Sentinel lymph node positivity in melanoma: Which risk prediction tool is most accurate?

BACKGROUND: Sentinel lymph node biopsy for melanoma determines treatment and prognostic factors and improves disease-specific survival. To risk-stratify patients for sentinel lymph node biopsy consideration, Memorial Sloan Kettering Cancer Center and Melanoma Institute Australia developed nomograms to predict sentinel lymph node positivity. We aimed to compare the accuracy of these 2 nomograms. METHODS: A multi-institutional study of patients with melanoma receiving sentinel lymph node biopsy between September 2018 and December 2022 was performed. The accuracy of the 2 risk prediction tools in determining a positive sentinel lymph node biopsy was analyzed using receiver operating characteristic curves and area under the curve. RESULTS: In total, 532 patients underwent sentinel lymph node biopsy for melanoma; 98 (18.4%) had positive sentinel lymph node. Increasing age was inversely related to sentinel lymph node positivity (P < .01); 35.7% of patients ≤30 years had positive sentinel lymph node compared with 9.7% of patients ≥75 years. When we analyzed the entire study population, accuracy of the 2 risk prediction tools was equal (area under the curveMemorial Sloan Kettering Cancer Center: 0.693; area under the curveMIA: 0.699). However, Memorial Sloan Kettering Cancer Center tool was a better predictor in patients aged ≥75 years (area under the curveMemorial Sloan Kettering Cancer Center: 0.801; area under the curveMelanoma Institute Australia: 0.712, P < .01) but Melanoma Institute Australia tool performed better in patients with a higher mitotic index (mitoses/mm2 ≥2; area under the curveMemorial Sloan Kettering Cancer Center: 0.659; area under the curveMelanoma Institute Australia: 0.717, P = .027). Both models were poor predictors of sentinel lymph node positivity in young patients (age ≤30 years; area under the curveMemorial Sloan Kettering Cancer Center: 0.456; area under the curveMelanoma Institute Australia: 0.589, P = .283). CONCLUSION: The current study suggests that the 2 risk stratification tools differ in their abilities to predict sentinel lymph node positivity in specific populations: Memorial Sloan Kettering Cancer Center tool is a better predictor for older patients, whereas Melanoma Institute Australia tool is more accurate in patients with a higher mitotic index. Both nomograms performed poorly in predicting sentinel lymph node positivity in young patients.

Characterizing Sentinel Lymph Node Status in Breast Cancer Patients Using a Deep-Learning Model Compared With Radiologists' Analysis of Grayscale Ultrasound and Lymphosonography.

ABSTRACT: The objective of the study was to use a deep learning model to differentiate between benign and malignant sentinel lymph nodes (SLNs) in patients with breast cancer compared to radiologists' assessments.Seventy-nine women with breast cancer were enrolled and underwent lymphosonography and contrast-enhanced ultrasound (CEUS) examination after subcutaneous injection of ultrasound contrast agent around their tumor to identify SLNs. Google AutoML was used to develop image classification model. Grayscale and CEUS images acquired during the ultrasound examination were uploaded with a data distribution of 80% for training/20% for testing. The performance metric used was area under precision/recall curve (AuPRC). In addition, 3 radiologists assessed SLNs as normal or abnormal based on a clinical established classification. Two-hundred seventeen SLNs were divided in 2 for model development; model 1 included all SLNs and model 2 had an equal number of benign and malignant SLNs. Validation results model 1 AuPRC 0.84 (grayscale)/0.91 (CEUS) and model 2 AuPRC 0.91 (grayscale)/0.87 (CEUS). The comparison between artificial intelligence (AI) and readers' showed statistical significant differences between all models and ultrasound modes; model 1 grayscale AI versus readers, P = 0.047, and model 1 CEUS AI versus readers, P < 0.001. Model 2 r grayscale AI versus readers, P = 0.032, and model 2 CEUS AI versus readers, P = 0.041.The interreader agreement overall result showed κ values of 0.20 for grayscale and 0.17 for CEUS.In conclusion, AutoML showed improved diagnostic performance in balance volume datasets. Radiologist performance was not influenced by the dataset's distribution.

Resource requirements to accelerate clinical applications of next generation sequencing and radiomics: Workshop commentary and review.

