Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma.

BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.).

Systemic Therapy for Non-Melanoma Skin Cancers: Latest Advances.

PURPOSE OF REVIEW: This review provides an update on approved and emerging systemic therapies in the treatment of locally advanced or metastatic non-melanoma skin cancers (squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma). RECENT FINDINGS: Many studies demonstrate the effectiveness of immunotherapy for all types of non-melanoma skin cancer. For basal cell carcinoma (BCC), hedgehog inhibitors (HHI) remain first-line but with poor tolerability. Numerous clinical trials studying both neoadjuvant and adjuvant use of anti-PD-1 and anti-PD-L1 therapies in advanced NMSC are under investigation. There is a growing number of systemic therapies available to treat non-melanoma skin cancers. The advent of immunotherapy has revolutionized the field and greatly improved survival compared to historical survival rates with cytotoxic chemotherapy.

Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study.

BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Salvage Cryoablation for Local Recurrences of Thyroid Cancer Inseparable from the Trachea and Neurovascular Structures.

PURPOSE: To demonstrate safety, feasibility, and effectiveness of cryoablation of recurrent papillary thyroid cancer ineligible for reoperation because of scarring, eligible for focal ablation as defined within 2015 American Thyroid Association guideline sections C16 and C17. MATERIALS AND METHODS: With multidisciplinary consensus, cryoablation was performed with curative intent for 15 tumors in 10 patients between January 2019 and July 2021. Demographics, procedural details, and serial postprocedural imaging findings were analyzed. RESULTS: The mean age was 72.5 years (range, 57-88 years), and 80% of the patients were women. The tumors (mean size, 16 mm ± 6; range, 9-29 mm) received 1 session of cryoablation with 100% technical success. The mean and median postcryoablation tumor volumetric involution rates were 88% and 99%, respectively, with 9 (60%) of 15 tumors involuting completely or down to the scar and 6 (40%) involuting partially at the end of the study period. Tumor size did not increase after cryoablation (0% local progression rate). All tumors abutted the trachea, skin, and/or vascular structures, and hydrodissection failed in all cases because of scarring. The major adverse event rate was 20% (3/15), with 2 cases of voice change and 1 case of Horner syndrome; all resolved at 6 months with no permanent sequelae. No vascular, tracheal, dermal, or infectious adverse events occurred during a mean follow-up of 242 days (range, 114-627 days). One patient died at 386 days after cryoablation because of unrelated cholangiocarcinoma. CONCLUSIONS: Cryoablation of local recurrences of papillary thyroid cancer abutting the trachea and/or neurovascular structures in the setting of hydrodissection failure because of scarring yielded a mean volumetric involution of 88%, primary efficacy of 60%, and objective response rate of 100% with no local recurrences or permanent complications during a mean follow-up of 242 days. The secondary efficacy and longer-term outcomes remain forthcoming.

Anatomical Survey Versus Fetal Echocardiograms for Diagnosis of Cardiac Defects with a Single Umbilical Artery Cases: A Retrospective Cohort Study and Diagnostic Meta-analysis.

OBJECTIVE: To determine the utility of fetal echocardiography in diagnosing cardiac defects in fetuses with a single umbilical artery (SUA). METHODS: A retrospective cohort study of prenatally diagnosed SUA was conducted over a 10-year period at a single institution. Cardiac anatomy on detailed anatomical survey was compared with fetal echocardiogram for fetuses with prenatally diagnosed SUA. A diagnostic meta-analysis of studies comparing fetal anatomical survey to fetal echocardiogram in fetuses with SUA between 2010 to 2019 was also performed. RESULTS: Three hundred and twenty fetuses with SUA were identified, 113 of which had completed both ultrasound and echocardiography. There were 36 cases of cardiac defects on prenatal echocardiogram and all had abnormal anatomical ultrasounds. There were zero cases of abnormal cardiac exams (0%) when the cardiac views on anatomical survey were normal. The sensitivity, specificity, positive predictive value and negative predictive value of ultrasound were 100%, 77%, 73% and 100%, respectively. A summary ROC curve demonstrated a high predictive value of routine anatomic survey for cardiac defects (AUC: 0.99). CONCLUSION: Anatomic survey is highly predictive in the detection of cardiac defects in fetuses with SUA. Fetal echocardiogram is unnecessary in SUA when cardiac views are normal on ultrasound.

