Neck Squamous Cell Carcinoma Research Articles

Identification of immunogenic cell death-related damage-related molecular patterns (DAMPs) to predict outcomes in patients with head and neck squamous cell carcinoma.

Head and neck cancer is the sixth most common type of cancer worldwide, wherein the immune responses are closely associated with disease occurrence, development, and prognosis. Investigation of the role of immunogenic cell death-related genes (ICDGs) in adaptive immune response activation may provide cues into the mechanism underlying the outcome of HNSCC immunotherapy. ICDGs expression patterns in HNSCC were analyzed, after which consensus clustering in HNSCC cohort conducted. A 4-gene prognostic model was constructed through LASSO and Cox regression analyses to analyze the prognostic index using the TCGA dataset, followed by validation with two GEO datasets. The distribution of immune cells and the response to immunotherapy were compared between different risk subtypes through multiple algorithms. Moreover, immunohistochemical (IHC) analyses were conducted to validate the prognostic value of HSP90AA1 as a predictor of HNSCC patient prognosis. In vitro assays were performed to further detect the effect of HSP90AA1 in the development of HNSCC. A novel prognostic index based on four ICDGs was constructed and proved to be useful as an independent factor of HNSCC prognosis. The risk score derived from this model grouped patients into high- and low-risk subtypes, wherein the high-risk subtype had worse survival outcomes and poorer immunotherapy response. IHC analysis validated the applicability of HSP90AA1 as a predictor of prognosis of HNSCC patients. HSP90AA1 expression in tumor cells promotes the progression of HNSCC. Together, these results highlight a novel four-gene prognostic signature as a valuable tool to assess survival status and prognosis of HNSCC patients.

Immunotherapy for Head and Neck Squamous Cell Carcinoma: Present and Future Approaches and Challenges.

Despite significant progress and improving outcomes in the management of head and neck squamous cell carcinoma (HNSCC), there are few effective treatment options for patients with recurrent or metastatic head and neck squamous cell carcinoma. The advent of immune checkpoint inhibitors has changed the treatment algorithm of head and neck squamous cell carcinoma and are approved in the frontline setting for recurrent and metastatic (R/M) head and neck squamous cell carcinomas. Although promising for some patients, most patients with R/M HNSCC do not derive clinical benefit from currently approved checkpoint inhibitors. Many studies are underway to identify the patient population that would benefit the most from immunotherapy as well as postimmunotherapy treatment failures, including novel combinations of immunomodulatory therapies. In this review, we summarize the clinical development of all major clinical trials of immunotherapy in HNSCC.

CD271 mRNA/hnRNPA2B1 complex promotes proliferation and stemness in oral and head and neck squamous cell carcinoma.

RNAs, such as noncoding RNA, microRNA, and recently mRNA, have been recognized as signal transduction molecules. CD271, also known as nerve growth factor receptor, has a critical role in cancer, although the precise mechanism is still unclear. Here, we show that CD271 mRNA, but not CD271 protein, facilitates spheroid cell proliferation. We established CD271-/- cells lacking both mRNA and protein of CD271, as well as CD271 protein knockout cells lacking only CD271 protein, from hypopharyngeal and oral squamous cell carcinoma lines. Sphere formation was reduced in CD271-/- cells but not in CD271 protein knockout cells. Mutated CD271 mRNA, which is not translated to a protein, promoted sphere formation. CD271 mRNA bound to hnRNPA2B1 protein at the 3'-UTR region, and the inhibition of this interaction reduced sphere formation. In surgical specimens, the CD271 mRNA/protein expression ratio was higher in the cancerous area than in the noncancerous area. These data suggest CD271 mRNA has dual functions, encompassing protein-coding and noncoding roles, with its noncoding RNA function being predominant in oral and head and neck squamous cell carcinoma.