The National Institutes of Health (NIH)/U.S. Food and Drug Administration (FDA) Joint Leadership Council Next-Generation Sequencing (NGS) and Radiomics Working Group (NGS&R WG) was formed by the NIH/FDA Joint Leadership Council to promote the development and validation of innovative NGS tests, radiomic tools, and associated data analysis and interpretation enhanced by artificial intelligence (AI) and machine-learning (ML) technologies. A two-day workshop was held on September 29-30, 2021 to convene members of the scientific community to discuss how to overcome the "ground truth" gap that has frequently been acknowledged as one of the limiting factors impeding high-quality research, development, validation, and regulatory science in these fields. This report provides a summary of the resource gaps identified by the WG and attendees, highlights existing resources and the ways they can potentially be leveraged to accelerate growth in these fields, and presents opportunities to support NGS and radiomic tool development and validation using technologies such as AI and ML.

The Five Periampullary Cancers, not Just Different Siblings but Different Families: An International Multicenter Cohort Study.

BACKGROUND: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. METHODS: This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC. RESULTS: Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size. CONCLUSIONS: Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.

The road to tailored adjuvant chemotherapy for all four non-pancreatic periampullary cancers: An international multimethod cohort study.

BACKGROUND: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. PATIENTS AND METHODS: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). RESULTS: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). DISCUSSION: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.

Poly(ß-aminoester) Physicochemical Properties Govern the Delivery of siRNA from Electrostatically Assembled Coatings.

Localized short interfering RNA (siRNA) therapy has the potential to drive high-specificity molecular-level treatment of a variety of disease states. Unfortunately, effective siRNA therapy suffers from several barriers to its intracellular delivery. Thus, drug delivery systems that package and control the release of therapeutic siRNAs are necessary to overcome these obstacles to clinical translation. Layer-by-layer (LbL) electrostatic assembly of thin film coatings containing siRNA and protonatable, hydrolyzable poly(ß-aminoester) (PBAE) polymers is one such drug delivery strategy. However, the impact of PBAE physicochemical properties on the transfection efficacy of siRNA released from LbL thin film coatings has not been systematically characterized. In this study, we investigate the siRNA transfection efficacy of four structurally similar PBAEs in vitro. We demonstrate that small changes in structure yield large changes in physicochemical properties, such as hydrophobicity, pKa, and amine chemical structure, driving differences in the interactions between PBAEs and siRNA in polyplexes and in LbL thin film coatings for wound dressings. In our polymer set, Poly3 forms the most stable interactions with siRNA (Keff,w/w = 0.298) to slow release kinetics and enhance transfection of reporter cells in both colloidal and thin film coating approaches. This is due to its unique physiochemical properties: high hydrophobicity (clog P = 7.86), effective pKa closest to endosomal pH (pKa = 6.21), and high cooperativity in buffering (nhill = 7.2). These properties bestow Poly3 with enhanced endosomal buffering and escape properties. Taken together, this work elucidates the connections between small changes in polymer structure, emergent properties, and polyelectrolyte theory to better understand PBAE transfection efficacy.

A Digital Intervention to Improve Skin Self-Examination Among Survivors of Melanoma: Protocol for a Type-1 Hybrid Effectiveness-Implementation Randomized Trial.

BACKGROUND: Although melanoma survival rates have improved in recent years, survivors remain at risk of recurrence, second primary cancers, and keratinocyte carcinomas. The National Comprehensive Cancer Network recommends skin examinations by a physician every 3 to 12 months. Regular thorough skin self-examinations (SSEs) are recommended for survivors of melanoma to promote the detection of earlier-stage, thinner melanomas, which are associated with improved survival and lower treatment costs. Despite their importance, less than a quarter of survivors of melanoma engage in SSEs. OBJECTIVE: Previously, our team developed and evaluated a web-based, fully automated intervention called mySmartSkin (MSS) that successfully improved SSE among survivors of melanoma. Enhancements were proposed to improve engagement with and outcomes of MSS. The purpose of this paper is to describe the rationale and methodology for a type-1 hybrid effectiveness-implementation randomized trial evaluating the enhanced MSS versus control and exploring implementation outcomes and contextual factors. METHODS: This study will recruit from state cancer registries and social media 300 individuals diagnosed with cutaneous malignant melanoma between 3 months and 5 years after surgery who are currently cancer free. Participants will be randomly assigned to either enhanced MSS or a noninteractive educational web page. Surveys will be collected from both arms at baseline and at 3, 6, 12, and 18 months to assess measures of intervention engagement, barriers, self-efficacy, habit, and SSE. The primary outcome is thorough SSE. The secondary outcomes are the diagnosis of new or recurrent melanomas and sun protection practices. RESULTS: Multilevel modeling will be used to examine whether there are significant differences in survivor outcomes between MSS and the noninteractive web page over time. Mixed methods will evaluate reach, adoption, implementation (including costs), and potential for maintenance of MSS, as well as contextual factors relevant to those outcomes and future scale-up. CONCLUSIONS: This trial has the potential to improve outcomes in survivors of melanoma. If MSS is effective, the results could guide its implementation in oncology care and nonprofit organizations focused on skin cancers. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/52689.