Immunotherapy in Head and Neck Cancer: Treatment Paradigms, Future Directions, and Questions.

The use of immunotherapy in head and neck squamous cell carcinoma (HNSCC)has increased treatment options for patients who may not be candidates for traditional cytotoxic chemotherapy. Recent studies have resulted in the approval of immunotherapy in the first and second line setting for recurrent/metastatic disease. Various combinations of immunotherapy with targeted therapies, monoclonal antibodies, or human papilloma virus vaccines are also being studied in recurrent/metastatic disease. Currently, programmed death-ligand 1 status is the main marker utilized to assess potential response to immunotherapy. Studies are focused on identifying additional markers, which may help better predict response to immunotherapy for HNSCC patients.

Real-world practice patterns and outcomes for RAI-refractory differentiated thyroid cancer.

Background: The optimal timing for initiating multi-kinase inhibitors (MKIs) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC) remains unclear. Thus, we evaluated the real-world practice patterns and outcomes in asymptomatic patients with progressive RAI-R DTC (≥1 lesion ≥1 cm in diameter) in the USA (US population) and outside the USA (non-US population). Methods: In this prospective, non-interventional, open-label study, eligible patients were chosen by treating physicians to receive MKI therapy (cohort 1) or undergo active surveillance (cohort 2) at study entry. Cohort 2 patients were allowed to transition to MKI therapy later. The primary endpoint was time to symptomatic progression (TTSP) from study entry. Data were compared descriptively. When endpoints were inestimable, 36-month rates were calculated. Results: Of the 647 patients, 478 underwent active surveillance (cohort 2) and 169 received MKI treatment (cohort 1). Patients underwent surveillance at a higher rate in the US (92.6%) vs the non-US (66.9%) populations. Half of US and non-US patients who qualified for MKI treatment had initial American Thyroid Association (ATA) low-to-intermediate-risk disease. In cohort 2, the 36-month TTSP rates from study entry were 65.6% and 66.5% in the US and non-US populations, respectively. Cohort 2 patients treated later demonstrated 36-month TTSP rates of 30.8% and 55.8% in the US and non-US populations, respectively. Conclusions: Active surveillance is a viable option for asymptomatic patients with progressive RAI-R DTC. However, early intervention with MKI therapy may be more suitable for others. Further research is needed to identify patients who are optimal for active surveillance. Registration: NCT02303444.

A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors.

PURPOSE: Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks). Dose escalation began with dasatinib 70 mg orally (PO) daily and gemcitabine 800 mg/m(2) intravenously (IV) weekly. RESULTS: Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100 mg PO qd and gemcitabine 600 mg/m(2) IV weekly. The most common grade 3-4 toxicities were anemia (21.5 %), thrombocytopenia (26.2 %), leukopenia (26.2 %), and pleural effusion (10.7 %). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed. CONCLUSIONS: The combination was well tolerated at doses of dasatinib 100 mg PO daily and gemcitabine 600 mg/m(2) IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.

Assessing the Accuracy and Reliability of AI-Generated Medical Responses: An Evaluation of the Chat-GPT Model.

Background: Natural language processing models such as ChatGPT can generate text-based content and are poised to become a major information source in medicine and beyond. The accuracy and completeness of ChatGPT for medical queries is not known. Methods: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes/no) or descriptive answers. The physicians then graded ChatGPT-generated answers to these questions for accuracy (6-point Likert scale; range 1 - completely incorrect to 6 - completely correct) and completeness (3-point Likert scale; range 1 - incomplete to 3 - complete plus additional context). Scores were summarized with descriptive statistics and compared using Mann-Whitney U or Kruskal-Wallis testing. Results: Across all questions (n=284), median accuracy score was 5.5 (between almost completely and completely correct) with mean score of 4.8 (between mostly and almost completely correct). Median completeness score was 3 (complete and comprehensive) with mean score of 2.5. For questions rated easy, medium, and hard, median accuracy scores were 6, 5.5, and 5 (mean 5.0, 4.7, and 4.6; p=0.05). Accuracy scores for binary and descriptive questions were similar (median 6 vs. 5; mean 4.9 vs. 4.7; p=0.07). Of 36 questions with scores of 1-2, 34 were re-queried/re-graded 8-17 days later with substantial improvement (median 2 vs. 4; p<0.01). Conclusions: ChatGPT generated largely accurate information to diverse medical queries as judged by academic physician specialists although with important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction.

Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency. Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information. Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023. Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses. Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002). Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Comparisons between murine polyomavirus and Simian virus 40 show significant differences in small T antigen function.

Although members of a virus family produce similar gene products, those products may have quite different functions. Simian virus 40 (SV40) large T antigen (LT), for example, targets p53 directly, but murine polyomavirus LT does not. SV40 small T antigen (SVST) has received considerable attention because of its ability to contribute to transformation of human cells. Here, we show that there are major differences between SVST and polyomavirus small T antigen (POLST) in their effects on differentiation, transformation, and cell survival. Both SVST and POLST induce cell cycle progression. However, POLST also inhibits differentiation of 3T3-L1 preadipocytes and C2C12 myoblasts. Additionally, POLST induces apoptosis of mouse embryo fibroblasts. SVST reduces the proapoptotic transcriptional activity of FOXO1 through phosphorylation. On the other hand, SVST complements large T antigen and Ras for the transformation of human mammary epithelial cells (HMECs), but POLST does not. Mechanistically, the differences between SVST and POLST may lie in utilization of protein phosphatase 2A (PP2A). POLST binds both Aα and Aß scaffolding subunits of PP2A while SVST binds only Aα. Knockdown of Aß could mimic POLST-induced apoptosis. The two small T antigens can target different proteins for dephosphorylation. POLST binds and dephosphorylates substrates, such as lipins, that SVST does not.

Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors.

PURPOSE: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. RESULTS: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. CONCLUSIONS: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Guiding immunotherapy combinations: Who gets what?

Although PD-1 and CTLA-4 inhibitors have proven successful in a range of malignancies, there are subsets of patients that do not respond to these agents due to upregulation of adaptive and innate resistance mechanisms by the tumor and its surrounding microenvironment. As new immunotherapeutic strategies are developed, there is a need for rational implementation of novel immunotherapy combinations that target complementary mechanisms of immunotherapy resistance intrinsic to each patient and tumor type. In this short review, we cover mechanisms by which tumors evade the immune system, as well as summarize available clinical data on emerging therapeutic agents that target these defense mechanisms. Rational implementation of combination immunotherapy targeting patient- and malignancy-specific immune evasion mechanisms may thus lead to enhanced response rates and allow immunotherapy to be effective even in tumors that are historically considered poorly responsive to immunotherapy.

Making progress in a rare disease: emerging therapeutics in soft tissue sarcomas.

Sarcomas are rare tumors derived from mesenchymal connective tissues in the body. Because there are well over 50 histologic sarcoma subtypes, including malignant and non-malignant pathologies, clinical courses and therapeutic management are widely divergent. In general, therapeutic options across all soft tissue sarcomas are limited in number and are often generalized across multiple sarcoma histologies. The recent emergence of molecularly targeted therapies and immune-based agents presents a future of refined systemic treatment practices that are rationally tailored to the tumor by histologic subtype and biologic mechanisms.

Tongue piercing as risk factor to periodontal health.

Body piercing has grown in popularity among teenagers and young adults. Dating back to antiquity, piercing is a cultural practice used in ceremonial or religious rites; however, today, it is commonly exercised as a method of self-expression. Different complications and side effects are associated with intraoral piercing, including pain, swelling, infection, gingival trauma, chipped or fractured teeth, increased salivary flow, calculus buildup, and interference with speech and swallowing. We present a case report of periodontal treatment of traumatized gingival tissue caused by a tongue stud. The step-by-step periodontal surgical management of the case has been elaborated. The role of oral and dental health care professionals in managing the growing problem of tongue piercing as a periodontal risk factor has also been highlighted.