Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells.

Our bodies are equipped with powerful immune surveillance to clear cancerous cells as they emerge. How tumor-initiating stem cells (tSCs) that form and propagate cancers equip themselves to overcome this barrier remains poorly understood. To tackle this problem, we designed a skin cancer model for squamous cell carcinoma (SCC) that can be effectively challenged by adoptive cytotoxic T cell transfer (ACT)-based immunotherapy. Using single-cell RNA sequencing (RNA-seq) and lineage tracing, we found that transforming growth factor ß (TGF-ß)-responding tSCs are superior at resisting ACT and form the root of tumor relapse. Probing mechanism, we discovered that during malignancy, tSCs selectively acquire CD80, a surface ligand previously identified on immune cells. Moreover, upon engaging cytotoxic T lymphocyte antigen-4 (CTLA4), CD80-expressing tSCs directly dampen cytotoxic T cell activity. Conversely, upon CTLA4- or TGF-ß-blocking immunotherapies or Cd80 ablation, tSCs become vulnerable, diminishing tumor relapse after ACT treatment. Our findings place tSCs at the crux of how immune checkpoint pathways are activated.

Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells.

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.

Current treatment and future directions in the management of anal cancer.

Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter-preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin-C and 5-fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity-modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3-dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de-escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern-day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.

Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis.

BACKGROUND: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. METHODS: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. FINDINGS: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. INTERPRETATION: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. FUNDING: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Construction of a prognostic model with CAFs for predicting the prognosis and immunotherapeutic response of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is one of the subtypes of lung cancer (LC) that contributes to approximately 25%-30% of its prevalence. Cancer-associated fibroblasts (CAFs) are key cellular components of the TME, and the large number of CAFs in tumour tissues creates a favourable environment for tumour development. However, the function of CAFs in the LUSC is complex and uncertain. First, we processed the scRNA-seq data and classified distinct types of CAFs. We also identified prognostic CAFRGs using univariate Cox analysis and conducted survival analysis. Additionally, we assessed immune cell infiltration in CAF clusters using ssGSEA. We developed a model with a significant prognostic correlation and verified the prognostic model. Furthermore, we explored the immune landscape of LUSC and further investigated the correlation between malignant features and LUSC. We identified CAFs and classified them into three categories: iCAFs, mCAFs and apCAFs. The survival analysis showed a significant correlation between apCAFs and iCAFs and LUSC patient prognosis. Kaplan-Meier analysis showed that patients in CAF cluster C showed a better survival probability compared to clusters A and B. In addition, we identified nine significant prognostic CAFRGs (CLDN1, TMX4, ALPL, PTX3, BHLHE40, TNFRSF12A, VKORC1, CST3 and ADD3) and subsequently employed multivariate Cox analysis to develop a signature and validate the model. Lastly, the correlation between CAFRG and malignant features indicates the potential role of CAFRG in promoting tumour angiogenesis, EMT and cell cycle alterations. We constructed a CAF prognostic signature for identifying potential prognostic CAFRGs and predicting the prognosis and immunotherapeutic response for LUSC. Our study may provide a more accurate prognostic assessment and immunotherapy targeting strategies for LUSC.

Trends in epidemiology and primary treatment of anal squamous cell carcinoma in the Netherlands (1990-2021).

A rapid increase in the incidence of anal squamous cell carcinoma (SCC) was reported in several countries over the past decades. This study assessed trends in epidemiology and primary treatment over a 32-year period (1990-2021) using the Netherlands Cancer Registry. The study population included 4273 patients, 44.2% male and 55.8% female (median age 63 years). The age-standardised incidence rate (European Standardised Rate, ESR) increased from 0.5 to 1.6 per 100,000, which entailed an average annual percentage change (AAPC) of 5.0% (95% confidence interval [CI]: 4.5%-5.8%). While incidence among females increased continuously over the total period (AAPC 4.9%; 95%CI: 4.4%-5.6%), to 1.8 per 100,000 ESR in 2021, incidence among males increased until 2016 (annual percentage change [APC] of 6.3%; 95%CI: 5.6%-10.7%), after which it seemed to stabilise (APC -2.1%; 95%CI: -16.8%-4.5%). Significant trends were also observed in distribution of age, tumour stage and primary treatment modalities. Five-year relative survival (RS) was estimated using the Pohar-Perme estimator, and this improved from 56.1% in 1990-1997 (95%CI: 49.3%-62.4%) to 67.9% in 2014-2021 (95%CI: 64.7%-70.9%), but remained poor for stage IV disease. Evaluation through a multivariable Poisson regression model demonstrated diagnosis in the most recent period to be independently associated with better RS, in addition to female sex, younger age, early disease stage and any treatment. In conclusion, the rising incidence of anal SCC seems to decline in males, but not in females, and advances in diagnostics and therapeutic management have likely contributed to improved prognosis.

Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer. METHODS: We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival. RESULTS: The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group. CONCLUSIONS: Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.).

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes.

BACKGROUND: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. METHODS: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. RESULTS: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. CONCLUSIONS: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.

Monocyte infiltration is an independent positive prognostic biomarker in vulvar squamous cell carcinoma.

BACKGROUND: Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment. METHODS: A total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan-Meier analyses). RESULTS: Healthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADR-CD11c-CD14+CD68-CD163-CD33-) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001). CONCLUSION: A hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.

Long-term survival after anti-PD-1 discontinuation in advanced cutaneous squamous cell carcinoma (cSCC): a proof of concept of benefit of concomitant cemiplimab and radiotherapy.

BACKGROUND: In a princeps study we conducted in patients with advanced cutaneous squamous cell carcinoma treated with concomitant anti-Programmed cell death protein 1 (PD-1) and radiotherapy, we demonstrated a clinico radiological response to cemiplimab that appeared to persist over time, 1 year after treatment discontinuation. METHOD: We conducted a single-center descriptive study at Caen Hospital from September 1, 2021 to September 2023, in 14 patients with advanced carcinoma treated with cemiplimab until September 1, 2021. The aim of this update is to examine clinical and radiological follow-up 2 years after discontinuation of cemiplimab. RESULTS: Of the 12 patients with a partial or complete response, we report 8 (66.7%) persistent responses 2 years after stopping cemiplimab, with only 2 patients progressing to distant disease, one lost to follow-up, and one death a priori unrelated to the disease. CONCLUSION: Our study confirms a long-term and persistent effect despite discontinuation of cemiplimab at least up to 2 years later.

From pixels to patient care: deep learning-enabled pathomics signature offers precise outcome predictions for immunotherapy in esophageal squamous cell cancer.

BACKGROUND: Immunotherapy has significantly improved survival of esophageal squamous cell cancer (ESCC) patients, however the clinical benefit was limited to only a small portion of patients. This study aimed to perform a deep learning signature based on H&E-stained pathological specimens to accurately predict the clinical benefit of PD-1 inhibitors in ESCC patients. METHODS: ESCC patients receiving PD-1 inhibitors from Shandong Cancer Hospital were included. WSI images of H&E-stained histological specimens of included patients were collected, and randomly divided into training (70%) and validation (30%) sets. The labels of images were defined by the progression-free survival (PFS) with the interval of 4 months. The pretrained ViT model was used for patch-level model training, and all patches were projected into probabilities after linear classifier. Then the most predictive patches were passed to RNN for final patient-level prediction to construct ESCC-pathomics signature (ESCC-PS). Accuracy rate and survival analysis were performed to evaluate the performance of ViT-RNN survival model in validation cohort. RESULTS: 163 ESCC patients receiving PD-1 inhibitors were included for model training. There were 486,188 patches of 1024*1024 pixels from 324 WSI images of H&E-stained histological specimens after image pre-processing. There were 120 patients with 227 images in training cohort and 43 patients with 97 images in validation cohort, with balanced baseline characteristics between two groups. The ESCC-PS achieved an accuracy of 84.5% in the validation cohort, and could distinguish patients into three risk groups with the median PFS of 2.6, 4.5 and 12.9 months (P < 0.001). The multivariate cox analysis revealed ESCC-PS could act as an independent predictor of survival from PD-1 inhibitors (P < 0.001). A combined signature incorporating ESCC-PS and expression of PD-L1 shows significantly improved accuracy in outcome prediction of PD-1 inhibitors compared to ESCC-PS and PD-L1 anlone, with the area under curve value of 0.904, 0.924, 0.610 for 6-month PFS and C-index of 0.814, 0.806, 0.601, respectively. CONCLUSIONS: The outcome supervised pathomics signature based on deep learning has the potential to enable superior prognostic stratification of ESCC patients receiving PD-1 inhibitors, which convert the images pixels to an effective and labour-saving tool to optimize clinical management of ESCC patients.

CT-based delta-radiomics nomogram to predict pathological complete response after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma patients.