Novel Form of Breast Intraoperative Radiation Therapy with CT-Guided High-Dose-Rate Brachytherapy: Interim Results of a Prospective Phase-II Clinical Trial.

BACKGROUND: Precision breast intraoperative radiation therapy (PB-IORT) is a novel method of IORT that uses customized CT-based treatment plans and high-dose-rate (HDR) brachytherapy. We conducted a phase-II multi-institution trial to evaluate the efficacy of PB-IORT. STUDY DESIGN: Between 2015 and 2022, 3 centers enrolled women aged 45 years and older with invasive or in situ carcinoma measuring 3 cm or smaller and N0 status (n = 358). Breast-conserving surgery was performed, and a multilumen balloon catheter was placed in the lumpectomy bed. CT images were used to create customized HDR brachytherapy plans that delivered 12.5 Gy to the tumor bed. The primary outcome assessed was the 5-year rate of index quadrant tumor recurrence. An interim analysis was conducted after one-third of eligible participants completed 5 years of follow-up. This trial is registered with clinicaltrials.gov (NCT02400658). RESULTS: The cohort comprised 153 participants with a median age of 64 years and median follow-up time of 5.9 years. The estimated 5-year index quadrant tumor recurrence rate and overall survival were 5.08% (95% CI 2.23 to 9.68) and 95.1%, respectively. Locoregional (ipsilateral breast and axilla) and distant recurrence rates were each 1.96%. Seven deaths occurred during the first 5 years of follow-up, with only 1 attributable to breast cancer. Overall, 68.6% of patients experienced any adverse effects, and 4 cases of breast-related severe toxicities were observed. CONCLUSIONS: This study presents the results of a planned interim analysis of a phase-II trial investigating PB-IORT and demonstrates the efficacy and safety of single-fraction, CT-based, HDR brachytherapy after breast-conserving surgery. These findings provide valuable insights into the use of PB-IORT as a treatment modality.

Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis.

BACKGROUND: The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. METHODS: Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). RESULTS: After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). CONCLUSIONS: The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. TRIAL REGISTRATION NUMBER: NCT02301611.

pH-Responsive, Charge-Reversing Layer-by-Layer Nanoparticle Surfaces Enhance Biofilm Penetration and Eradication.

Microbes entrenched within biofilms can withstand 1000-fold higher concentrations of antibiotics, in part due to the viscous extracellular matrix that sequesters and attenuates antimicrobial activity. Nanoparticle (NP)-based therapeutics can aid in delivering higher local concentrations throughout biofilms as compared to free drugs alone, thereby enhancing the efficacy. Canonical design criteria dictate that positively charged nanoparticles can multivalently bind to anionic biofilm components and increase biofilm penetration. However, cationic particles are toxic and are rapidly cleared from circulation in vivo, limiting their use. Therefore, we sought to design pH-responsive NPs that change their surface charge from negative to positive in response to the reduced biofilm pH microenvironment. We synthesized a family of pH-dependent, hydrolyzable polymers and employed the layer-by-layer (LbL) electrostatic assembly method to fabricate biocompatible NPs with these polymers as the outermost surface. The NP charge conversion rate, dictated by polymer hydrophilicity and the side-chain structure, ranged from hours to undetectable within the experimental timeframe. LbL NPs with an increasingly fast charge conversion rate more effectively penetrated through, and accumulated throughout, wildtype (PAO1) and mutant overexpressing biomass (ΔwspF) Pseudomonas aeruginosa biofilms. Finally, tobramycin, an antibiotic known to be trapped by anionic biofilm components, was loaded into the final layer of the LbL NP. There was a 3.2-fold reduction in ΔwspF colony forming units for the fastest charge-converting NP as compared to both the slowest charge converter and free tobramycin. These studies provide a framework for the design of biofilm-penetrating NPs that respond to matrix interactions, ultimately increasing the efficacious delivery of antimicrobials.

