CSChighE-cadherinlow immunohistochemistry panel predicts poor prognosis in oral squamous cell carcinoma.

Identifying marker combinations for robust prognostic validation in primary tumour compartments remains challenging. We aimed to assess the prognostic significance of CSC markers (ALDH1, CD44, p75NTR, BMI-1) and E-cadherin biomarkers in OSCC. We analysed 94 primary OSCC and 67 metastatic lymph node samples, including central and invasive tumour fronts (ITF), along with clinicopathological data. We observed an increase in ALDH1+/CD44+/BMI-1- tumour cells in metastatic lesions compared to primary tumours. Multivariate analysis highlighted that elevated p75NTR levels (at ITF) and reduced E-cadherin expression (at the tumour centre) independently predicted metastasis, whilst ALDH1high exhibited independent predictive lower survival at the ITF, surpassing the efficacy of traditional tumour staging. Then, specifically at the ITF, profiles characterized by CSChighE-cadherinlow (ALDH1highp75NTRhighE-cadherinlow) and CSCintermediateE-cadherinlow (ALDH1 or p75NTRhighE-cadherinlow) were significantly associated with worsened overall survival and increased likelihood of metastasis in OSCC patients. In summary, our study revealed diverse tumour cell profiles in OSCC tissues, with varying CSC and E-cadherin marker patterns across primary tumours and metastatic sites. Given the pivotal role of reduced survival rates as an indicator of unfavourable prognosis, the immunohistochemistry profile identified as CSChighE-cadherinlow at the ITF of primary tumours, emerges as a preferred prognostic marker closely linked to adverse outcomes in OSCC.

Open vs minimally invasive radical trachelectomy in early-stage cervical cancer: International Radical Trachelectomy Assessment Study.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005-2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20-42) years for open surgery vs 31 (18-45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0-31) mm for open surgery and 12 (0.8-40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20-16.70) years for open surgery and 3.1 years (0.02-11.10) years for minimally invasive surgery (P<.001). At 4.5 years, 17 of 358 patients (4.7%) with open surgery and 18 of 288 patients (6.2%) with minimally invasive surgery had recurrence (P=.40). The 4.5-year disease-free survival rates were 94.3% (95% confidence interval, 91.6-97.0) for open surgery and 91.5% (95% confidence interval, 87.6-95.6) for minimally invasive surgery (log-rank P=.37). Post hoc propensity score analysis of recurrence risk showed no difference between surgical approaches (P=.42). At 4.5 years, there were 6 disease-related deaths (open surgery, 3; minimally invasive surgery, 3) (log-rank P=.49). The 4.5-year overall survival rates were 99.2% (95% confidence interval, 97.6-99.7) for open surgery and 99.0% (95% confidence interval, 79.0-99.8) for minimally invasive surgery. CONCLUSION: The 4.5-year disease-free survival rates did not differ between open radical trachelectomy and minimally invasive radical trachelectomy. However, recurrence rates in each group were low. Ongoing prospective studies of conservative management of early-stage cervical cancer may help guide future management.

Assessment of TSPAN Expression Profile and Their Role in the VSCC Prognosis.

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.

Implication of the New AJCC pT Classification of SCC of the Lip Comparing With Other Oral Subsites.

OBJECTIVE: To determine the implication of the new AJCC staging system for pT classification in a cohort of patients with SCC of the lip mucosa and compare it to other oral cavity sites. METHODS: Retrospective cohort of 744 patients treated between 2002 and 2017, by the Head and Neck Surgery Department of the University of Sao Paulo. RESULTS: Of 95 lip patients, 42 had pT upstage (58.1% of pT1 to pT2-3 and 50% of pT2 to pT3). Similar DFS/OS observed for those pT1 maintained or upstaged to pT2-3, pT2 patients upstaged to pT3 presented worse OS (49.4% versus 92.3%, P = .032). The comparison between lip and other mouth topographies, denoted better prognosis for pT1-2, but not for pT3-4a. Lip tumors had lower DOI, rates of perineural/angiolymphatic invasion, nodal metastasis, recurrence, and death. CONCLUSION: The inclusion of DOI to the new pT classification better stratifies patients with SCC of the lip mucosa upstaged to pT3 by assessing inferior OS. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2770-E2776, 2021.