BACKGROUND: This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT). METHODS: The study retrospectively analyzed 232 ESCC patients who underwent pretreatment and post-treatment CT scans. Patients were divided into training (n = 186) and validation (n = 46) sets through fivefold cross-validation. 837 radiomics features were extracted from regions of interest (ROIs) delineations on CT images before and after nCRT to calculate delta values. The LASSO algorithm selected delta-radiomics features (DRF) based on classification performance. Logistic regression constructed a nomogram incorporating DRFs and clinical factors. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses evaluated nomogram performance for predicting pCR. RESULTS: No significant differences existed between the training and validation datasets. The 4-feature delta-radiomics signature (DRS) demonstrated good predictive accuracy for pCR, with α-binormal-based and empirical AUCs of 0.871 and 0.869. T-stage (p = 0.001) and differentiation degree (p = 0.018) were independent predictors of pCR. The nomogram combined the DRS and clinical factors improved the classification performance in the training dataset (AUCαbin = 0.933 and AUCemp = 0.941). The validation set showed similar performance with AUCs of 0.958 and 0.962. CONCLUSIONS: The CT-based delta-radiomics nomogram model with clinical factors provided high predictive accuracy for pCR in ESCC patients after nCRT.

Survival benefits of human papillomavirus 16 infection in patients with esophageal squamous cell carcinoma undergoing chemoradiotherapy: A retrospective cohort study.

The role of human papillomavirus 16 (HPV 16) in esophageal squamous cell carcinoma (ESCC) remains uncertain. Therefore, this study aimed to investigate the prevalence of HPV 16 in patients with ESCC and its impact on theirprognosis. HPV 16 was detected using FISH, and TP53 status was evaluated via immunohistochemistry. The factors influencing prognosis were ananalyzed using the Log-rank test and Cox regression analyses. Among 178 patients with ESCC, 105 and 73 patients were categorized into concurrent chemoradiotherapy (CCRT) and postoperative chemoradiotherapy (POCRT) cohorts, respectively. Among 178 patients, 87 (48.87%) tested positive for HPV 16. Log-rank tests revealed that the overall survival (OS) of patients with ESCC who were HPV 16-positive was longer than that of those who were HPV 16-negative (median OS: 57 months vs. 27 months, p < 0.01**). HPV 16 infection and TP53 mutation status were identified as independent events. The OS of patients with mutant TP53 who were HPV 16-positive was longer than that of those who were HPV 16-negative in both CCRT and POCRT cohorts (p = 0.002** for CCRT cohorts and p = 0.0023** for POCRT cohorts). Conversely, HPV 16 infection had no effect on OS in the wild-type TP53 subgroup (p = 0.13 and 0.052 for CCRT and POCRT cohorts, respectively). As a conclusion, the positive rate of HPV 16 in ESCC in this study was 48.87% (87/178). Among the patients with ESCC who had TP53 mutation, those who were HPV 16-positive exhibited a better prognosis than those who were HPV 16-negative.

Advances and residual knowledge gaps in the neck management of head and neck squamous cell carcinoma patients with advanced nodal disease undergoing definitive (chemo)radiotherapy for their primary.

PURPOSE: Substantial changes have been made in the neck management of patients with head and neck squamous cell carcinomas (HNSCC) in the past century. These have been fostered by changes in cancer epidemiology and technological progress in imaging, surgery, or radiotherapy, as well as disruptive concepts in oncology. We aimed to review changes in nodal management, with a focus on HNSCC patients with nodal involvement (cN+) undergoing (chemo)radiotherapy. METHODS: A narrative review was conducted to review current advances and address knowledge gaps in the multidisciplinary management of the cN+ neck in the context of (chemo)radiotherapy. RESULTS: Metastatic neck nodes are associated with poorer prognosis and poorer response to radiotherapy, and have therefore been systematically treated by surgery. Radical neck dissection (ND) has gradually evolved toward more personalized and less morbid approaches, i.e., from functional to selective ND. Omission of ND has been made feasible by use of positron-emission tomography/computed tomography to monitor the radiation response in cN+ patients. Human papillomavirus-driven oropharyngeal cancers and their cystic nodes have shown dramatically better prognosis than tobacco-related cancers, justifying a specific prognostic classification (AJCC) creation. Finally, considering the role of lymph nodes in anti-tumor immunity, de-escalation of ND and prophylactic nodal irradiation in combination are intense areas of investigation. However, the management of bulky cN3 disease remains an issue, as aggressive multidisciplinary strategies or innovative combined treatments have not yet significantly improved their prognosis. CONCLUSION: Personalized neck management is an increasingly important aspect of the overall therapeutic strategies in cN+ HNSCC.

