Purpose: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence. Patients and Methods: Newly diagnosed or recurrent stage III–IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response. Results: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9–54.3] had partial responses by RECIST, 14 patients (70%; 95% CI, 45.7–88.1) had a pCR (n = 11) or MPR (n = 3). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7–26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9–100), 89.5% (95% CI, 76.7–100), and 95% (95% CI, 85.9–100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR. Conclusions: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas, the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors, but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in keratinocyte carcinoma tumorigenesis and tumor characteristics that have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of keratinocyte carcinoma continue to increase, strategies for prevention, including effective sun-protective behavior, educational interventions, and reduction of tanning bed access and usage, are essential. Gaps in our knowledge requiring additional research to reduce the high morbidity and costs associated with keratinocyte carcinoma include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types¹, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1^−/−) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of a nerve, explore the neuronal biomarkers found in tumor sites, and discuss clinical correlates between tumor neurobiology and patient prognosis.

Although the majority of published cases of lead poisoning come from occupational exposures, some traditional remedies may also contain toxic amounts of lead. Ayurveda is a system of traditional medicine that is native to India and is used in many parts of world as an alternative to standard treatment regimens. Here, we report the case of a 58-year-old woman who presented with abdominal pain, anemia, liver function abnormalities, and an elevated blood lead level. The patient was found to have been taking the Ayurvedic medicine Jambrulin prior to presentation. Chemical analysis of the medication showed high levels of lead. Following treatment with an oral chelating agent, the patient's symptoms resolved and laboratory abnormalities normalized. This case highlights the need for increased awareness that some Ayurvedic medicines may contain potentially harmful levels of heavy metals and people who use them are at risk of developing associated toxicities.