A novel 12-gene signature as independent prognostic model in stage IA and IB lung squamous cell carcinoma patients.

BACKGROUND: There is currently no formal consensus on the administration of adjuvant chemotherapy to stage I lung squamous cell carcinoma (LUSC) patients despite the poor prognosis. The side effects of adjuvant chemotherapy need to be balanced against the risk of tumour recurrence. Prognostic markers are thus needed to identify those at higher risks and recommend individualised treatment regimens. METHODS: Clinical and sequencing data of stage I patients were retrieved from the Lung Squamous Cell Carcinoma project of the Cancer Genome Atlas (TCGA) and three tissue microarray datasets. In a novel K-resample gene selection algorithm, gene-wise Cox proportional hazard regressions were repeated for 50 iterations with random resamples from the TCGA training dataset. The top 200 genes with the best predictive power for survival were chosen to undergo an L1-penalised Cox regression for further gene selection. RESULTS: A total of 602 samples of LUSC were included, of which 42.2% came from female patients, 45.3% were stage IA cancer. From an initial pool of 11,212 genes in the TCGA training dataset, a final set of 12 genes were selected to construct the multivariate Cox prognostic model. Among the 12 selected genes, 5 genes, STAU1, ADGRF1, ATF7IP2, MALL and KRT23, were adverse prognostic factors for patients, while seven genes, NDUFB1, CNPY2, ZNF394, PIN4, FZD8, NBPF26 and EPYC, were positive prognostic factors. An equation for risk score was thus constructed from the final multivariate Cox model. The model performance was tested in the sequestered TCGA testing dataset and validated in external tissue microarray datasets (GSE4573, GSE31210 and GSE50081), demonstrating its efficacy in stratifying patients into high- and low-risk groups with significant survival difference both in the whole set (including stage IA and IB) and in the stage IA only subgroup of each set. The prognostic power remains significant after adjusting for standard clinical factors. When benchmarked against other prominent gene-signature based prognostic models, the model outperformed the rest in the TCGA testing dataset and in predicting long-term risk at eight years in all three validation datasets. CONCLUSION: The 12-gene prognostic model may serve as a useful complementary clinical risk-stratification tool for stage I and especially stage IA lung squamous cell carcinoma patients to guide clinical decision making.

CDK1 promotes the stemness of lung cancer cells through interacting with Sox2.

OBJECTIVES: The promoting roles of cyclin dependent kinase 1 (CDK1) have been revealed in various tumors, however, its effects in the progression of cancer stem cells are still confusing. This work aims to explore the roles of CDK1 in regulating the stemness of lung cancer cells. METHODS: Online dataset analysis was performed to evaluate the correlation between CDK1 exression and the survival of lung cancer patients. RT-qPCR, western blot, cell viability, sphere-formation analysis and ALDH activity detection were used to investigate the roles of CDK1 on lung cancer cell stemness, viability and chemotherapeutic sensitivity. Immunocoprecipitation (Co-IP) analysis and rescuing experiments were performed to reveal the underlying mechanisms contributing to CDK1-mediated effects on lung cancer cell stemness. RESULTS: CDK1 mRNA expression was negatively correlated with the overall survival of lung cancer patients and remarkably increased in tumor spheres formed by lung cancer cells compared to the parental cells. Additionally, CDK1 positively regulated the stemness of lung cancer cells. Mechanistically, CDK1 could interact with Sox2 protein, but not other stemness markers (Oct4, Nanog and CD133). Furthermore, CDK1 increased the phosphorylation, cytoplasm-nuclear translocation and transcriptional activity of Sox2 protein in lung cancer cells. Moreover, CDK1 positively regulated the stemness of lung cancer cells in a Sox2-dependent manner. Finally, we revealed that inhibition of CDK1 enhanced the chemotherapeutic sensitivity, which was also rescued by Sox2 overexpression. CONCLUSIONS: This work reveals a novel CDK1/Sox2 axis responsible for maintaining the stemness of lung cancer cells.

The hidden curve behind COVID-19 outbreak: the impact of delay in treatment initiation in cancer patients and how to mitigate the additional risk of dying-the head and neck cancer model.

PURPOSE: The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time-to-treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model. METHODS: An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data. RESULTS: The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time-to-treatment initiation. CONCLUSIONS: This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model.

