Tumor mutational burden predictability in head and neck squamous cell carcinoma patients treated with immunotherapy: systematic review and meta-analysis.

BACKGROUND: Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. METHODS: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. RESULTS: The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74-3.94; p < 0.0001) and a survival advantage (HR = 0.53; 95% CI 0.39-0.71; p < 0.0001) after ICI treatment. CONCLUSION: This is the first meta-analysis to demonstrate a higher response and clinical benefit from ICI therapy in HNSCC patients with high TMB.

Association of neurocognitive disorders with morbidity and mortality in older adults undergoing major surgery in the USA: a retrospective, population-based, cohort study.

BACKGROUND: Neurocognitive disorders become increasingly common as patients age, and increasing numbers of surgical interventions are done on older patients. The aim of this study was to understand the clinical characteristics and outcomes of surgical patients with neurocognitive disorders in the USA in order to guide future targeted interventions for better care. METHODS: This retrospective cohort study used claims data for US Medicare beneficiaries aged 65 years and older with a record of inpatient admission for a major diagnostic or therapeutic surgical procedure between Jan 1, 2017, and Dec 31, 2018. Data were retrieved through a data use agreement between Dartmouth Hitchcock Medical Center and US Centers for Medicare and Medicaid Services via the Research Data Assistance Center. The exposure of interest was the presence of a pre-existing neurocognitive disorder as defined by diagnostic code within 3 years of index hospital admission. The primary outcome was mortality at 30 days, 90 days, and 365 days from date of surgery among all patients with available data. FINDINGS: Among 5 263 264 Medicare patients who underwent a major surgical procedure, 767 830 (14·59%) had a pre-existing neurocognitive disorder and 4 495 434 (85·41%) had no pre-existing neurocognitive disorder. Adjusting for demographic factors and comorbidities, patients with a neurocognitive disorder had higher 30-day (hazard ratio 1·24 [95% CI 1·23-1·25]; p<0·0001), 90-day (1·25 [1·24-1·26]; p<0·0001), and 365-day mortality (1·25 [1·25-1·26]; p<0·0001) compared with patients without a neurocognitive disorder. INTERPRETATION: Our findings suggest that the presence of a neurocognitive disorder is independently associated with an increased risk of mortality. Identification of a neurocognitive disorder before surgery can help clinicians to better disclose risks and plan for patient care after hospital discharge. FUNDING: Department of Anesthesiology and Perioperative Medicine at Dartmouth Hitchcock Medical Center.

Medium and long-term prognosis in hospitalised older adults with multimorbidity. A prospective cohort study.

BACKGROUND: Data about long-term prognosis after hospitalisation of elderly multimorbid patients remains scarce. OBJECTIVES: Evaluate medium and long-term prognosis in hospitalised patients older than 75 years of age with multimorbidity. Explore the impact of gender, age, frailty, physical dependence, and chronic diseases on mortality over a seven-year period. METHODS: We included prospectively all patients hospitalised for medical reasons over 75 years of age with two or more chronic illnesses in a specialised ward. Data on chronic diseases were collected using the Charlson comorbidity index and a questionnaire for disorders not included in this index. Demographic characteristics, Clinical Frailty Scale, Barthel index, and complications during hospitalisation were collected. RESULTS: 514 patients (46% males) with a mean age of 85 (± 5) years were included. The median follow-up was 755 days (interquartile range 25-75%: 76-1,342). Mortality ranged from 44% to 68%, 82% and 91% at one, three, five, and seven years. At inclusion, men were slightly younger and with lower levels of physical impairment. Nevertheless, in the multivariate analysis, men had higher mortality (p<0.001; H.R.:1.43; 95% C.I.95%:1.16-1.75). Age, Clinical Frailty Scale, Barthel, and Charlson indexes were significant predictors in the univariate and multivariate analysis (all p<0.001). Dementia and neoplastic diseases were statistically significant in the unadjusted but not the adjusted model. In a cluster analysis, three patterns of patients were identified, with increasing significant mortality differences between them (p<0.001; H.R.:1.67; 95% CI: 1.49-1.88). CONCLUSIONS: In our cohort, individual diseases had a limited predictive prognostic capacity, while the combination of chronic illness, frailty, and physical dependence were independent predictors of survival.