Aspartate β-Hydroxylase Is Upregulated in Head and Neck Squamous Cell Carcinoma and Regulates Invasiveness in Cancer Cell Models

Aspartate β-hydroxylase (ASPH) is a protein associated with malignancy in a wide range of tumors. We hypothesize that inhibition of ASPH activity could have anti-tumor properties in patients with head and neck cancer. In this study, we screened tumor tissues of 155 head and neck squamous cell carcinoma (HNSCC) patients for the expression of ASPH using immunohistochemistry. We used an ASPH inhibitor, MO-I-1151, known to inhibit the catalytic activity of ASPH in the endoplasmic reticulum, to show its inhibitory effect on the migration of SCC35 head and neck cancer cells in cell monolayers and in matrix-embedded spheroid co-cultures with primary cancer-associated fibroblast (CAF) CAF 61137 of head and neck origin. We also studied a combined effect of MO-I-1151 and HfFucCS, an inhibitor of invasion-blocking heparan 6-O-endosulfatase activity. We found ASPH was upregulated in HNSCC tumors compared to the adjacent normal tissues. ASPH was uniformly high in expression, irrespective of tumor stage. High expression of ASPH in tumors led us to consider it as a therapeutic target in cell line models. ASPH inhibitor MO-I-1151 had significant effects on reducing migration and invasion of head and neck cancer cells, both in monolayers and matrix-embedded spheroids. The combination of the two enzyme inhibitors showed an additive effect on restricting invasion in the HNSCC cell monolayers and in the CAF-containing co-culture spheroids. We identify ASPH as an abundant protein in HNSCC tumors. Targeting ASPH with inhibitor MO-I-1151 effectively reduces CAF-mediated cellular invasion in cancer cell models. We propose that the additive effect of MO-I-1151 with HfFucCS, an inhibitor of heparan 6-O-endosulfatases, on HNSCC cells could improve interventions and needs to be further explored.

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA-mediated modulation of the RIPK1-FADD-Caspase 8 complex.

Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas-Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit-8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments. The quantitative real-time reverse-transcription polymerase chain reaction, Western blot analysis and flow cytometry were used. FADD and RIPK1 expressions were differentially expressed in Chemosensitive and drug-resistant patients. Furthermore, patients with tumors exhibiting high expression of FADD and RIPK1 had significantly greater risk for chemoresistance and mortality than patients with tumors that had low levels of these proteins. Moreover, Tan IIA reduced the expression of RIPK1 and FADD in HNSCC chemoresistant cell lines, which could increase the chemosensitivity of cisplatin and promote apoptosis. Overexpression of RIPK1 led to attenuation of therapeutic effects of Tan IIA, which were mainly realized through regulation of the RIPK1-FADD-Caspase 8 complex. This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1-FADD-Caspase 8 complex.

Abstract PO1-20-04: STX-478-101: A phase 1/2, first-in-human study of STX-478 monotherapy or in combination with fulvestrant in patients with breast cancer or other advanced solid tumors (trial in progress)

