Citations

Background: Among the 1.5 million cases of cutaneous squamous cell carcinoma (cSCC) diagnosed annually in the United States, a subset of aggressive tumors recur or metastasize. Treatment options include total margin-controlled surgery, such as Mohs micrographic surgery or other forms of peripheral and deep en face margin assessment (MMS/PDEMA), and standard excision with postoperative vertical section margin assessment (SEVMA). NCCN Guidelines recommend MMS/PDEMA for the management of cSCC classified as very high risk based on NCCN risk stratification criteria. This study aims to validate the recommendation of MMS/PDEMA as the preferred surgical approach for NCCN very high-risk cSCCs, using data from a multicenter, multinational cohort. Methods: A multicenter cohort study was conducted across 12 sites, including 10 in the United States, 1 in Spain, and 1 in Brazil, comprising 2,752 primary NCCN very high-risk cSCCs treated with MMS/PDEMA or SEVMA. Propensity score–weighted analysis was used to balance baseline characteristics. Outcomes included local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Results: After balancing baseline characteristics, SEVMA was associated with a 2-fold higher rate of poor outcomes, including recurrence, metastasis, and DSD, compared with MMS/PDEMA. The 3-year cumulative incidence of poor outcomes was higher for SEVMA: LR (12.5% vs 5.9%), NM (11.6% vs 6.0%), DM (4.3% vs 1.9%), and DSD (6.2% vs 3.3%). Conclusions: This study supports the NCCN recommendation of MMS/PDEMA for NCCN very high-risk cSCC, showing reduced recurrence, metastasis, and cSCC-specific mortality compared with SEVMA.

Circulating tumor DNA (ctDNA) testing is a minimally invasive alternative to tissue biopsy and is ideal for inaccessible tumors or limited samples. It captures tumor heterogeneity over time and different anatomic locations, unlike the static snapshot provided by a biopsy. In this report, we describe a 68-year-old female with an initial diagnosis of metastatic pancreatic adenocarcinoma (a pancreas head mass with multiple bilateral lung nodules). Mutation profiling of the pancreatic mass biopsy using a comprehensive cancer next-generation sequencing (NGS) panel was unsuccessful due to insufficient tissue. Consequently, ctDNA testing using a pan-cancer NGS panel was performed, and an EGFR p.L858R variant at 2.15% was identified. Interestingly, this activating variant is highly specific to non–small cell lung cancer (NSCLC), which raised the possibility of a synchronous tumor unrelated to the pancreatic mass. Immunohistochemistry showed the EGFR variant in station 7 lymph nodes but not in pancreatic biopsy tissue, supporting the inference that the variant originated from the lung mass. Droplet digital PCR on the limited pancreatic biopsy identified a KRAS p.Q61 variant, which was absent by ctDNA testing, suggesting a pancreatic primary with low ctDNA levels. In addition to diagnosing a primary lung cancer, ctDNA testing guided treatment decisions. With a primary EGFR p.L858R–mutant NSCLC, osimertinib was administered, resulting in a partial response within 10 months. In addition, given the synchronous primary pancreatic adenocarcinoma, germline testing was performed, revealing a CDKN2A p.I49T variant consistent with melanoma-pancreatic cancer syndrome, prompting comprehensive cancer surveillance and familial testing. This case illustrates how ctDNA testing enabled a comprehensive evaluation by clarifying the diagnosis, identifying actionable biomarkers, and facilitating genetic risk assessment, ultimately having a significant impact on the patient’s clinical management.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cervical Cancer provide diagnostic workup, staging, and various treatment recommendations for cervical cancer based on clinical and surgical staging. This selection from the NCCN Guidelines for cervical cancer specifically focuses on diagnosis and workup, principles of staging and surgery, and primary treatment recommendations for early-stage and advanced disease and provides a detailed overview of systemic therapy recommendations for cervical cancer.

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs.

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd.

Abstract Background To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS). Methods A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities. Results Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and 59 were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (P = .16). Like LF rates, there was no benefit in dose escalation for OS (P = .28) and CSS (P = .22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (P = .069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (P = .13). Conclusions This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation. Clinical Trial Information NCT00592748.

BACKGROUND: Increasing interest in neurosurgery residency has led to a growing number of unmatched applicants, who often struggle to find appropriate guidance for their next steps. The authors examined trends, opinions, and options available to unmatched neurosurgery residency reapplicants. STUDY DESIGN: Demographic data of US applicants from MD programs obtained from the National Resident Matching Program (2009 to 2024) were analyzed using 1-way ANOVA analysis of time-interval averages. Opinions about reapplicants were assessed via an online survey of national neurosurgery leaders, including residency program directors and chairpersons (N = 356). RESULTS: All application trends showed greater change over time; however, the rate of accepted reapplicants showed no significant change among early (2009 to 2013: 4.8 ± 1.8), mid (2014 to 2018: 7.6 ± 4.8), and recent periods (2019 to 2024: 9.8 ± 2.5; p = 0.068). The survey had a 23.0% response rate (82 of 356). Commonly indicated reasons for failure to match included poor interview skills, weak recommendation letters, and personality issues. Although most survey respondents supported candidates reapplying, dual applications (applying to more than 1 specialty) were not widely encouraged. For those reapplying, pursuing a preliminary general surgery or research fellowship, obtaining new letters of recommendation from new subinternships, and publishing higher-quality research were the most endorsed uses of time before reapplying. However, most programs reported interviewing reapplicants sometimes to rarely and matching a reapplicant rarely to never. CONCLUSIONS: The number of reapplicants successfully matching into neurosurgery has not changed significantly during the past 15 years. Surveys indicate that leaders view reapplicants unfavorably, despite reapplicants’ efforts to improve their applications. These results suggest that neurosurgery mentors may do a disservice to potential reapplicants based on how residency program leadership considers reapplications. Candid guidance is needed for reapplicants in the residency matching process.

Abstract Objectives There are striking differences among caregivers of people with dementia in their health and well-being during active caregiving and after caregiving has ended. A key factor influencing caregiver health is the emotional quality of the caregiver–care recipient relationship, which may be reflected in the emotional language caregivers use when describing this relationship. The present study assessed whether caregivers’ positive and negative language is associated with their current and future depression trajectories. Methods Active caregivers responded to an open-ended question about a recent time they felt connected to the care recipient. We summed the number of positive and negative emotion words and divided them by the total words in the response. We evaluated whether caregivers’ emotional language (a proxy for the emotional quality of the caregiver–care recipient relationship) was associated with their depression assessed both concurrently (N = 347 active caregivers) and longitudinally (N = 224 former caregivers). Results Neither positive nor negative emotional language significantly correlated with caregiver depression during active caregiving. Structural equation modeling revealed caregivers’ greater positive emotional language (accounting for baseline depression) was associated with less steep increases in depression after the care recipient’s death. Results were robust when accounting for negative emotional language and covariates. Negative emotional language was not significantly associated with changes in caregiver depression. Discussion Caregivers who use more positive words when describing their connection with the care recipient may be more resilient, underscoring the potential role of positive emotional qualities of the caregiving relationship in preserving caregivers’ mental health after caregiving ends.