Current Transthoracic Supra-Aortic Trunk Surgical Reconstruction Has Similar 30-Day Cardiovascular Outcomes Compared to Extra-Anatomic Revascularization but With Higher Morbidity Burden.

BACKGROUND: Operative risk for supra-aortic trunk (SAT) surgical revascularization for occlusive disease, particularly transthoracic reconstruction (TR), remains ill-defined. This study sought to describe and compare 30-day outcomes of TR and extra-anatomic (ER) SAT surgical reconstruction for an occlusive indication across the United States over a contemporary 15-year period. METHODS: Using the National Surgical Quality Improvement Program, TR and ER performed during 2005-2019 were identified. Procedures performed for nonocclusive indications and those concomitant with coronary or valve operations were excluded. Rates of stroke, death, myocardial infarction (MI) and these as composite outcome (S/D/M) were compared. Logistic regression with stabilized inverse probability weighting (IPW) was used to compare groups via average treatment effect (ATE) while adjusting for covariate imbalances. RESULTS: Over the 15-year period, 166 TR and 1,900 ER patients were identified. The majority of ERs were carotid-subclavian bypass (n = 1,344; 70.7%) followed by carotid-carotid bypass (n = 261; 13.7%) and subclavian/carotid transpositions (n = 123; 6.5%). TR consisted of aorto-SAT bypass (n = 120; 72.3%) and endarterectomy (n = 46; 27.7%). The median age was 64 years for TR and 65 years in ER (P = 0.039). Those undergoing TR were more often women (69.0% vs. 56.9%; P = 0.001) and less likely to have undergone previous cardiac surgery (9.2% vs. 20.8%; P = 0.006). TR were also less frequently hypertensive (68.1% vs. 75.4%; P = 0.038) and had statistically lower preoperative creatinine levels (0.86 vs 0.91; P = 0.002). Unadjusted rates of MI (0.6% vs. 1.3%; P = 0.72) and stroke (3.6% vs. 1.9%; P = 0.15) were similar between groups with mortality (3.6% vs. 1.5%; P = 0.05) and S/D/M (6.6% vs. 3.9%; P = 0.10) trending higher with TR. IPWs could be calculated for 1,754 patients (148 TR; 1,606 ER). The estimated probability of S/D/M was 3.8% in the ER group and 6.2% in TR; no difference was seen in ATE (2.4%; 95% confidence interval [CI]: -1.5 to 6.2; P = 0.23). No differences were seen in individual component ATEs (stroke: 3.0% vs. 1.7%; ATE = 1.3%; 95% CI: -3.9 to 1.3; P = 0.32; mortality: 3.8% vs. 1.4%; ATE = 2.4%; 95% CI: -5.6 to 0.7; P = 0.13). Secondary outcomes showed TR patients were more likely to have non-home discharge (18.7% vs. 6.6%; ATE = 12.1%; 95% CI: 5.0-19.2; P < 0.001) and longer lengths of stay (6.1 vs. 4.0; ATE = 2.2 days; 95% CI: 0.9-3.4; P < 0.001). Moreover, TR patients were more likely to require transfusion (22.7% vs. 5.0%; ATE = 17.7%; 95% CI: 10.2-25.2; P < 0.001) and develop sepsis (2.7% vs. 0.2%; ATE = 2.5%; 95% CI: 0.1-5.0; P = 0.04). CONCLUSIONS: Transthoracic and extra-anatomic surgical reconstruction of the SATs for occlusive disease have similar operative cardiovascular risk. However, morbidity tends to be higher with TR due to higher transfusion requirements, sepsis risk, and need for facility stay. These results suggest ER as a first-line approach in those with proper disease anatomy is reasonable with lower morbidity, while TR remains justified in appropriate patients.

Implementation of a Novel Patient Decision Aid for Women with Elevated Breast Cancer Risk Who Are Considering MRI Screening: A Pilot Study.