Factors Associated With Upstaging of Melanoma Thickness on Final Excision.

INTRODUCTION: The incidence and risk factors associated with upstaging from initial biopsy to definitive excision in cutaneous melanoma have not been established. The aim of this study was to determine the incidence of tumor stage upstaging and associated risk factors using the National Cancer Database. METHODS: A retrospective study of the National Cancer Database between 2012 and 2016 was performed. The cohort of patients undergoing excision of melanoma with available data comprised 133,592 patients. Differences in characteristics for upstaging were determined using Wilcox rank-sum, chi-square, or Fisher's exact tests. Multivariable analysis was performed using logistic regression to determine factors associated with upstaging. RESULTS: Incidence of upstaging was 5.2%. Upstaged patients were older, male, of non-White race, and of lower education level (P < 0.001). Lesions of the head/neck and lower extremity had increased incidence of upstaging compared to the trunk (P < 0.001). Nodular and acral lentiginous melanoma was associated with higher incidence of upstaging compared to superficial spreading melanoma (P < 0.001). Patients with lymphovascular invasion had increased risk of upstaging (P < 0.001). CONCLUSIONS: Upstaging of melanoma is infrequent but is significantly more prevalent in non-White patients and those with lower educational status. Provider and patient education should include the higher risk of upstaging in these groups and the possible need for further surgical intervention, such as re-excision of margins and sentinel lymph node biopsy.

Facebook Intervention for Young-Onset Melanoma Survivors and Families: Protocol for a Randomized Controlled Trial.

BACKGROUND: Individuals diagnosed with melanoma before the age of 40 years (young-onset melanoma survivors) and their first-degree relatives (FDRs) are a growing population at risk for developing recurrent melanoma or new melanomas. Regular surveillance using clinical skin examination (CSE) and skin self-examination (SSE) and engagement in preventive behaviors including sun protection are recommended. Given the growing population of survivors and their families who are at increased risk, it is surprising that no behavioral interventions have been developed and evaluated to improve risk-reduction behaviors. OBJECTIVE: We describe the rationale and methodology for a randomized controlled trial evaluating the efficacy of a Facebook intervention providing information, goal setting, and peer support to increase CSE, SSE, and sun protection for young-onset melanoma survivors and their FDRs. METHODS: Overall, 577 survivors and 577 FDRs will be randomly assigned to either the Young Melanoma Family Facebook Group or the Melanoma Family Healthy Lifestyle Facebook Group condition. Participants will complete measures of CSE, SSE, and sun protection, and mediator measures of attitudes and beliefs before and after the intervention. The primary aim is to evaluate the impact of the Young Melanoma Family Facebook intervention versus the Melanoma Family Healthy Lifestyle Facebook intervention on CSE, SSE frequency and comprehensiveness, and sun protection among FDRs. The secondary aims examine the efficacy of the Young Melanoma Family Facebook intervention on survivors' SSE frequency and comprehensiveness and sun protection behaviors and mechanisms of intervention efficacy for intervention impact on FDR and survivor outcomes. The exploratory aim is to evaluate the efficacy of the 2 interventions on perceived stress, physical activity, and healthy eating. RESULTS: This project was funded by the National Institutes of Health (R01CA221854). The project began in May 2018, and recruitment started in January 2019. We anticipate completing enrollment by November 2023. Power calculations recommended a sample size of 577 survivors and 577 FDRs. Multilevel modeling treating family as the upper-level sampling unit and individual as the lower-level sampling unit will be the primary data analytic approach. Fixed effect predictors in these models will include condition, role, sex, all 2- and 3-way interactions, and covariates. CONCLUSIONS: The Young Melanoma Family Facebook intervention aims to improve primary and secondary skin cancer prevention for young-onset melanoma survivors and their family members. The intervention's delivery via a popular, freely available social media platform increases its impact because of the potential for dissemination in many contexts. If efficacious, this program could be disseminated by dermatologist practices, public health or nonprofit organizations focused on melanoma, and existing melanoma and skin cancer Facebook groups, thereby expanding its reach. This project will produce a content library of posts and a moderation guide for others. TRIAL REGISTRATION: ClinicalTrials.gov NCT03677739; https://clinicaltrials.gov/ct2/show/NCT03677739. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39640.