Abstract Background: The phosphoinositide 3-kinase-alpha (PI3Kα)/AKT/mTOR pathway is one of the major pathways in oncogenesis. PI3Kα alterations are especially prevalent in breast, gynecological, and head and neck squamous cell carcinomas. PI3Kα oncogenic mutations are highly enriched for kinase (H1047X) and helical (E542K, E545K) domain hotspots. The therapeutic potential of isoform-selective PI3Kα inhibition in PI3Kα-mutant cancers was established with alpelisib, which shows equipotent activity against both wild-type (WT) and mutant PI3Kα. However, alpelisib use is limited by toxicities induced by WT PI3Kα inhibition, e.g. hyperglycemia and mucositis. This suggests that mutant-selective PI3Kα inhibitors have the potential to improve efficacy while sparing WT-related toxicity. STX-478 is an investigational allosteric, mutant-selective PI3Kα inhibitor. Preclinical testing in human breast cancer xenografts bearing helical- or kinase-domain mutant PI3Kα demonstrated that STX-478 monotherapy and combinations with fulvestrant and/or CDK4/6 inhibitors provided robust efficacy without the metabolic dysfunction observed with alpelisib. Trial Design: This first-in-human, multicenter, phase 1/2 study (NCT05768139) evaluates the optimal dosing, safety, and preliminary efficacy of STX-478 as monotherapy in patients with locally-advanced or metastatic HR+/HER2− breast cancer or other solid tumor types with PI3Kα H1047X mutations, other kinase domain mutations, or helical domain mutations (Part 1), and STX-478 in combination with fulvestrant in patients with locally-advanced or metastatic HR+/HER2− breast cancer with PI3Kα H1047X or other kinase domain mutations (Part 2). Part 1 comprises 2 subparts (Table 1) to define the optimally biologically active dose (OBD) and maximum tolerated dose (MTD) in Part 1.1, and recommended phase 2 dose (RP2D) of STX-478 monotherapy in Part 1.2. At the conclusion of each dose-level in Part 1.1 (3 + 3 design), a backfill cohort will be initiated in patients with HR+/HER2− breast cancer with PI3Kα H1047X mutations or other kinase domain mutations, who will receive STX-478 at the determined safe dose. Part 2 comprises two subparts (Table 2) to define RP2D and assess the initial efficacy of STX-478 in combination with fulvestrant in patients with HR+/HER2− breast cancer expressing PI3Kα H1047X or other kinase domain mutations. Key Eligibility Criteria: Adults with a PI3Kα-mutant advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable, ECOG performance status score of 0–1, and no prior PI3K/AKT/mTOR inhibitor(s) use (except with prior intolerance) are eligible. Individuals with diabetes mellitus type 1 or uncontrolled diabetes mellitus type 2 are excluded. Cohort-specific eligibility criteria are provided in Tables 1 and 2. Endpoints: Efficacy, safety, pharmacokinetics, pharmacodynamics, patient-reported quality of life, and biomarkers (e.g., glucose metabolism, circulating tumor DNA) will be assessed. Trial Status: Recruitment opened April 2023 in the US and is ongoing, with potential for ex-US site expansion. Contact clinicaltrials@scorpiontx.com for additional information. Table 1. Part 1 Dose Escalation, RP2D Selection, and RP2D Expansion (STX-478 Monotherapy) Table 2. Part 2 RP2D Selection and Expansion (STX-478 + Fulvestrant Combination Therapy) Citation Format: Alberto Montero, Douglas Orr, Pamela Munster, Patricia LoRusso, Komal Jhaveri, Timothy Pluard, Ira Winer, Michael Streit, Monica Patterson, Simon Roberts, Stefani Corsi-Travali, Courtney Ewert, Dejan Juric. STX-478-101: A phase 1/2, first-in-human study of STX-478 monotherapy or in combination with fulvestrant in patients with breast cancer or other advanced solid tumors (trial in progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-04.

Treatment regimens and survival among patients with head and neck squamous cell carcinoma from Mizo tribal population in northeast India – a single centre, retrospective cohort study