PURPOSE: To determine the feasibility and acceptability of using a patient decision aid (DA) for women with elevated breast cancer risk who are considering MRI screening. METHODS: This pilot study employed a mixed methods design to develop, modify, and test an interactive DA. The DA was administered among a consecutive patient sample with an estimated Tyrer-Cuzick v.8 lifetime breast cancer risk of 20% or greater and without a pathologic genetic mutation. The decisional conflict scale was used to measure decisional conflict. Post-intervention provider and patient feedback evaluated shared decision-making, feasibility, and acceptability. RESULTS: Twenty-four patients participated, with a median age of 44 years. Prior to DA use, sixteen patients (67%) were unsure whether to add MRI to their screening, six patients elected MRI (25%), and two patients declined MRI (8%). Following DA use, thirteen of sixteen of the initially undecided participants (81%) established a preference, with eleven electing to add MRI screening. Of participants with an initial preference, all maintained the same decision following use of the DA. Prior to the DA, the median decisional conflict score among participants was 25% (range 0-60%) compared with 0% (range 0-25%) after the DA. Healthcare providers reported that the DA was useful and easily incorporated into clinical workflow. CONCLUSIONS: This pilot study shows that there may be a benefit to DA utilization in the high-risk breast cancer clinic to guide shared decision-making in establishing a screening preference. The findings warrant further research to test the use of the DA in a larger, multi-site trial.

Somatic mutations show no clear association with red blood cell or human leukocyte antigen alloimmunization in de novo or therapy-related myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a marrow failure disease. As patients often require chronic transfusion, many develop red blood cell (RBC) alloimmunization or immune-mediated platelet refractoriness. MDS represents a spectrum of diseases with specific categorizations and genetic abnormalities, and we set out to determine if these characteristics predispose patients to antibody formation. STUDY DESIGN AND METHODS: A natural language search identified MDS patients with pre-transfusion testing from 2015 to 2020. Marrow reports, cytogenetic results, and next-generation sequencing panels were gathered. Transfusion history and testing were collected from the laboratory information system. RESULTS: The group consisted of 226 biopsy-proven MDS patients. The prevalence of RBC alloimmunization was 11.1% (25 of 226). Half (23 of 46) of all RBC alloantibodies were against Rh (C, c, E, e) and Kell (K) antigens. There was a relative enrichment for JAK2 positivity among the RBC alloimmunized group. A total of 7.1% (16 of 226) of patients had immune-mediated platelet refractoriness and had increased transfusion requirements (p ≤ 0.01). No disease type or genetic abnormality was significantly associated with alloimmunization or immune-mediated platelet refractoriness. DISCUSSION: While JAK2 specific mutations were enriched among RBC alloimmunized patients, this association failed to reach statistical significance in our single-center cohort. Further study using larger patient cohorts is warranted. Overall, this cohort of MDS patients had very similar RBC alloimmunization prevalence and anti-RBC antibody specificities as other recent literature. Our data reinforce the finding that MDS patients are at greater risk for alloimmunization and support the use of extended phenotype matching for these at-risk patients.

Characterization and comparison of innate and adaptive immune responses at vaccine sites in melanoma vaccine clinical trials.

The strength and durability of systemic anti-tumor immune responses induced by cancer vaccines depends on adjuvants to support an immunogenic vaccine site microenvironment (VSME). Adjuvants include water-in-oil emulsions with incomplete Freund's adjuvant (IFA) and combinations of toll-like receptor (TLR) agonists, including a preparation containing TLR4 and TLR9 agonists with QS-21 (AS15). IFA-containing vaccines can promote immune cell accumulation at the VSME, whereas effects of AS15 are largely unexplored. Therefore, we assessed innate and adaptive immune cell accumulation and gene expression at the VSME after vaccination with AS15 and compared to effects with IFA. We hypothesized that AS15 would promote less accumulation of innate and adaptive immune cells at the VSME than IFA vaccines. In two clinical trials, patients with resected high-risk melanoma received either a multipeptide vaccine with IFA or a recombinant MAGE-A3 protein vaccine with AS15. Vaccine site biopsies were obtained after one or multiple vaccines. T cells accumulated early after vaccines with AS15, but this was not durable or of the same magnitude as vaccination in IFA. Vaccines with AS15 increased durable expression of DC- and T cell-related genes, as well as PD-L1 and IDO1, suggesting complex activation and regulation of innate and adaptive immune function with AS15. These changes were generally greater with vaccines containing IFA, but IFA induced reduction in myeloid suppressor cells markers. Evidence of tertiary lymphoid structure (TLS) formation was observed with both adjuvants. Our findings highlight adjuvant-dependent changes in immune features at the VSME that may impact systemic immune responses.

Determining the Association Between Unplanned Reoperation and Readmission in Selected General Surgery Operations.