Is lung resection appropriate for late octogenarians? Surgical outcomes of patients aged ≥ 80 years with lung cancer.

PURPOSE: This study aimed to determine the outcomes and prognostic factors associated with octogenarians who underwent pulmonary resection for lung cancer. METHODS/PATIENTS: From 2009 to 2018, 76 octogenarians underwent pulmonary surgery for lung cancer at the Kanazawa Medical University, Japan. They were divided into two groups (early and late octogenarians), and their clinicopathological characteristics and outcomes were investigated. Overall survival rates and recurrence-free survival rates were determined using Kaplan-Meier curves. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Limited surgery was performed more often in the late octogenarian group; however, most perioperative factors were not significantly different between the two groups. The 3-year overall survival and recurrence-free survival rates were 61.2% and 52.8%, respectively. The median observation period was 37.5 (8.9-112.3) months postoperatively. Kaplan-Meier curves showed that age ≥ 85 years (late octogenarian), smoking history, and squamous cell carcinoma on histology were associated with worse survival rates. Multivariate analysis identified age ≥ 85 years (late octogenarian) (p = 0.011) and cigarette smoking (p = 0.025) as unfavorable prognostic factors for overall survival and recurrence-free survival, respectively. CONCLUSIONS: Most octogenarians with an indication for surgery can tolerate pulmonary surgery. However, owing to the limitations of this retrospective, single-center study, future studies involving multiple-institutions are required to confirm our findings.

Metformin use and lung cancer survival: a population-based study in Norway.

BACKGROUND: We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. METHODS: The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005-2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. RESULTS: Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62-0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47-0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73-0.95), in patients with SCC (HR = 0.75; 95%CI 0.57-0.98), regional stage LC (HR = 0.74; 95%CI 0.59-0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38-0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. CONCLUSIONS: Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.

Outcomes in Patients With Non-small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy.

BACKGROUND: Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited. PATIENTS AND METHODS: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation. RESULTS: Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy. CONCLUSIONS: Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.

Long-term outcomes of concomitant cisplatin plus radiotherapy versus radiotherapy alone in patients with stage IIIB squamous cervical cancer: A randomized controlled trial.

OBJECTIVE: The present analysis determined the disease free survival (DFS) and overall survival (OS) at up to 14 years of follow-up in women who participated in our previous phase 3 randomized controlled clinical trial, in which women with stage IIIB squamous cervical cancer received either cisplatin plus RT or RT alone for treatment. The first study showed that the addition of cisplatin to RT offered a significant benefit in DFS, but not in OS. METHODS: The present analysis examined DFS and OS in 146 women from the original cohort (72 patients in the CRT arm and 74 patients in the RT-only arm) with follow-up of up to 14 years. RESULTS: Longer term follow-up showed that treatment with CRT offers a significant benefit in DFS and OS compared with treatment with RT only. Patients who received RT alone had significantly worse OS (HR, 1.88; 95% CI, 1.09-3.24) and DFS (HR, 1.82; 95% CI, 1.07-3.08) compared with patients who received CRT. The multivariate analyses also showed that the patients with baseline Karnofsky performance status (KPS) <90% showed significantly worse OS (HR, 3.11; 95% CI, 1.78-5.43), as did those with hemoglobin <10 mg/dL (HR, 4.32; 95% CI, 2.23-8.36). Patients with baseline KPS < 90% showed significantly worse DFS (HR, 2.83; 95% CI, 1.60-5.01), as did those with hemoglobin <10 mg/dL (HR, 4.16; 95% CI, 2.17-7.95). CONCLUSIONS: For stage IIIB cervical cancer, treatment with CRT offers a significant benefit in DFS and OS compared with treatment with RT only.

Penile cancer trends and economic burden in the Brazilian public health system.