Patients with early-stage head and neck squamous cell carcinoma (HNSCC) are treated using a single-modality approach that involves either surgery (S) or radiotherapy (RT). Conversely, those with advanced-stage disease are treated using a multi-modality approach incorporating a combination of chemotherapy (CT), RT and S. In addition to behavioural factors, such as alcohol and tobacco use, clinical parameters, such as leukocyte and neutrophil counts and T and N classification, have been linked to the survival of patients with head and neck cancer. This retrospective study was designed to provide insights into the types of treatment (induction chemotherapy [IC], concurrent chemoradiotherapy [CCRT], S and RT) administered to patients with HNSCC in Mizoram, analyse their 2-year outcome, and identify potential factors that may affect the response to treatment. A retrospective cohort study was conducted using patients diagnosed with HNSCC between 2017 and 2020 in Mizoram, northeast India. Data on clinical and demographic factors and treatments provided were collected from medical records from the Mizoram State Cancer Institute, Mizoram. Overall survival (OS) and progression free survival (PFS) were determined for each factor using the Kaplan-Meier method and compared using the log-rank test. Cox regression analysis was used to identify the factors that affected OS and PFS. Multicollinearity test was performed between the predictors using a variance inflation factor cut-off point of2. A retrospective study was performed on 210 patients with HNSCC who were followed up for a period of 2 years. The findings revealed that hypopharynx was the most affected site, followed by the nasopharynx, oral cavity, oropharynx, and larynx. Regarding treatment regimens, 85/210 (40.5%) of the patients received IC along with CCRT or RT in a sequential manner. Moreover, 86/210 (41.0%) underwent CCRT alone, 22/210 (10.5%) received RT alone and 17/210 (8.1%) underwent surgery followed by adjuvant CCRT or RT. Two-year OS and PFS estimated using the Kaplan-Meier analysis were 78.1% (95% CI=72.4%-84.2%) and 57.4% (95% CI=50.8%-64.8%), respectively. Log-rank test showed that leucocytosis (p=0.015) and neutrophilia (p=0.014) exerted effects on OS, whereas nodal involvement (p=0.005), neutrophilia (p=0.043) and IC (p=0.010) exerted effects on PFS. Multivariate analysis indicated that leucocytosis (p=0.010 [OS], 0.025 [PFS]), neutrophilia (p=0.029, 0.033), cancer site (laryngeal) (p=0.009, 0.028) and nodal involvement (N2) (p=0.020, 0.001) were predictors of poor OS and PFS. OS was better than PFS in HNSCC patients from Mizo population. Multi-modality approach offered survival advantages over single-modality approach. Leucocytosis, neutrophilia, nodal involvement, and cancer sites were associated with poor OS and PFS. More comprehensive research with a larger sample size is needed to confirm the findings from this study. There is no funding for this study.

Interdisciplinary plastic and reconstructive surgery of head and neck squamous cell carcinomas.

Squamous cell carcinomas are the most common malignancies in the oral cavity, pharynx, and larynx. Even in the age of the most modern drug treatment methods, radical resection of these tumors is and currently remains the therapeutic gold standard. The loss of anatomical structures associated with surgery inevitably increases the functional deficits caused by the tumor itself. In this context, the extent of functional deficits is largely determined by the extent of resection. Complete organ resections, such as glossectomy, complete palate resection, laryngectomy, or transverse pharyngo-laryngectomy, lead to severe functional deficits, such as swallowing disturbances with life-threatening aspiration and articulation disorders up to the inability to speak. With the help of plastic reconstructive surgery, the lost tissue can be replaced and the specific functions of the upper aerodigestive tract can be preserved or restored.In recent decades, reconstructive surgical procedures have developed enormously in the treatment of malignant tumors of the head and neck. In order to make optimal use of them, a comprehensive, interdisciplinary therapy concept is a prerequisite for positive oncological and functional outcome. In addition to general medical and social parameters, surgical parameters play a crucial role in the choice of the reconstruction method. The extent to which the surgical measures must be interdisciplinary depends on the localization of the defects in the head and neck region and on the type of replacement tissue required. Here, the expertise of plastic surgery, oral and maxillofacial surgery, and abdominal surgery comes into play in particular. The use of different tissues, the combination of different grafts and flaps, or the preforming of donor regions allow reconstructions far beyond the level of simply restoring surface integrity. The functional results and thus the quality of life of patients after surgical therapy of extensive tumors of the mentioned localizations depend decisively on the type of reconstruction. Therefore, in the following review, special emphasis 1 be placed on the choice of reconstruction method and reconstruction technique for tissue loss after resections of HNSCC.

[Concurrent simultaneous integrated boost radiotherapy and cetuximab in head and neck squamous cell cancer patients: is it feasible in daily clinical practice?]