Variables associated with cortical motor mapping thresholds: A retrospective data review with a unique case of interlimb motor facilitation.

Introduction: Intraoperative neuromonitoring (IONM) is crucial to preserve eloquent neurological functions during brain tumor resections. We observed a rare interlimb cortical motor facilitation phenomenon in a patient with recurrent high-grade glioma undergoing craniotomy for tumor resection; the patient's upper arm motor evoked potentials (MEPs) increased in amplitude significantly (up to 44.52 times larger, p < 0.001) following stimulation of the ipsilateral posterior tibial nerve at 2.79 Hz. With the facilitation effect, the cortical MEP stimulation threshold was reduced by 6 mA to maintain appropriate continuous motor monitoring. It likely has the benefit of reducing the occurrence of stimulation-induced seizures and other adverse events associated with excessive stimulation. Methods: We conducted a retrospective data review including 120 patients who underwent brain tumor resection with IONM at our center from 2018 to 2022. A broad range of variables collected pre-and intraoperatively were reviewed. The review aimed to determine: (1) whether we overlooked this facilitation phenomenon in the past, (2) whether this unique finding is related to any specific demographic information, clinical presentation, stimulation parameter (s) or anesthesia management, and (3) whether it is necessary to develop new techniques (such as facilitation methods) to reduce cortical stimulation intensity during intraoperative functional mapping. Results: There is no evidence suggesting that clinical presentation, stimulation configuration, or intraoperative anesthesia management of the patient with the facilitation effect were significantly different from our general patient cohort. Even though we did not identify the same facilitation effect in any of these patients, we were able to determine that stimulation thresholds for motor mapping are significantly associated with the location of stimulation (p = 0.003) and the burst suppression ratio (BSR) (p < 0.001). Stimulation-induced seizures, although infrequent (4.05%), could occur unexpectedly even when the BSR was 70%. Discussion: We postulated that functional reorganization and neuronal hyperexcitability induced by glioma progression and repeated surgeries were probable underlying mechanisms of the interlimb facilitation phenomenon. Our retrospective review also provided a practical guide to cortical motor mapping in brain tumor patients under general anesthesia. We also underscored the need for developing new techniques to reduce the stimulation intensity and, hence, seizure occurrence.

Learning the Treatment Impact on Time-to-Event Outcomes: The Transcarotid Artery Revascularization Simulated Cohort.

Proportional hazard Cox regression models are overwhelmingly used for analyzing time-dependent outcomes. Despite their associated hazard ratio is a valuable index for the difference between populations, its strong dependency on the underlying assumptions makes it a source of misinterpretation. Recently, a number of works have dealt with the subtleties and limitations of this interpretation. Besides, a number of alternative indices and different Cox-type models have been proposed. In this work, we use synthetic data, motivated by a real-world problem, for showing the strengths and weaknesses of some of those methods in the analysis of time-dependent outcomes. We use the power of synthetic data for considering observable results but also utopian designs.

Impact of Spirometrically Confirmed Chronic Obstructive Pulmonary Disease on Arterial Stiffness and Surfactant Protein D After Percutaneous Coronary Intervention. The CATEPOC Study.