OBJECTIVE: To gather information on penile cancer epidemiologic trends and its economic impact on the Brazilian Public Health System across the last 25 years. METHODS: The Brazilian Public Health System database was used as the primary source of data from January 1992 to December 2017. Mortality and incidence data from the Instituto Nacional de Câncer José Alencar Gomes da Silva was collected using the International Classification of Diseases ICD10 C60. Demographic data from the Brazilian population was obtained from the last census by the Brazilian Institute of Geography and Statistics, performed in 2010 and its 2017 review. RESULTS: There were 9,743 hospital admissions related to penile cancer from 1992 to 2017. There was a reduction (36%) in the absolute number of admissions per year related to penile cancer in 2017, as compared to 1992 (2.7versus 1.7 per 100,000; p<0.001). The expenses with admissions related to this condition in this period were US$ 3,002,705.73 (US$ 115,488.68/year). Approximately 38% of the total amount was spent in Northeast Region. In 1992, penile cancer costed US$ 193,502.05 to the public health system, while in 2017, it reduced to US$ 47,078.66 (p<0.02). Penile cancer incidence in 2017 was 0.43/100,000 male Brazilian, with the highest incidence rate found in the Northeast Region. From 1992 to 2017, the mortality rates of penile cancer in Brazil were 0.38/100,000 man, and 0.50/100,000 man in the North Region. CONCLUSION: Despite the decrease in admissions, penile cancer still imposes a significant economic and social burden to the Brazilian population and the Public Health System.

Ulcera de Marjolin (carcinoma escamoso) sobre eventración abdominal / Marjolin ulcer (squamous carcinoma) over abdominal hernia

Introducción: Las úlceras de Marjolin son neoplasias cutáneas que asientan sobre pieles afectadas por úlceras crónicas, quemaduras, cicatrices, estasis venosa o heridas cutáneas. Generalmente se diagnostica por medio de biopsias, siendo los carcinomas escamosos la variedad más frecuente. Existe escasa información sobre su desarrollo en heridas quirúrgicas abdominales previas, y aún menos casos reportados de su aparición sobre un defecto de la pared abdominal. Objetivo: Reporte de un caso de un paciente con antecedente de múltiples cirugías abdominales que desarrolló un carcinoma escamoso sobre cicatriz de laparotomía previa. Pacientes y Métodos: Presentación de un de un paciente masculino de 61 años, con antecedente de laparotomía exploradora, que consultó por una tumoración, de 6 meses de evolución, vegetante sobre eventración de mediana suprainfraumbilical. Se realiza exéresis de lesión en bloque de pared con enterectomia, anastomosis primaria y eventroplastia con malla de reemplazo. Cursa internación prolongada y con mala evolución, falleciendo al 77 día postoperatorio. Conclusión: Los carcinomas de células escamosas que se desarrollan sobre lesiones cutáneas previas presentan una agresividad mayor a aquellos desarrollados espontáneamente, tienen alto porcentaje de recidiva y metástasis asociadas. Se propone abordajes quirúrgicos radicales para su tratamiento, aun asi presentando una morbimortalidad elevada

Background: Marjolin ulcers are skin malignancies that appear on skin affected by chronic ulcers, burns, scars, venous stasis or skin wounds. They are generally diagnosed through a biopsy and the most frequent type is the squamous cell carcinoma. There is little information on its development in existing abdominal surgical wounds, and there are even fewer cases reported in relation to its appearance upon an abdominal wall defect. Objective: To report a case of a patient with a history of multiple abdominal surgeries who developed a squamous cell carcinoma in an existing laparotomy scar in association with an incisional hernia. Patient and Methods: A 61-year-old male patient, with history of an exploratory laparotomy in 1986, presents with a 6-month-old vegetating tumor upon a supra-infraumbilical median eventration. An excision of the lesion that included the abdominal wall and an associated enterectomy, primary anastomosis, and eventroplasty with replacement mesh was performed. During his prolonged hospital stay, he underwent with many medical intercurrences and even an additional surgery was needed. Eventually, the patient dies 77 days after the surgery. Conclusion: Squamous cell carcinomas that develop in existing skin lesions tend to be more aggressive than those that develop spontaneously. They have a high percentage of recurrence and associated metastases. Radical surgical approaches are suggested for its treatment, although it has a high morbidity and mortality rate.

Role of a genetic variation in the microRNA-4421 binding site of ERP29 regarding risk of oropharynx cancer and prognosis.