Locally advanced head and neck squamous cell carcinoma (LA-Hnscc) is a true therapeutical challenge in the modern era and the scientific community is trying to face this challenge with new therapeutical strategies, including combinations of monoclonal antibodies and radiation therapy. The aim of this study is to evaluate clinical outcomes in LA-Hnscc patients unfit to receive platinum-based chemotherapy, treated with concurrent simultaneous integrated boost-intensity modulated radiotherapy (Sib-Imrt) + cetuximab (Ctx) in daily clinical practice. LA-Hnscc patients not included in other prospective studies treated in 4 Italian radiotherapy units (2 Messina, 1 Rome, and 1 Lecce) using Sib-Imrt and Ctx were included in this study. Acute and late toxicities and overall survival (OS) have been evaluated. Data regarding 27 patients with squamous tumour were collected and reviewed. The primary tumour sites were oropharynx in 14 patients (51.9%), oral cavity in 7 (25.9%), larynx in 3 (11%) and other sites in 3(11%). There were 20 (74%) patients had stage IV (16 IVa and 4 IVb). Complete remission was observed in 18 patients (66.7%), a partial remission in 4 (14.8%) whilst 4 had a progression disease (14.8%). After 3 year of follow-up 7/27 patients were deaths. The OS was 95.5%, 62.5% and 52.9% respectively at 1,2 and 3 years. Acute toxicities were observed in all treated patients (mucositis, dermatitis and dysphagia) while 66.7% of patients developed late toxicities. All observed toxicities were grade 1 to 3 and just 1 patient developed a G4 toxicity. The concurrent bio-radiotherapy of Sib-Imrt and cetuximab is feasible in real-life daily clinical practice for LA-Hnscc patients unfit for platinum-based chemoradiotherapy.

Neoadjuvant immunotherapy for head and neck squamous cell carcinoma.

The neoadjuvant immunotherapy approach marks a significant shift in the treatment paradigm of potentially curable HNSCC. Here, current therapies, despite being highly individualized and advanced, often fall short in achieving satisfactory long-term survival rates and are frequently associated with substantial morbidity.The primary advantage of this approach lies in its potential to intensify and enhance treatment regimens, offering a distinct modality that complements the existing triad of surgery, radiotherapy, and chemotherapy. Checkpoint inhibitors have been at the forefront of this evolution. Demonstrating moderate yet significant survival benefits in the recurrent-metastatic setting with a relatively better safety profile compared to conventional treatments, these agents hold promise when considered for earlier stages of HNSCC.On the other hand, a significant potential benefit of introducing immunotherapy in the neoadjuvant phase is the possibility of treatment de-escalation. By reducing the tumor burden before surgery, this strategy could lead to less invasive surgical interventions. The prospect of organ-sparing protocols becomes a realistic and highly valued goal in this context. Further, the early application of immunotherapy might catalyze a more effective and durable immune response. The induction of an immune memory may potentially lead to a more effective surveillance of residual disease, decreasing the rates of local, regional, and distant recurrences, thereby enhancing overall and recurrence-free survival.However, neoadjuvant immunotherapy is not without its challenges. One of the primary concerns is the safety and adverse events profile. While data suggest that adverse events are relatively rare and manageable, the long-term safety profile in the neoadjuvant setting, especially in the context of curative intent, remains a subject for ongoing research. Another unsolved issue lies in the accurate assessment of treatment response. The discrepancy between radiographic assessment using RECIST criteria and histological findings has been noted, indicating a gap in current imaging techniques' ability to accurately reflect the true efficacy of immunotherapy. This gap underscores the necessity for improved imaging methodologies and the development of new radiologic and pathologic criteria tailored to evaluate the response to immunotherapy accurately.Treatment combinations and timing represent another layer of complexity. There is a vast array of possibilities in combining immunotherapy agents with conventional chemotherapy, targeted therapy, radiation, and other experimental treatments. Determining the optimal treatment regimen for individual patients becomes an intricate task, especially when comparing small, single-arm, non-randomized trials with varying regimens and outcome measures.Moreover, one needs to consider the importance of pre- and intraoperative decision-making in the context of neoadjuvant immunotherapy. As experience with this treatment paradigm grows, there is potential for more tailored surgical approaches based on the patient's remaining disease post-neoadjuvant treatment. This consideration is particularly relevant in extensive surgeries, where organ-sparing protocols could be evaluated.In practical terms, the multi-modal nature of this treatment strategy introduces complexities, especially outside clinical trial settings. Patients face challenges in navigating the treatment landscape, which involves coordination across multiple medical disciplines, highlighting the necessity for streamlined care pathways at specialized centers to facilitate effective treatment management if the neoadjuvant approach is introduced to the real-world.These potential harms and open questions underscore the critical need for meticulously designed clinical trials and correlational studies to ensure patient safety and efficacy. Only these can ensure that this new treatment approach is introduced in a safe way and fulfils the promise it theoretically holds.