Background: Several mechanisms have been proposed to explain why chronic obstructive pulmonary disease (COPD) impairs the prognosis of coronary events. We aimed to explore COPD variables related to a worse prognosis in patients undergoing percutaneous coronary intervention (PCI). Methods: Patients with an acute coronary event treated by PCI were prospectively included. One month after discharge, clinical characteristics, comorbidities measured with the Charlson index, and prognostic coronary scales (logistic EuroSCORE; GRACE 2.0) were collected. Post-bronchodilator spirometry, arterial stiffness, and serum inflammatory and myocardial biomarkers were measured. Lung plasmatic biomarkers (Surfactant protein D, desmosine, and Clara cell secretory protein-16) were determined with ELISA. COPD was defined by the fixed ratio (FEV1/FVC <70%). Spirometric values were also analyzed as continuous variables using adjusted and non-adjusted ANCOVA analysis. Finally, we evaluated the presence of a respiratory pattern defined by non-stratified spirometric values and pulmonary biomarkers. Results: A total of 164 patients with a mean age of 65 (±10) years (79% males) were included. COPD was diagnosed in 56 (34%) patients (68% previously undiagnosed). COPD patients had a longer smoking history, higher scores on the EuroSCORE (p < 0.0001) and GRACE 2.0 (p < 0.001) scales, and more comorbidities (p = 0.006). Arterial stiffness determined by pulse wave velocity was increased in COPD patients (7.35 m/s vs 6.60 m/s; p = 0.006). Serum values of high sensitive T troponin (p = 0.007) and surfactant protein D (p = 0.003) were also higher in COPD patients. FEV1% remained significantly associated with arterial stiffness and surfactant protein D in the adjusted ANCOVA analysis. In the cluster exploration, 53% of the patients had a respiratory pattern. Conclusion: COPD affects one-third of patients with an acute coronary event and frequently remains undiagnosed. Several mechanisms, including arterial stiffness and SPD, were increased in COPD patients. Their relationship with the prognosis should be confirmed with longitudinal follow-up of the cohort.

Arsenic exposure and respiratory outcomes during childhood in the INMA study.

Ingested inorganic arsenic (iAs) is a human carcinogen that is also linked to other adverse health effects, such as respiratory outcomes. Yet, among populations consuming low-arsenic drinking water, the impact of iAs exposure on childhood respiratory health is still uncertain. For a Spanish child study cohort (INfancia y Medio Ambiente-INMA), low-arsenic drinking water is usually available and ingestion of iAs from food is considered the major source of exposure. Here, we explored the association between iAs exposure and children's respiratory outcomes assessed at 4 and 7 years of age (n = 400). The summation of 4-year-old children's urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) was used as a biomarker of iAs exposure (∑As) (median of 4.92 µg/L). Children's occurrence of asthma, eczema, sneeze, wheeze, and medication for asthma and wheeze at each assessment time point (i.e., 4- and 7-year) was assessed with maternal interviewer-led questionnaires. Crude and adjusted Poisson regression models using Generalized Estimating Equation (GEE) were performed to account for the association between natural logarithm transformed (ln) urinary ∑As in µg/L at 4 years and repeated assessments of respiratory symptoms at 4 and 7 years of age. The covariates included in the models were child sex, maternal smoking status, maternal level of education, sub-cohort, and children's consumption of vegetables, fruits, and fish/seafood. The GEE-splines function using Poisson regression showed an increased trend of the overall expected counts of respiratory symptoms with high urinary ∑As. The adjusted expected counts (95% confidence intervals) at ln-transformed urinary ∑As 1.57 (average concentration) and 4.00 (99th percentile concentration) were 0.63 (0.36, 1.10) and 1.33 (0.61, 2.89), respectively. These exploratory findings suggest that even relatively low-iAs exposure levels, relevant to the Spanish and other populations, may relate to an increased number of respiratory symptoms during childhood.

Confirmatory Mediastinoscopy after Negative Endobronchial Ultrasound-guided Transbronchial Needle Aspiration for Mediastinal Staging of Lung Cancer: Systematic Review and Meta-analysis.

Rationale: Current guidelines for non-small cell lung cancer (NSCLC) mediastinal staging recommend starting invasive staging with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, the indication to confirm a negative result of EBUS-TBNA by means of video-assisted mediastinoscopy (VAM) before resection differs in every guideline. Objectives: Our aim was to evaluate the current evidence regarding the added value of confirmatory VAM after a negative EBUS-TBNA result for mediastinal staging in patients with NSCLC. Methods: Systematic searches of studies on EBUS-TBNA for NSCLC mediastinal staging with or without confirmatory VAM but with surgical confirmation of negative results were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement in PubMed, SCOPUS, the Cochrane Library, and guidelines from 2005 through November 2021. In the meta-analysis, the sensitivity of confirmatory VAM after a negative EBUS-TBNA result, as well as the sensitivity and negative predictive value of the combination EBUS-TBNA plus confirmatory VAM, alongside the number of confirmatory VAMs required to detect additional N2/3 disease (number needed to treat [NNT]), in patients with a previous negative EBUS-TBNA result were estimated. Results: A total of 5,412 articles were found, of which 29 studies were included. Random effects meta-analysis showed a sensitivity of 66.9% (95% confidence interval [CI], 55.8-77.1%) for confirmatory VAM, and 96.7% (95% CI, 95.1-98%) for the combination EBUS-TBNA plus confirmatory VAM. Negative predictive value in studies with confirmatory VAM increased of 79.2% (95% CI, 71.4-86.1%) for EBUS-TBNA alone to 91.8% (95% CI, 87.1-95.5%) for EBUS-TBNA plus confirmatory VAM. The NNT of confirmatory VAM in patients with a previous negative EBUS-TBNA result was 23.8 (95% CI, 19.3-31.2). Conclusions: Confirmatory VAM after negative EBUS-TBNA reduces the rate of unforeseen N2/3 disease, but with a high NNT, and it should be recommended only for certain cases yet to be defined.