We conducted a two-stage association study on patients with oropharynx (OP) squamous cell carcinoma (SCC) and healthy controls to identify single nucleotide variants (SNVs) located at the microRNA (miR)-binding sites of carcinogenesis genes associated with risk and prognosis of the disease. In stage 1, 49 patients and 49 controls were analyzed using Genome-Wide Human SNV Arrays to identify variants in the 3'-untranslated region (3'-UTR) of carcinogenesis-related genes, and one SNV was selected for data validation in stage 2 by TaqMan assays in 250 OPSCC patients and 250 controls. The ERP29 c.*293A > G (rs7114) SNV located at miR-4421 binding site was selected for data validation among 46 SNVs. The ERp29 and miR-4421 levels were evaluated by quantitative-PCR and Western blotting. Interaction between miR-4421 with 3'-UTR of ERP29 was evaluated by luciferase reporter assay. Event-free survival (EFS) was calculated by Kaplan-Meier and Cox methods. ERP29 GG variant genotype was more common in OPSCC patients than in controls (6.4% vs 3.6%, p = 0.02; odds ratio: 5.67; 95% confidence interval (CI) 1.27-25.26). Shorter EFS were seen in the base of tongue (BT) SCC patients with GG genotype (0.0% vs 36.2%, p = 0.01; hazard ratio: 2.31; 95% CI: 1.03-5.15). Individuals with ERP29 AG or GG genotypes featured lower levels of ERP29 mRNA (p = 0.005), ERp29 protein (p < 0.001) and higher levels of miR-4421 (p = 0.02). The miR-4421 showed more efficient binding with 3'-UTR of the variant G allele when compared with wild-type allele A (p = 0.001). Our data suggest that ERP29 rs7114 SNV may alter the risk and prognosis of OPSCC due to variation in the ERp29 production possibly modulated by miR-4421.

Cell-in-cell phenomenon associates with aggressive characteristics and cancer-related mortality in early oral tongue cancer.

BACKGROUND: Cell-in-cell structures (caused by cell cannibalistic activity) have been related to prognosis of many cancers. This is the first multi-institutional study to assess the prognostic impact of cell-in-cell structures in a large cohort of early oral tongue squamous cell carcinomas (OTSCC). METHODS: A total of 308 cases from five Finnish University Hospitals and from the A.C. Camargo Cancer Center, São Paulo, Brazil, were included in this study. Cell-in-cell structures were evaluated on surgical postoperative sections that stained with hematoxylin and eosin staining. RESULTS: We found that cell-in-cell structures associated with cancer-related mortality in univariable analysis with a hazard ratio (HR) of 2.99 (95%CI 1.52-5.88; P = 0.001). This association was confirmed in multivariable analysis (HR 2.22, 95%CI 1.12-4.44; P = 0.024). In addition, statistically significant associations were observed between the cell-in-cell structures and other adverse histopathologic characteristics including deep invasion (P <  0.001), high index of tumor budding (P = 0.007), worst pattern of invasion (P <  0.001), perineural invasion (P = 0.01), and stroma-rich pattern (P = 0.001). CONCLUSIONS: Our findings demonstrate a significant relationship between cell-in-cell formation and aggressive characteristics of early OTSCC. Cell-in-cell structures have a distinct impact as a novel prognostic indicator in early OTSCC and they can be easily assessed during routine pathology practice.

Análisis de supervivencia de carcinoma escamoso de laringe en una cohorte retrospectiva chilena del Hospital Carlos Van Buren de Valparaíso / Survival analysis of laryngeal squamous cell carcinoma in a chilean retrospective cohort at the Carlos Van Buren Hospital of Valparaíso

Resumen Introducción: El cáncer laríngeo es una de las neoplasias de cabeza y cuello más frecuentes, asociado al envejecimiento y a los hábitos de vida. Los análisis de supervivencia de cáncer laríngeo en Chile son escasos. Objetivo: Calcular y analizar la supervivencia y las características clínicas del cáncer laríngeo en pacientes del Servicio de Otorrinolaringología del Hospital Carlos Van Buren, Valparaíso, Chile. Material y Método: Se realizó un estudio retrospectivo de cohorte, incluyendo pacientes diagnosticados con carcinoma escamoso de laringe entre 2007 y 2018. Se calculó la supervivencia con el método de Kaplan-Meier. Se aplicaron las pruebas de log rank, t de Student y exacta de Fisher. Resultados: Se incluyeron 211 pacientes, 90,52% hombres, con un promedio de edad de 68 años. El factor de riesgo más frecuente fue el tabaquismo. La ubicación tumoral más frecuente fue la glotis (59,44%) y el motivo de consulta más común la disfonía (52,66%). Un 70,48% presentó estadios avanzados. En 23,92% se realizó laringectomía total como tratamiento primario. La supervivencia global a 2 años fue de 86,6% en estadio precoz y 45,2% en estadio avanzado, mientras que a 5 años fue de 77,4% y 33%, respectivamente. Conclusión: La supervivencia estimada fue menor que en otros estudios nacionales, lo que puede asociarse al tamaño de la muestra analizada, a factores etarios y/o a mayor latencia de inicio de tratamiento. Se enfatiza el mejoramiento de los registros clínicos y la gestión sanitaria para un manejo oportuno.