Therapeutic Targeting of Thioredoxin Reductase 1 Causes Ferroptosis while Potentiating Anti-PD-1 Efficacy in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1–mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8+ T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.

Next-generation sequencing (NGS) for the personalized treatment of head and neck squamous cell carcinoma (HNSCC)

Next-generation sequencing (NGS) for the personalized treatment of head and neck squamous cell carcinoma (HNSCC)

No prime time yet for checkpoint inhibitors in localised head and neck squamous cell carcinoma

No prime time yet for checkpoint inhibitors in localised head and neck squamous cell carcinoma

Evaluation of pap smears with cyto-histopathological correlation–our experience at a tertiary care hospital in Telangana

Background: The World Health Organization states that cervical carcinoma is the fourth most common cancer among women worldwide. Pap smear is the simplest and easiest test to detect this prevalent cancer at its nascent stages. Aims and Objectives: This study aims to evaluate Pap smears using the conventional method (Bethesda 2014) and correlate the abnormal smears with cervical biopsy. Materials and Methods: The study is a combined retrospective and prospective study, from January 2021 to August 2023. Pap smears received were evaluated according to Bethesda 2014. Those cases categorized as Epithelial Cell Abnormality (ECA), were correlated with corresponding histopathology on cervical biopsy. Results: Out of the 615 pap smears in this study, 525 cases (91%) were categorized as Negative for Intraepithelial Lesion or Malignancy, 53 cases (9%) as Epithelial Cell Abnormality, and 37 cases (6%) as unsatisfactory. In the Negative for Intraepithelial Lesion or Malignancy category, 353 cases (67.2%) were reactive cellular changes including inflammation, four cases (0.7%) were squamous metaplasia, and 24 cases (4.6%) were atrophic smears. In the ECA category–21 cases (39.6%) were Atypical squamous cells of undetermined significance, two cases (3.8%) were Low-grade squamous intraepithelial lesion, five cases (9.4%) were Atypical squamous cells-cannot exclude HSIL(ASC-H), 14 cases (26.4%) were High grade squamous intraepithelial lesion (HSIL) and 3 cases (5.6%) were squamous cell carcinoma (SCC) cervix, seven cases were of ECA-glandular type (13.2%). On histopathological correlation, the maximum correlation was found for HSIL and SCC cases, 71% and 100%, respectively. Conclusion: Pap smear is a crucial screening tool to diagnose cervical carcinoma at its nascent stage. This study showed a positive correlation for high-grade lesions on Pap smears.

CHMP2A regulates broad immune cell-mediated antitumor activity in an immunocompetent in vivo head and neck squamous cell carcinoma model

BackgroundNatural killer (NK) cells are key effector cells of antitumor immunity. However, tumors can acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying mechanisms that mediate this resistance enables us...

Programmed Death Ligand-1 and Tumor Burden Score Dictate Treatment Responses in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Background: The significance of tumor burden for survival is unknown for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The purpose of our study was to evaluate the prognostic impact of programmed death ligand-1 (PD-L1) and tumor burden score (TBS) in patients with R/M HNSCC. Patients and Methods: R/M HNSCC patients who were treated with cisplatin, 5-fluorouracil plus cetuximab (EPF) or pembrolizumab (PPF) as first-line treatment were included in our study. PD-L1 and TBS were estimated and correlated with treatment responses. Kaplan–Meier curves were plotted for outcomes estimation. Results: A total of 252 R/M HNSCC patients were included, with 126 high tumor burden (HTB) and 126 low tumor burden (LTB) patients. Median progression-free survival (PFS) was 7.1 months in LTB and 3.9 months in HTB (p < 0.001) and median overall survival (OS) was 14.2 months in LTB and 9.2 months in HTB (p = 0.001). Patients with LTB had better PFS and OS than those with HTB independent of PD-L1 status. Subgroup analysis showed HTB patients treated with EPF had better survival than those treated with PPF, regardless of PD-L1 expression. For LTB PD-L1 positive patients, there was a longer survival with PPF than EPF, while for LTB PD-L1 negative patients, survival was similar between PPF and EPF. Multivariate analysis exhibited that tumor burden was significantly correlated with OS. Conclusions: Tumor burden is significantly correlated with survival in patients with R/M HNSCC. PD-L1 and TBS should be taken into consideration to determine first-line treatment.