Ex vivo therapeutic screening of metastatic cSCC: A review of methodological considerations for clinical implementation.

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy worldwide, with most deaths caused by locally advanced and metastatic disease. Treatment of resectable metastases is typically limited to invasive surgery with adjuvant radiotherapy; however, many patients fail to respond and there is minimal data to predict response or propose effective alternatives. Precision medicine could improve this, though genomic biomarkers remain elusive in the high mutational background and genomic complexity of cSCC. A phenotypic approach to precision medicine using patient-derived ex vivo tumour models is gaining favour for its capacity to directly assess biological responses to therapeutics as a functional, predictive biomarker. However, the use of ex vivo models for guiding therapeutic selection has yet to be employed for metastatic cSCC. This review will therefore evaluate the existing experimental models of metastatic cSCC and discuss how ex vivo methods could overcome the shortcomings of these existing models. Disease-specific considerations for a prospective methodological pipeline will also be discussed in the context of precision medicine.

Neoadjuvant chemotherapy followed by surgery versus concurrent chemoradiotherapy in patients with stage IIB cervical squamous cell carcinoma: a retrospective cohort study.

PURPOSE: This study aims to compare treatment outcomes between neoadjuvant chemotherapy (NACT) followed by surgery and concurrent chemoradiotherapy (CCRT) in patients with stage IIB cervical squamous cell carcinoma (CSCC). MATERIALS AND METHODS: We conducted a retrospective cohort study involving patients with stage IIB CSCC treated at Guangxi Medical University Cancer Hospital between June 2012 and June 2019. We compared overall survival (OS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS) between the NACT + surgery and CCRT groups. RESULTS: A total of 257 patients were enrolled: 165 underwent NACT + surgery and 92 received CCRT. Before propensity score matching, the NACT + surgery group exhibited lower 5-year OS (68.2% vs. 85.6%; hazard ratio [HR] = 2.50, 95% confidence interval [CI]: 1.26-4.96; P = 0.009), LRFS (85.2% vs. 96.9%; HR = 5.88, 95% CI: 1.33-25.94; P = 0.019), and DMFS (81.9% vs. 97.4%; HR = 6.65, 95% CI: 1.51-29.23; P = 0.012) compared to the CCRT group. After propensity score matching, OS, LRFS, and DMFS remained worse in the NACT + surgery group compared to the CCRT group. CONCLUSION: NACT followed by surgery is associated with decreased OS, LRFS, and DMFS compared to CCRT among patients with stage IIB CSCC.

Impact of treatment interval between neoadjuvant immunochemotherapy and surgery in lung squamous cell carcinoma.

OBJECTIVE: The optimal timing for surgery following neoadjuvant immunochemotherapy for lung squamous cell carcinoma appears to be a topic of limited data. Many clinical studies lack stringent guidelines regarding this timing. The objective of this study is to explore the effect of the interval between neoadjuvant immunochemotherapy and surgery on survival outcomes in patients with lung squamous cell carcinoma. METHODS: This study conducted a retrospective analysis of patients with lung squamous cell carcinoma who underwent neoadjuvant immunochemotherapy between January 2019 and October 2022 at The First Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups based on the treatment interval: ≤33 days and > 33 days. The primary observational endpoints of the study were Disease-Free Survival (DFS) and Overall Survival (OS). Secondary observational endpoints included Objective response rate (ORR), Major Pathological Response (MPR), and Pathological Complete Remission (pCR). RESULTS: Using the Kaplan-Meier methods, the ≤ 33d group demonstrated a superior DFS curve compared to the > 33d group (p = 0.0015). The median DFS for the two groups was 952 days and 590 days, respectively. There was no statistical difference in the OS curves between the groups (p = 0.66), and the median OS was not reached for either group. The treatment interval did not influence the pathologic response of the tumor or lymph nodes. CONCLUSIONS: The study observed that shorter treatment intervals were associated with improved DFS, without influencing OS, pathologic response, or surgical safety. Patients should avoid having a prolonged treatment interval between neoadjuvant immunochemotherapy and surgery.

SPP1 is associated with adverse prognosis and predicts immunotherapy efficacy in penile cancer.