Abstract Introduction: Laryngeal carcinoma is one of the most frequent head and neck neoplasms, being associated with ageing and lifestyles. In Chile, survival analyses of laryngeal carcinoma are scarce. Aim: To estimate and analyze the survival and clinical characteristics of laryngeal carcinoma in patients attended at the Otorhinolaryngology Department of the Carlos Van Buren Hospital, Valparaíso, Chile. Material and Method: We conducted a retrospective cohort study, including patients diagnosed with laryngeal squamous cell carcinoma between 2007 and 2018. Kaplan-Meier estimator was applied for survival analysis. Log rank test, Student's t-test and Fisher's exact test were applied. Results: 211 patients were included, 90,52% were men, with an average age of 68 years. The main risk factor was smoking (80%). The most frequent tumor location was in the glottis (59,44%) and the most frequent reason for consultation was dysphonia (52,66%). Most cases (70,48%) presented at advanced stages. Laryngectomy was performed as a primary treatment in 23,92%. The 2-year overall survival rate was 86,6% for early stages and 45,2% for advanced stages; the 5-year overall survival rate was 77,4% and 33%, respectively. Conclusion: The estimated survival rate was lower than those referred by other national studies, which may be associated with the analyzed sample size, age-related factors and/or period of latency until the beginning of treatment. We emphasize the necessity of an improvement in clinical records and the health management to the timely treatment.

Adipose-derived mesenchymal stem cells promote the malignant phenotype of cervical cancer.

Epidemiological studies indicate that obesity negatively affects the progression and treatment of cervical-uterine cancer. Recent evidence shows that a subpopulation of adipose-derived stem cells can alter cancer properties. In the present project, we described for the first time the impact of adipose-derived stem cells over the malignant behavior of cervical cancer cells. The transcriptome of cancer cells cultured in the presence of stem cells was analyzed using RNA-seq. Changes in gene expression were validated using digital-PCR. Bioinformatics tools were used to identify the main transduction pathways disrupted in cancer cells due to the presence of stem cells. In vitro and in vivo assays were conducted to validate cellular and molecular processes altered in cervical cancer cells owing to stem cells. Our results show that the expression of 95 RNAs was altered in cancer cells as a result of adipose-derived stem cells. Experimental assays indicate that stem cells provoke an increment in migration, invasion, angiogenesis, and tumorigenesis of cancer cells; however, no alterations were found in proliferation. Bioinformatics and experimental analyses demonstrated that the NF-kappa B signaling pathway is enriched in cancer cells due to the influence of adipose-derived stem cells. Interestingly, the tumor cells shift their epithelial to a mesenchymal morphology, which was reflected by the increased expression of specific mesenchymal markers. In addition, stem cells also promote a stemness phenotype in the cervical cancer cells. In conclusion, our results suggest that adipose-derived stem cells induce cervical cancer cells to acquire malignant features where NF-kappa B plays a key role.

Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGF-A in cervical cancer patient survival: a competing risk analysis.