Sentinel Lymph Node Identification in Post Neoadjuvant Chemotherapy Breast Cancer Patients Undergoing Surgical Excision Using Lymphosonography.

OBJECTIVES: This study evaluated the efficacy of lymphosonography in the identification of sentinel lymph nodes (SLNs) in post neoadjuvant chemotherapy patients with breast cancer scheduled to undergo surgical excision. METHODS: Seventy-nine subjects scheduled for breast cancer surgery with SLN excision completed this IRB-approved study, out of which 18 (23%) underwent neoadjuvant chemotherapy before surgery. Subjects underwent percutaneous Sonazoid (GE Healthcare) injections around the tumor area for a total of 1.0 mL. Lymphosonography was performed using CPS on an S3000 HELX scanner (Siemens Healthineers) with a linear probe. Subjects received blue dye and radioactive tracer as part of their standard of care. Excised SLNs were classified as positive or negative for the presence of blue dye, radioactive tracer and Sonazoid. The results were compared between methods and pathology findings. RESULTS: Seventy-two SLNs were surgically excised from 18 subjects, 29 were positive for blue dye, 63 were positive for radioactive tracer and 57 were positive for Sonazoid. Comparison with blue dye showed that both radioactive tracer and lymphosonography achieved an accuracy of 53% (P > .50). Comparison with radioactive tracer showed that blue dye had an accuracy of 53%, while lymphosonography achieved an accuracy of 67% (P < .01). Of the 72 SLNs, 15 were determined malignant by pathology; the detection rate was 47% for blue dye (7/15), 67% for radioactive tracer (10/15) and 100% for lymphosonography (15/15) (P < .001). CONCLUSIONS: Lymphosonography achieved similar accuracy as radioactive tracer and higher accuracy than blue dye for identifying SLNs. The 15 SLNs positive for malignancy were all identified by lymphosonography.

Divergent clinical outcomes in a phase 2B trial of the TLPLDC vaccine in preventing melanoma recurrence and the impact of dendritic cell collection methodology: a randomized clinical trial.

BACKGROUND: A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods. METHODS: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups. RESULTS: 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity. CONCLUSIONS: Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.

Sentinel Lymph Node Identification in Patients With Breast Cancer Using Lymphosonography.

The objective of the work described here was to evaluate the efficacy of lymphosonography in identifying sentinel lymph nodes (SLNs) in patients with breast cancer undergoing surgical excision. Of the 86 individuals enrolled, 79 completed this institutional review board-approved study. Participants received subcutaneous 1.0-mL injections of ultrasound contrast agent (UCA) around the tumor. An ultrasound scanner with contrast-enhanced ultrasound (CEUS) capabilities was used to identify SLNs. Participants were administered with blue dye and radioactive tracer to guide SLN excision as standard-of-care. Excised SLNs were classified as positive or negative for the presence of blue dye, radioactive tracer and UCA, and sent for pathology. Two hundred fifty-two SLNs were excised; 158 were positive for blue dye, 222 were positive for radioactive tracer and 223 were positive for UCA. Comparison with blue dye revealed accuracies of 96.2% for radioactive tracer and 99.4% for lymphosonography (p > 0.15). Relative to radioactive tracer, blue dye had an accuracy of 68.5%, and lymphosonography achieved 86.5% (p < 0.0001). Of 252 SLNs excised, 34 were determined to be malignant by pathology; 18 were positive for blue dye (detection rate = 53%), 23 for radioactive tracer (detection rate = 68%) and 34 for UCA (detection rate = 100%) (p < 0.0001). Lymphosonography was similar in accuracy to radioactive tracer and higher in accuracy than blue dye in identifying SLNs. All 34 malignant SLNs were identified by lymphosonography.

Yeast Smy2 and its human homologs GIGYF1 and -2 regulate Cdc48/VCP function during transcription stress.

The "last resort" pathway results in ubiquitylation and degradation of RNA polymerase II in response to transcription stress and is governed by factors such as Def1 in yeast. Here, we show that the SMY2 gene acts as a multi-copy suppressor of DEF1 deletion and functions at multiple steps of the last resort pathway. We also provide genetic and biochemical evidence from disparate cellular processes that Smy2 works more broadly as a hitherto overlooked regulator of Cdc48 function. Similarly, the Smy2 homologs GIGYF1 and -2 affect the transcription stress response in human cells and regulate the function of the Cdc48 homolog VCP/p97, presently being explored as a target for cancer therapy. Indeed, we show that the apoptosis-inducing effect of VCP inhibitors NMS-873 and CB-5083 is GIGYF1/2 dependent.