BACKGROUND: The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC. METHOD: Eight paired penile cancer specimens (including penile cancer tissue, paracancerous tissue, and positive lymph node tissue) subjected to whole transcriptome sequencing were analysed to identify differentially expressed genes. We used immunohistochemistry to detect the expression of SPP1 protein and immune cell related proteins in penile cancer tissue. Then, we performed weighted gene coexpression network analysis (WGCNA) to identify the genes related to SPP1 in penile cancer tissue and positive lymph node tissue. Based on the GSE57955 dataset, the CIBERSORT and ssGSEA algorithms were carried out to investigate the immune environment of PSCC. GSVA analysis was conducted to identify the signaling pathways related to SPP1 subgroups. Enzyme-linked immunosorbent assay (ELISA) method was adopted to detect SPP1 level in the serum of 60 patients with penile cancer. RESULTS: Differential analysis indicated that SPP1 was the most differentially upregulated gene in both penile cancer tissues and positive lymph node tissues. Survival analysis suggested that the prognosis of the low-SPP1 group was significantly poorer than that of the high-SPP1 group. Subsequently, immune-related bioinformatics showed that SPP1 was significantly associated with B cells, CD8 + T cells, CD4 + T cells, macrophages, helper T cells, neutrophils and dendritic cells. The immunohistochemical results showed that the high-SPP1 group was characterized by relatively high expression of CD16 and relatively low expression of CD4. GSVA analysis indicated that high-SPP1 group was significantly associated with immune-related pathways such as PD-L1 expression and the PD-1 checkpoint pathway in cancer and the TNF signaling pathway. ELISA demonstrated that the serum level of SPP1 in patients with positive lymph node metastasis of penile cancer was significantly higher than that in patients with negative lymph node metastasis of penile cancer. CONCLUSION: Our study shows that the SPP1 gene might be an effective biomarker for predicting the prognosis and the efficacy of immunotherapy in PSCC patients.

Systemic and Local Administration of a Dual-siRNA Complex Efficiently Inhibits Tumor Growth and Bone Invasion in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral and oropharyngeal cancer cases and is characterized by high mortality and poor prognosis. RNA-based gene therapies have been developed as an emerging option for cancer treatment, but it has not been widely explored in OSCC. In this work, we developed an efficient siRNA cationic micelle DOTAP-mPEG-PCL (DMP) by self-assembling the cationic lipid DOTAP and monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) polymer. We tested the characteristics and transformation efficiency of this micelle and combined DMP with siRNA targeting STAT3 and TGF-ß to evaluate the antitumor effect and bone invasion interfering in vitro and in vivo. The average size of the DMP was 28.27 ± 1.62 nm with an average zeta potential of 54.60 ± 0.29 mV. The DMP/siRNA complex showed high delivery efficiency, with rates of 97.47 ± 0.42% for HSC-3. In vitro, the DMP/siSTAT3 complex exhibited an obvious cell growth inhibition effect detected by MTT assay (an average cell viability of 25.1%) and clonogenic assay (an average inhibition rate of 51.9%). Besides, the supernatant from HSC-3 transfected by DMP/siTGF-ß complexes was found to interfere with osteoclast differentiation in vitro. Irrespective of local or systemic administration, DMP/siSTAT3+siTGF-ß showed antitumor effects and bone invasion inhibition in the OSCC mice mandibular invasion model according to tumor volume assays and Micro-CT scanning. The complex constructed by DMP cationic micelles and siSTAT3+siTGF-ß represents a potential RNA-based gene therapy delivery system for OSCC.

Genomic characterization of vulvar squamous cell carcinoma reveals differential gene expression based on clinical outcome.

OBJECTIVE: The greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. METHODS: From 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumors from 21 patients were subjected to whole exome sequencing of DNA and RNA, immunohistochemistry (IHC) antibodies of PD-L1 and P16, and in-situ hybridization (ISH) for high-risk HPV. RESULTS: Analysis of DNA and RNA revealed six genes that were strongly differentially expressed between group A and B: TGM3, ACVR2A, ROS1, NFEL2, CCND1 and BCL6. Clinically relevant DNA mutations were significantly greater in group A versus B: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable and tumor mutational burden (TMB) was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. CONCLUSIONS: ACVR2A and TGM3 are significantly under-expressed in tumors with poor outcome, suggesting they may play a role in tumor suppression. Clinical outcome of VSCC appears independent of MSI, TMB, or PD-L1 status.