BACKGROUND: Unplanned reoperations and unplanned readmissions can increase morbidity and mortality. Few studies however, have explored the association of reoperation and readmission among general surgery patients. Our aim was to examine this relationship in selected abdominal operations. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Participant Use Data Files from 2014 to 2018 were utilized. Six groups of operations, defined by ACS NSQIP procedure codes for ventral hernia repair, colectomy, appendectomy, proctectomy, small bowel resection, and gastrectomy, were assessed. Patients discharged ≤ 14 days after operation were included in the study. This time period was selected to reduce ACS NSQIP 30 day post-surgery follow-up bias. Unplanned reoperations were defined as those occurring during the index hospitalization. The primary outcome was unplanned readmission that occurred ≤ 14 days from the date of discharge. Logistic regression models were used to examine variables associated with unplanned readmission for each procedure group. RESULTS: A total of 787,118 patients were included: ventral hernia repair 35.2%, colectomy 30.6%, appendectomy 26.5%, proctectomy 3.7%, small bowel resection 3.2%, and gastrectomy 0.8%. Unplanned reoperation was independently associated with unplanned readmission for ventral hernia repair (OR 2.84, 95% CI 2.28-3.54, P < 0.001), colectomy (OR 1.58, CI 1.42- 1.76, P < 0.001), appendectomy (OR 2.91, CI 2.21-3.84, P < 0.001), and proctectomy (OR 1.41, CI 1.10-1.81, P = 0.006). Other clinically relevant covariates associated with readmission were partially dependent functional status before colectomy (OR 1.34, CI 1.23-1.46, P < 0.001), ventral hernia repair (OR 1.79, CI 1.54-2.09, P < 0.001), and small bowel resection (OR 1.44, CI 1.18-1.77, P < 0.001; and ASA 4/5 classification for colectomy (OR 2.71, CI 2.36-3.11, P < 0.001), proctectomy (OR 2.10, CI 1.48-2.97, P < 0.001), ventral hernia repair (OR 8.19, CI 6.78-9.88, P < 0.001), appendectomy (OR 2.80, CI 2.35-3.34, P < 0.001), and small bowel resection (OR 3.42, CI 2.20-5.32, P < 0.001). ASA 2, ASA 3 classification, age, and sex were also associated with unplanned readmission for most procedures. CONCLUSIONS: Unplanned reoperations are associated with an increase in unplanned readmission after selected abdominal operations included in this study. This factor should be considered in discharge and follow-up planning to help reduce unplanned readmissions.

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

OBJECTIVE: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD. METHODS: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models. RESULTS: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (ß=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (ß=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (ß=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (ß=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (ß=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (ß=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (ß=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls. CONCLUSION: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.

A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites.

INTRODUCTION: Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m. but not i.d. or s.c. This study tests hypotheses that the i.d./s.c. route is safe and will increase CD4(+) and CD8(+) T cell responses to MAGE-A3. PATIENTS AND METHODS: Twenty-five patients with resected stage IIB-IV MAGE-A3(+) melanoma were randomized to immunization with recMAGE-A3 combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) either i.m. (group A, n = 13) or i.d./s.c. (group B, n = 12). Adverse events were recorded. Ab responses to MAGE-A3 were measured by ELISA. T cell responses to overlapping MAGE-A3 peptides were assessed in PBMC and a sentinel immunized node (SIN) after 1 in vitro stimulation with recMAGE-A3, by IFN-γ ELISPOT assay and by flow cytometry for multifunctional (TNF-α/IFN-γ) responses. RESULTS: Both routes of immunization were well tolerated without treatment-related grade 3 adverse events. All patients had durable Ab responses. For all 25 patients, the T cell response rate by ELISPOT assay was 30 % in SIN (7/23) but only 4 % (1/25) in PBMC. By flow cytometry, multifunctional CD8(+) T cell responses were identified in one patient in each group; multifunctional CD4(+) T cell response rates for groups A and B, respectively, were 31 and 64 % in SIN and 31 and 50 % in PBMC. CONCLUSION: The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4(+) T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration.

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

INTRODUCTION: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases. PATIENTS AND METHODS: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. RESULTS: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. CONCLUSION: The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.

Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases.

INTRODUCTION: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. PATIENTS AND METHODS: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. RESULTS AND CONCLUSIONS: Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.