Characterization of macrophages in head and neck squamous cell carcinoma and development of MRG-based risk signature

Macrophages are immune cells in the TME that can not only inhibit angiogenesis, extracellular matrix remodeling, cancer cell proliferation, and metastasis but also mediate the phagocytosis and killing of cancer cells after activation, making them key targets in anti-tumor immunotherapy. However, there is little research on macrophages and their relation to disease prognosis in HNSCC. Initially, we collected scRNA-seq, bulk RNA-seq, and clinical data. Subsequently, we identified macrophages and distinguished MRGs. Using the K-means algorithm, we performed consensus unsupervised clustering. Next, we used ssGSEA analysis to assess immune cell infiltration in MRG clusters. A risk model was established using multivariate Cox analysis. Then, Kaplan–Meier, ROC curves, univariate and multivariate COX analyses, and C-index was used to validate the predictive power of the signature. The TIDE method was applied to assess the response to immunotherapy in patients diagnosed with HNSCC. In addition, drug susceptibility predictions were made for the GDSC database using the calcPhenotype function. We found that 8 MRGs had prognostic potential. Patients in the MRG group A had a higher probability of survival, and MRG clusters A and B had different characteristics. Cluster A had a higher degree of expression and infiltration in MRG, indicating a closer relationship with MRG. The accuracy of the signature was validated using univariate and multivariate Cox analysis, C-index, and nomogram. Immune landscape analysis found that various immune functions were highly expressed in the low-risk group, indicating an improved response to immunotherapy. Finally, drugs with high sensitivity to HNSCC (such as 5-Fluorouracil, Temozolomide, Carmustine, and EPZ5676) were explored and analyze the malignant characteristics of HNSCC. We constructed a prognostic model using multivariate Cox analysis, consisting of 8 MRGs (TGM2, STC1, SH2D3C, PIK3R3, MAP3K8, ITGA5, ARHGAP4, and AQP1). Patients in the low-risk group may have a higher response to immunotherapy. The more prominent drugs for drug selection are 5-fluorouracil, temozolomide and so on. Malignant features associated with HNSCC include angiogenesis, EMT, and the cell cycle. This study has opened up new prospects for the prognosis, prediction, and clinical treatment strategy of HNSCC.

Optimizing Treatment Quality in Head and Neck Cancer Therapy: Impact of Adaptive Intensity-Modulated Radiotherapy on Plan Quality and Tumor Volume Changes

Objective: This research analyses whether volumetric changes and PTV shifting affect adaptive intensity-modulated radiotherapy (IMRT) plan quality and head and neck cancer therapy. Methods: The research was carried out at the Sohag Cancer Centre in Egypt, including a sample of 36 individuals diagnosed with head and neck squamous cell carcinoma (HNSCC). Patients were chosen on the basis of the following criteria: locally progressed and node-positive malignancy, oropharyngeal cancer, oral cavity cancer, and unknown primary. The research used dynamic intensity-modulated radiation therapy (D-IMRT) to establish treatment plans and Siemens SOMATOM DEFINITION CT scanners to acquire 3D anatomical images. A range of 1.64 to 2.12 Gy was observed for the median dosage per fraction. Using the conformance index (CI) and the homogeneity index, the quality of the plan was assessed (HI). The threshold for statistical significance was set at 0.05. Results: The study analysed patients with unilateral and bilateral HNSCC tumors, with a majority having bilateral tumors. The findings demonstrated that the tumor PTV was significantly reduced as a consequence of the suggested adaptive radiation techniques. Both the homogeneity index and the conformity index were used to evaluate the plan's quality (HI). The maximal homogeneity index (HI) was reached after 7 and 14 fractions, respectively. The positive correlation between PTV reduction and CI after 7 fractions, while a negative correlation found after fractions 14 and 21. It was also shown that HI is positively correlated with PTV changes after 7 and 14. Conclusion: The use of adaptive radiotherapy in intensity-modulated radiation therapy (IMRT) treatment planning improves plan quality and decreases error rates due to tumor margin movement. Following radiation fractions, PTV shifting affects the homogeneity index (HI).

