PURPOSE: The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND. METHODS: The Oncoplastic Breast Consortium-05/ICARO cohort study (ClinicalTrials.gov identifier: NCT06464341 ) retrospectively analyzed data from patients with stage I to III breast cancer with ITCs in SLNs after NAC from 62 centers in 18 countries. The primary end point was the 3-year rate of any axillary recurrence. The rate of any invasive recurrence was the secondary end point. RESULTS: In total, 583 patients were included, of whom 182 (31%) had completion ALND and 401 (69%) did not. The median age was 48 years. Most patients (74%) were clinically node-positive at diagnosis and 41% had hormone receptor–positive/human epidermal growth factor receptor 2–negative tumors. The mean number of SLNs with ITCs was 1.2. Patients treated with ALND were more likely to present with cN2/3 disease (17% v 7%, P < .001), have ITCs detected on frozen section (62% v 8%, P < .001), have lymphovascular invasion (38% v 24%, P < .001), and receive adjuvant chest wall (89% v 78%, P = .024) and nodal radiation (82% v 75%, P = .038). Additional positive nodes were found at ALND in 30% of patients, but only 5% had macrometastases. The 3-year rates of any axillary and any invasive recurrence were 2% (95% CI, 0.95 to 3.6) and 11% (95% CI, 8 to 14), respectively, with no statistical difference by type of axillary surgery. CONCLUSION: The nodal burden in patients with ypN0(i+) was low, and axillary recurrence after ALND omission was rare in patients selected for this approach. These results do not support routine ALND in all patients with ypN0(i+).

We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.

The early onset and rapid progression of cutaneous squamous cell carcinoma (cSCC) leads to high mortality rates in individuals with recessive dystrophic epidermolysis bullosa (RDEB). Currently, the molecular mechanisms underlying cSCC development in RDEB are not well understood and there are limited therapeutic options. RDEB-cSCC arises through the accumulation of genetic mutations; however, previous work analyzing gene expression profiles have not been able to explain its aggressive nature. Therefore, we generated a model to study RDEB-cSCC development using cellular reprograming and re-differentiation technology. We compared RDEB-cSCC to cSCC that were first reprogrammed into induced pluripotent stem cells (RDEB-cSCC-iPSC) and then differentiated back to keratinocytes (RDEB-cSCC-iKC). The RDEB-cSCC-iKC cell population had reduced proliferative capacities in vitro and in vivo, suggesting that reprogramming and re-differentiation leads to functional changes. Finally, we performed RNA-seq analysis for RDEB-cSCC, RDEB-cSCC-iPSC, and RDEB-cSCC-iKC and identified different gene expression signatures between these cell populations. Taken together, this cell culture model offers a valuable tool to study cSCC and provides a novel way to identify potential therapeutic targets for RDEB-cSCC.

Background/Aims: As oncology treatments evolve, classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new design strategies for trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We describe the overall incidence of dose-limiting toxicities during and after cycle 1, frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 dose-limiting toxicities on conclusions drawn from oncology phase 1 clinical trials. Methods: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. We used chi-square tests and multivariate logistic regression to describe predictors of reporting subsequent cycle toxicity data. Results: From 2000 to 2020, we identified 489 articles reporting on therapeutic phase 1 clinical trials. Of these, 421 (86%) reported data regarding cycle 1 dose-limiting toxicities and 170 (35%) reported data on cycle 1 dose modifications. Of the trials that reported cycle 1 dose-limiting toxicities, the median percentage of patients that experienced cycle 1 dose-limiting toxicities was 8.89%. Only 47 (9.6%) publications reported on post-cycle 1 dose-limiting toxicities and only 92 (19%) reported on dose modifications beyond cycle 1. Of the trials that reported post-cycle 1 dose-limiting toxicities, the median percentage of patients that experienced post-cycle 1 dose-limiting toxicities was 14.8%. Among the 371 studies with a recommended phase 2 dose, 89% did not report whether post-cycle 1 toxicities impacted the recommended phase 2 dose. More recent year of publication was independently associated with reduced odds of reporting subsequent cycle toxicity. Conclusion: Reporting of subsequent cycle toxicity is uncommon in oncology phase I clinical trial publications and becoming less common over time. Guidelines for reporting of phase I oncology clinical trials should expand to include toxicity data beyond the first cycle.

Background: Phase 1 or phase 1/2 trials are a first step in pediatric cancer drug development. Currently, there is a paucity of information regarding contemporary outcomes for pediatric patients enrolled in these trials. We describe characteristics and outcomes of patients enrolled in pediatric phase 1 clinical trials over a 9‐year period at a single institution. Methods: We queried our clinical trials management system to generate a list of patients enrolled and treated on pediatric phase 1 or phase 1/2 trials from 2011 to 2019. We collected baseline demographics, clinical data, efficacy, and safety endpoints post‐enrollment including: time to death, objective response to therapy, duration on therapy, need for dose modification, and occurrence of dose‐limiting toxicity. Overall survival was calculated using Kaplan–Meier methods. Results: A total of 224 unique patients accounted for 259 enrollments and 242 treatment episodes. The median age at enrollment was 11 years (range 0–27 years) and 56.2% were male. The majority were White (85.7%) and Non‐Hispanic (88.2%). English was the primary language for 86.3% of patients, and 54.9% had private insurance. Solid tumors were the most common malignancy (41.0%), followed by brain tumors (34.1%), and hematologic malignancies (24.9%). Among treatment episodes, 49.3% received targeted monotherapy. After first enrollment, 27.6% of patients had an objective response to therapy (52.9% for hematologic malignancies, 20.5% for brain tumors, and 15.8% for solid tumors). The median duration of therapy was 1.5 months. Median overall survival from first enrollment for 218 patients treated with available vital status was 13.1 months. Toxicity outcomes included 27 patients (11.2%) requiring dose modification and 22 patients (9.0%) having a DLT. Conclusions: Overall survival is poor for patients in pediatric oncology early phase trials, despite approximately a quarter having an initial response. These data are informative for discussions between providers and families regarding outcomes after phase 1 trial participation.