Orbital Metastases from Breast Cancer: Retrospective Analysis at an Academic Cancer Center.

Orbital metastases from breast cancer (BC) are rare, but often debilitating. BC accounts for nearly half of metastases to the orbit. Orbital metastases may be discovered years after the initial diagnosis of BC, and are rare at initial presentation. A search of the institutional data base at an academic cancer center identified BC patients who developed or presented with orbital metastases from 2000 to 2013. Baseline characteristics, treatment modalities, survival and treatment responses were collected from the electronic medical record. There were 20 patients identified with orbital metastases (0.7% of all BC cases). The median age at diagnosis of BC was 49 years; 80% had estrogen positive disease. The interval between the initial diagnosis of BC and the presentation of orbital metastases was 8.5 years (0-19 years). Orbital disease was the initial presentation of BC in two cases. Three patients developed bilateral orbital metastases and seven had accompanying brain metastases. The most common presentation was decreased vision (55%), followed by diplopia (25%). The median survival after orbital metastases was 24 months. Thirteen patients (65%) received local radiation therapy. Of those radiated, 90% reported improvement of orbital symptoms. Other treatments included intraocular bevacizumab, surgery, and systemic therapy. Orbital metastases tend to occur in estrogen receptor positive disease and are often found years after BC onset. Orbital metastases may be associated with the development of brain metastases. Radiotherapy is the preferred local therapy and had high symptom control in this cohort. Oncologists should be aware of the signs of orbital metastases and the treatment options.

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials' experience.

BACKGROUND: The impacts of patient age and gender on immune response (IR) and clinical outcome after cancer vaccines are not known. We hypothesized younger and female patients would have higher IR rates and better survival. METHODS: Patients with resected stage IIB-IV melanoma in three clinical trials (Mel43, Mel44, Mel48) were vaccinated with 12 melanoma-associated peptides restricted by class I MHC. The cumulative incidence rate of CD8(+) T cell responses (direct interferon-gamma ELIspot assay) by week 7 was compared by age and gender. Overall survival (OS) and disease-free survival (DFS) landmark analyses were compared by Kaplan-Meier estimates and in multivariate analyses. RESULTS: T cell responses were evaluated in 327 patients and detected in 50 % of males and 48 % of females, with no difference in IR by gender or menopausal status. Males had trends toward longer DFS (p = 0.12) and OS (p = 0.09). Cumulative incidence of IR was higher in patients <64 years of age versus older patients (p = 0.03). OS and DFS were similar by age group (p > 0.50). In multivariate modeling, younger age was associated with better IR (OR 0.40, p value 0.003), without an impact of age or gender on clinical outcomes. CONCLUSION: These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age 64 years.

The Risk Factors of Readmission in Postoperative Gynecologic Oncology Patients at a Single Institution.

INTRODUCTION: Hospital readmission rates are an important measure of quality care and have recently been tied to reimbursement. This study seeks to identify the risk factors for postoperative readmission in patients treated by a gynecologic oncology service. METHODS: A 7-year retrospective review (2007-2013) of all patients operated on by the University of Virginia gynecologic oncology service who were readmitted within 30 days of discharge was performed. Abstracted data included demographics, dates of surgery, operative details, cancer history, and relevant medical history. The readmitted patients (n = 166) were compared with randomly selected controls (n = 168) from the same service in a matching time frame and analyzed using univariate and multivariate models. RESULTS: In the study period, 2993 operations were performed. One hundred sixty-six unique patients (5.5%) were readmitted within 30 days of discharge from their operative procedure. On multivariate analysis, the factors that were associated with a higher risk of readmission were a history of psychiatric disease, postoperative complication, type of insurance, surgical modality, and lysis of adhesions at the time of surgery. The most common readmission diagnoses were infection (44%), nausea/vomiting (28%), thrombosis (6%), bowel leak (4%), and bleeding (4%). CONCLUSIONS: Postoperative readmissions are a common problem and are increasingly important as a measure of quality. Although patients were generally admitted for infections or gastrointestinal complaints, we also found that individual factors such as mental health and socioeconomic status also contributed. Our data suggest that we can preoperatively identify high-risk individuals for whom extra resources can be directed postoperatively to avoid unnecessary readmissions.

Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine.

Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4(+) and CD8(+) T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-γ ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4(+) T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE-A3281-295 (49 %) and tyrosinase386-406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8(+) T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4(+) and CD8(+) T cell responses against melanoma antigens. CD4(+) T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8(+) T cell responses suggests epitope spreading and systemic activity mediated at the tumor site.

Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.

BACKGROUND: Multipeptide vaccines for melanoma may cause inflammatory adverse events (IAE). We hypothesize that IAE are associated with a higher rate of immune response (IR) to vaccination and improved clinical outcomes. METHODS: Adult patients with resected, high-risk (stage IIB to IV) melanoma were vaccinated with a combination of 12 class I major histocompatibility complex (MHC)-restricted melanoma epitopes, and IAE were recorded. A separate category for hypopigmentation (vitiligo) was also assessed. CD8(+) T cell IR was assessed by direct interferon gamma ELISpot analysis. Overall survival and disease-free survival were analyzed by Cox proportional hazard modeling. RESULTS: Out of 332 patients, 57 developed IAE, the majority of which were dermatologic (minimum Common Terminology Criteria for Adverse Events [CTCAE] grade 3). Most nondermatologic IAE were CTCAE grade 1 and 2. Vitiligo developed in 23 patients (7 %). A total of 174 patients (53 %) developed a CD8(+) response. Presence of IAE was significantly associated with development of IR (70 vs. 49 %, p = 0.005) and with disease-free survival (hazard ratio 0.54, p = 0.043). There were no significant associations relating vitiligo or IR alone with clinical outcomes. CONCLUSIONS: IAE are associated with a higher rate of CD8(+) T cell response after vaccination therapy for high-risk melanoma. Our findings suggest either that antitumor activity induced by class I MHC-restricted peptide vaccines may depend on immunologic effects beyond simple expansion of CD8(+) T cells or that the intrinsic inflammatory response of patients contributes to clinical outcome in melanoma.

Effect of neoadjuvant temozolomide upon volume reduction and resection of diffuse low-grade glioma.

Maximal safe resection is associated with prolonged survival in patients with low-grade glioma (LGG). It has been suggested that neoadjuvant temozolomide may provide sufficient tumor shrinkage to facilitate aggressive surgical debulking. We examined the impact of temozolomide upon volume reduction and resectability of LGG. We retrospectively identified 20 adult patients with biopsy-proven, deemed not totally resectable LGGs, treated initially with temozolomide. Volumetric 3D (calculated from serial FLAIR images) and 2D tumor measurements were obtained prior to treatment and at 3 months post-treatment. The anticipated extent of resection (EOR) at the 2 time points was measured based on anatomical limitations, calculated as: [(total tumor volume - unresectable tumor volume)/total tumor volume] ×100. Eloquent cortex, deep structures and corpus callosum were considered unresectable. Mean tumor volume was 68.4 cm(3) pre-treatment and 49.5 cm(3) at 3 months post-treatment. The mean change from baseline to 3 months after treatment was -32.5 % (p < 0.001). Mean 2D pre-treatment area was 28.6 and 23.3 cm(2) at 3 months post-treatment. The 2D change was also significant, with mean change of -17% (p < 0.001). 5% had partial response; 40% minor response; 45% stable disease; and 10% progressive disease by RANO criteria. Mean pre-treatment anticipated EOR was 67.2 and 71.5% at 3 months post-treatment. The mean change from baseline was 4.3% (p = 0.10). Our findings demonstrate significant volumetric and 2D reduction of LGG with temozolomide. Although this tumor shrinkage might facilitate radical surgical resection in some cases, our data failed to show statistically significant improvement in anticipated EOR.

Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin.

BACKGROUND: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. METHODS: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). FINDINGS: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. CONCLUSIONS: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. FUNDING: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.

Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide.

We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund's adjuvant (IFA) alone, or a melanoma vaccine in IFA. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA. Lymphocytes isolated from replicate vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naïve and greater proportions of effector memory CD8(+) T cells (TCD8). The vast majority of TCD8 within the VSME were activated (CD69(+)), with a concentration of antigen-specific (tetramer(pos)) cells in the VSME, particularly in vaccine sites with peptide (group 2). CXCR3(+) lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. TCD8 expression of retention integrins αEß7 and α1ß1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). TCD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-γ production in response to peptide stimulation and few tetramer(pos) cells producing IFN-γ. These data suggest that vaccine-induced selective retention and dysfunction of antigen-specific TCD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide vaccines administered in IFA.