Validation of Biomarkers and Immunotherapy in Head and Neck Squamous Cell Carcinoma using Bioinformatics and Mendelian Randomization

ABSTRACT Background: To promote carcinogenesis through diverse molecular pathways involving dysregulation of gene expression and abnormalities. Methods: We employed Mendelian randomization (MR) to uncover causal relationships between genetic factors and HNSCC. We used the Inverse Variance Weighted (IVW) method as the primary MR analysis, and validated the results through complementary approaches like MR-Egger regression, weighted median, and mode analyses. Results: Our analysis identified 2210 genes that are differentially expressed in head and neck cancer (HNSCC) compared to normal tissues. Within the protein interaction network, the genes IL1B, CXCL8, CXCL1, and CCL2 stood out as central hubs. Further investigation revealed that these key genes are involved in important biological processes like skin development, wound healing, and fat metabolism. Notably, our Mendelian randomization analysis provided evidence for a causal relationship between the expression of the IL1B gene and the development of HNSCC. Conclusions: Our analysis identified 5 key genes - IL1B, CXCL8, CXCL1, CCL2, and IL1B - that show significant changes in expression in head and neck cancer. These genes could serve as important new biomarkers to help diagnose this disease and track how it progresses over time. Importantly, these genes are involved in regulating the immune system, suggesting that the body's immune response plays a critical role in head and neck cancer. This provides new avenues for future research to better understand the complex gene expression patterns underlying this type of cancer. Further investigation of these key genes and their regulatory networks could lead to important insights and potential new treatment approaches.

The role of the soft palate dose regarding normal tissue toxicities in older adults with head and neck cancer undergoing definitive radiotherapy.

The number of older adults with head and neck squamous cell carcinoma (HNSCC) is continuously increasing. Older HNSCC patients may be more vulnerable to radiotherapy-related toxicities, so that extrapolation of available normal tissue complication probability (NTCP) models to this population may not be appropriate. Hence, we aimed to investigate the correlation between organ at risk (OAR) doses and chronic toxicities in older patients with HNSCC undergoing definitive radiotherapy. Patients treated with definitive radiotherapy, either alone or with concomitant systemic treatment, between 2009 and 2019 in a large tertiary cancer center were eligible for this analysis. OARs were contoured based on international consensus guidelines, and EQD2 doses using α/ß values of 3Gy for late effects were calculated based on the radiation treatment plans. Treatment-related toxicities were graded according to Common Terminology Criteria for Adverse Events version 5.0. Logistic regression analyses were carried out, and NTCP models were developed and internally validated using the bootstrapping method. A total of 180 patients with a median age of 73 years fulfilled the inclusion criteria and were analyzed. Seventy-three patients developed chronic moderate xerostomia (grade 2), 34 moderate dysgeusia (grade 2), and 59 moderate-to-severe (grade 2-3) dysphagia after definitive radiotherapy. The soft palate dose was significantly associated with all analyzed toxicities (xerostomia: OR = 1.028, dysgeusia: OR = 1.022, dysphagia: OR = 1.027) in the multivariable regression. The superior pharyngeal constrictor muscle was also significantly related to chronic dysphagia (OR = 1.030). Consecutively developed and internally validated NTCP models were predictive for the analyzed toxicities (optimism-corrected AUCs after bootstrapping: AUCxerostomia=0.64, AUCdysgeusia=0.60, AUCdysphagia=0.64). Our data suggest that the dose to the soft palate is associated with chronic moderate xerostomia, moderate dysgeusia and moderate-to-severe dysphagia in older HNSCC patients undergoing definitive radiotherapy. If validated in external studies, efforts should be undertaken to reduce the soft palate dose in these patients.