Virtual Tumor Board Increases Provider Attendance and Case Presentations.

PURPOSE: Many cancer centers engage in multidisciplinary tumor board meetings to determine the optimal approach to complex cancer care. With the onset of the COVID-19 pandemic, many institutions changed the format of these meetings from in-person to virtual. The aim of this study was to determine if the change to a virtual meeting format had an impact on attendance and cases presented. METHODS: Tumor board records were analyzed to obtain attendance and case presentation information at a National Cancer Institute-designated Comprehensive Cancer Center. Twelve-month in-person tumor board data were compared with 12-month virtual tumor board data to assess for difference in attendance and case presentation patterns. RESULTS: Seven separate weekly tumor board meetings at the beginning of the study (breast, GI, gynecology, liver, lung, melanoma, and urology) were expanded to nine meetings on the virtual platform (+endocrine and pancreas). Overall attendance increased by 46% on the virtual platform compared with in-person meetings (4,030 virtual attendances v 2,753 in-person, P < .001). Increased attendance was present across all specialties on the virtual platform. In addition, the number of patient cases discussed increased from 2,127 in in-person meeting to 2,656 on the virtual platform (a 20% increase, P < .001). CONCLUSION: A significant increase was observed in overall tumor board attendance and in case presentations per meeting, requiring the expansion of additional weekly meetings. Furthermore, in a major cancer center with multiple community affiliates, virtual tumor boards may encourage increased participation from remote sites with the benefit of obtaining expert specialist advice as compared with geographically challenging in-person meetings.

Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery.

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of SLC46A3, which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.

Peptide-Based Cancer Vaccine Delivery via the STINGΔTM-cGAMP Complex.

With the advent of bioinformatic tools in efficiently predicting neo-antigens, peptide vaccines have gained tremendous attention in cancer immunotherapy. However, the delivery of peptide vaccines remains a major challenge, primarily due to ineffective transport to lymph nodes and low immunogenicity. Here, a strategy for peptide vaccine delivery is reported by first fusing the peptide to the cytosolic domain of the stimulator of interferon genes protein (STINGΔTM), then complexing the peptide-STINGΔTM protein with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The process results in the formation of self-assembled cGAMP-peptide-STINGΔTM tetramers, which enables efficient lymphatic trafficking of the peptide. Moreover, the cGAMP-STINGΔTM complex acts not only as a protein carrier for the peptide, but also as a potent adjuvant capable of triggering STING signaling independent of endogenous STING protein-an especially important attribute considering that certain cancer cells epigenetically silence their endogenous STING expression. With model antigen SIINFEKL, it is demonstrated that the platform elicits effective STING signaling in vitro, draining lymph node targeting in vivo, effective T cell priming in vivo as well as antitumoral immune response in a mouse colon carcinoma model, providing a versatile solution to the challenges faced in peptide vaccine delivery.

Effect of the COVID-19 pandemic on surgical oncology practice-Results of an SSO survey.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic significantly affected healthcare delivery, shifting focus away from nonurgent care. The aim of this study was to examine the impact of the pandemic on the practice of surgical oncology. METHODS: A web-based survey of questions about changes in practice during the COVID-19 pandemic was approved by the Society of Surgical Oncology (SSO) Research and Executive Committees and sent by SSO to its members. RESULTS: A total of 121 SSO members completed the survey, 77.7% (94/121) of whom were based in the United States. Breast surgeons were more likely than their peers to refer patients to neoadjuvant therapy (p = 0.000171). Head and neck surgeons were more likely to refer patients to definitive nonoperative treatment (p = 0.044), while melanoma surgeons were less likely to do so (p = 0.029). In all, 79.2% (95/120) of respondents are currently using telemedicine. US surgeons were more likely to use telemedicine (p = 0.004). Surgeons believed telemedicine is useful for long-term/surveillance visits (70.2%, 80/114) but inappropriate (50.4%, 57/113) for new patient visits. CONCLUSION: COVID-19 pandemic resulted in increased use of neoadjuvant therapy, delays in operative procedures, and increased use of telemedicine. Telemedicine is perceived to be most efficacious for long-term/surveillance visits or postoperative visits.