BACKGROUND: Expression of matrix metalloproteases 2, 9 and 14 (MMP-2, MMP-9, MMP-14), tissue inhibitors of metalloprotease 1 and 2 (TIMP-1, TIMP-2) and vascular endothelial growth factor A (VEGF-A) is involved in tumor invasion and metastasis via extracellular matrix degradation and angiogenesis. This study aimed to assess whether the expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2 in tumors and in the adjacent stroma is associated with cervical cancer prognosis. METHODS: This study analyzed a retrospective cohort of 64 patients. Protein expression was previously obtained by immunohistochemistry from biopsies containing both tumor and stroma. The expression and percentage of stained cells were categorized as high or low according to the cutoff points by using ROC curves. The follow-up data was collected from diagnosis to the last clinical visit. Clinical status categorized as alive without disease, alive with disease, death due to other causes, and death from the disease. The relative risk of death from the disease was evaluated according to the proteins expression using a cause-specific Cox regression model with a 95% confidence interval (95%CI). For the significant associations (p < 0.05), survival curves of patients with low and high expression were plotted for the competing risk survival curve analyses. RESULTS: High expression levels of stromal MMP-2 (RR; 95%CI: 3.91; 1.17-13.02) and stromal TIMP-2 (RR, 95%CI: 8.67; 1.15-65.27) were associated with a greater relative risk of death from the disease and with lower survival (p = 0.03; p = 0.04) than lower expression levels. Low expression levels of stromal MMP-9 (RR, 95%CI: 0.19; 0.05-0.65) and tumoral MMP-9 (HR, 95%CI: 0.19; 0.04-0.90) were protective factors against death from the disease and were associated with poorer survival. CONCLUSIONS: High expression levels of MMP-2 and TIMP-2 in the stroma were significantly associated with poor survival in cervical cancer patients. High expression of MMP-9 was associated with a favorable cervical cancer prognosis.

Impact of treatment modality on survival in patients with stage IV laryngeal cancer: A population-based propensity score analysis.

INTRODUCTION: The treatment of advanced stage laryngeal suffered a major shift away from surgery and towards larynx-preservation alternatives after the publication of major clinical trials. But its applicability in real-world situations is not consensual. MATERIALS AND METHODS: We reviewed a population-based database from Brazil regarding patients treated for laryngeal cancer and selected those with stage IV disease at presentation. Survival analysis was realized by the Cox proportional hazards method and propensity scores were used to compensate for non-random allocation to different treatment arms. RESULTS: A total of 5577 patients were included in the analyses, with 4243 staged as CS IVa, 1010 as CS IVb and 324 as CS IVc. In univariate and multivariate analysis, gender, cT stage, cN stage, cM stage and treatment modality were significant predictors of disease-specific survival. In patients with CS IVa, age, gender, payment modality, location within the larynx, cT and cN stages and treatment modality were significant. After propensity score adjustment, treatment modality remained significant, favoring primary surgery with disease-specific survival (HR: 0.5041, 95% CI: 0.4494-0.5644, p < 0.001) and overall survival (HR: 0.5485, 95% CI: 0.4955-0.6072, p < 0.001) as outcomes of interest. Patients staged as cT4a cN0 were selected and analyzed as a distinct subset. In multivariate analysis, treatment modality was the only variable with significant prognostic impact with improved outcome for surgery-based treatment (HR: 2.521, 95% CI: 1.897-3.350, p < 0.001). CONCLUSIONS: The extrapolation of clinical trials to the real-world facilities must be carefully weighted. The setting of trial conduction may influence its outcome and may not be reproducible. Our results show that patient selection and the facilities of clinical trials may play a significant role in the success of non-surgical approaches to non-metastatic stage IV laryngeal cancer.

Elemental characterization of oral cavity squamous cell carcinoma and its relationship with smoking, prognosis and survival.

Oral cancer squamous cell carcinoma (OCSCC) mainly affects individuals aged between 50 and 70 years who consume tobacco and alcohol. Tobacco smoke contains hundreds of known toxic and carcinogenic molecules, and a few studies have sought to verify the relationship of such trace elements as risk or prognostic factors for head and neck cancer. We obtained 78 samples of tumor tissues from patients with OCSCC, and performed a qualitative elemental characterization using the micro X-Ray Fluorescence technique based on synchrotron radiation. We found the presence of magnesium, phosphorus, sulfur, chlorine, potassium, calcium, chromium, manganese, iron, zinc, cobalt, nickel, copper, arsenic and bromine in OCSCC samples. Magnesium, chlorine, chromium, manganese, nickel, arsenic and bromine are associated with smoking. We observed a significant association between relapse and chlorine and chromium. The presence of chlorine in the samples was an independent protective factor against relapse (OR = 0.105, CI = 0.01-0.63) and for best disease-free survival (HR = 0.194, CI = 0.04-0.87). Reporting for the first time in oral cancer, these results suggest a key relationship between smoking and the presence of certain elements. In addition, chlorine proved to be important in the context of patient prognosis and survival.