed randomized clinical trial studying the effects of erythropoietin and blood transfusions on neurological recovery after severe TBI. Assigned hemoglobin thresholds (10 g/dl vs 7 g/dl) were maintained with packed red blood cell transfusions during the acute phase after injury. PHI was defined as the presence of new or enlarging intracranial hematomas on CT as long as 10 days after injury. A severe PHI was defined as an event that required an escalation of medical management or surgical intervention. Clinical and imaging parameters and transfusion thresholds were used in a multivariate Cox regression analysis to identify independent risk factors for PHI. RESULTS Among 200 patients enrolled in the trial, PHI was detected in 61 patients (30.5%). The majority of patients with PHI had a new, delayed contusion (n = 29) or an increase in contusion size (n = 15). The mean time interval between injury and identification of PHI was 17.2 ± 15.8 hours. The adjusted risk of severe PHI was 2.3 times higher for patients with a transfusion threshold of 10 g/dl (95% confidence interval 1.1-4.7; p = 0.02). Diffuse brain injury was associated with a lower risk of PHI events, whereas higher initial intracranial pressure increased the risk of PHI (p < 0.001). PHI was associated with a longer median length of stay in the intensive care unit (18.3 vs 14.4 days, respectively; p = 0.04) and poorer Glasgow Outcome Scale scores (42.9% vs 25.5%, respectively; p = 0.02) at 6 months. CONCLUSIONS A higher transfusion threshold of 10 g/dl after severe TBI increased the risk of severe PHI events. These results indicate the potential adverse effect of using a higher hemoglobin transfusion threshold after severe TBI.

The incidence of ARDS and associated mortality in severe TBI using the Berlin definition.

BACKGROUND: The incidence of adult respiratory distress syndrome (ARDS) in severe traumatic brain injury (TBI) is poorly reported. Recently, a new definition for ARDS was proposed, the Berlin definition. The percentage of patients represented by TBI in the Berlin criteria study is limited. This study describes the incidence and associated mortality of ARDS in TBI patients. METHODS: The study was an analysis of the safety of erythropoietin administration and transfusion threshold on the incidence of ARDS in severe TBI patients. Three reviewers independently assessed all patients enrolled in the study for acute lung injury/ARDS using the Berlin and the American-European Consensus Conference (AECC) definitions. A Cox proportional hazards model was used to assess the relationship between ARDS and mortality and 6-month Glasgow Outcome Scale (GOS) score. RESULTS: Two hundred patients were enrolled in the study. Of the patients, 21% (41 of 200) and 26% (52 of 200) developed ARDS using the AECC and Berlin definitions, respectively, with a median time of 3 days (interquartile range, 3) after injury. ARDS by either definition was associated with increased mortality (p = 0.04) but not with differences in functional outcome as measured by the GOS score at 6 months. Adjusted analysis using the Berlin criteria showed an increased mortality associated with ADS (p = 0.01). CONCLUSION: Severe TBI is associated with an incidence of ARDS ranging from 20% to 25%. The incidence is comparable between the Berlin and AECC definitions. ARDS is associated with increased mortality in severe TBI patients, but further studies are needed to validate these findings. LEVEL OF EVIDENCE: Epidemiologic study, level II.

Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury.

BACKGROUND: The effect of red blood cell (RBC) storage on oxygenation in critically ill patients is still unknown. The objective of this study was to determine the association of RBC storage with oxygenation, long-term neurologic recovery, and death after traumatic brain injury. METHODS: We used data from a 2 × 2 factorial randomized controlled trial of administration of erythropoietin or placebo and of assignment to transfusion threshold of less than 7g/dL or less than 10 g/dL in neurosurgical intensive care units in two US Level 1 trauma centers. Patients had severe traumatic brain injury with closed head injury, were unable to follow commands, and were enrolled within 6 hours of injury. Blood oxygenation 1 hour after the transfusion as measured by jugular venous oxygen saturation (n = 59) was the primary outcome. Secondary outcomes were brain tissue oxygenation (n = 77), 6-month Glasgow Outcome Scale (GOS) score (n = 122) collected using a structured interview and dichotomized into favorable (good recovery or moderate disability) or unfavorable outcome (severe disability, vegetative state, or dead), and mortality (n = 125). RBC age was defined as the maximum age of RBCs over all units in one transfusion per patient. For long-term outcomes, RBC age was defined as the mean age over all units given. RESULTS: We failed to detect an association of RBC age with jugular venous oxygen saturation (linear regression ß = 1.59; 95% confidence interval [CI], -2.99 to 6.18; p = 0.49), brain tissue oxygenation (linear regression ß = 0.20; 95% CI, -0.23 to 0.63; p = 0.36), GOS score (odds ratio, 1.37; 95% CI, 0.53-3.57; p = 0.52), and mortality (hazard ratio, 1.35; 95% CI, 0.61-2.98; p = 0.46). CONCLUSION: Limitations of this study include the fact that the RBC ages were not randomized, although this was a prospective study. We conclude that older blood does not seem to have adverse effects in severe traumatic brain injury. LEVEL OF EVIDENCE: Prognostic study, level III.

Polymorphisms of the T cell receptor CD3delta and CD3epsilon chains affect anti-CD3 antibody binding and T cell activation.

T cell receptor (TCR) structure and function have been thoroughly studied for decades. Production and analyses of knock-out and knock-in mice with mutations in the CD3 chains have contributed significantly to these studies. The generation of such gene-modified mice relies on the availability of suitable embryonic stem (ES) cell lines. Traditionally, ES cell lines from the 129 mouse strains have been used followed by backcrossing to the C57BL/6 strain. In the present study, we demonstrate the existence of polymorphisms in the CD3 genes from mice of the 129 and C57BL/6 strains. These polymorphisms result in amino acid substitutions in the ectodomains of both the CD3delta and CD3epsilon chains in 129 mice compared to C57BL/6 mice. The amino acid substitutions do not change the stoichiometry or surface expression level of the TCR complex in 129 T cells but cause reduced anti-CD3 antibody binding to 129 T cells. Further, when stimulated with mitogenic anti-CD3 antibodies, T cells from the 129 strains show reduced expression of the activation marker CD69, Ca(2+) flux, IL-2 production and proliferative responses compared to C57BL/6 T cells. These findings demonstrate that polymorphisms of the CD3delta and epsilon ectodomains exist in mice, and that some of these polymorphisms lead to amino acid substitutions which cause structural changes and affect anti-CD3 antibody binding. Thus, functional T cell studies should be interpreted with caution when anti-CD3 antibodies are used for stimulation of T cells derived from gene-modified mice originating from 129 ES cell lines.