A robust hazard ratio for general modeling of survival-times.

Hazard ratios (HR) associated with the well-known proportional hazard Cox regression models are routinely used for measuring the impact of one factor of interest on a time-to-event outcome. However, if the underlying real model does not fit with the theoretical requirements, the interpretation of those HRs is not clear. We propose a new index, gHR, which generalizes the HR beyond the underlying survival model. We consider the case in which the study factor is a binary variable and we are interested in both the unadjusted and adjusted effect of this factor on a time-to-event variable, potentially, observed in a right-censored scenario. We propose non-parametric estimations for unadjusted gHR and semi-parametric regression-induced techniques for the adjusted case. The behavior of those estimators is studied in both large and finite sample situations. Monte Carlo simulations reveal that both estimators provide good approximations of their respective inferential targets. Data from the Health and Lifestyle Study are used for studying the relationship of the tobacco use and the age of death and illustrate the practical application of the proposed technique. gHR is a promising index which can help facilitate better understanding of the association of one study factor on a time-dependent outcome.

Prenatal exposure to arsenic and lung function in children from the New Hampshire Birth Cohort Study.

Prenatal arsenic exposure is associated with an increased risk of lung cancer along with multiple non-carcinogenic outcomes, including respiratory diseases in arsenic-contaminated areas. Limited epidemiologic data exist on whether in utero arsenic exposure influences lung development and subsequent respiratory health. We investigated the association between gestational arsenic exposure and childhood lung function in the New Hampshire Birth Cohort Study. Urinary arsenic speciation including inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and arsenobetaine was measured in maternal urine samples collected during pregnancy and spirometry was performed in offspring at a median age of 7.4 years. Forced vital capacity (FVC), forced expiratory volume in the first second of exhalation (FEV1), and forced expiratory flow between 25% and 75% of FVC (FEF25-75) standardized z-scores were assessed in linear models as dependent variables with the log2-transformed summation of urinary arsenic species (ΣAs = iAs + MMA + DMA) corrected for specific gravity as an independent variable and with adjustment for maternal smoking status, children's age, sex and height. Among the 358 children in the study, a doubling of ΣAs was associated with a -0.08 (ß) decrease in FVC z-scores (95% confidence interval (CI) from -0.14 to -0.01) and -0.10 (ß) (95% CI from -0.18 to -0.02) decrease in FEV1 z-scores. The inverse association appeared stronger among those mothers with lower secondary methylation index (urinary DMA/MMA), especially among girls. No association was observed for FEF25-75 z-scores. Our results suggest that gestation arsenic exposure at levels relevant to the general US population during the vulnerable period of lung formation may adversely affect lung function in childhood.

Long-term Reintervention After Endovascular Abdominal Aortic Aneurysm Repair.

OBJECTIVE: To describe the long-term reintervention rate after endovascular abdominal aortic aneurysm repair (EVR), and identify factors predicting reintervention. SUMMARY OF BACKGROUND DATA: EVR is the most common method of aneurysm repair in America, and reintervention after EVR is common. Clinical factors predicting reintervention have not been described in large datasets with long-term follow-up. METHODS: We studied patients who underwent EVR using the Vascular Quality Initiative registry linked to Medicare claims. Our primary outcome was reintervention, defined as any procedure related to the EVR after discharge from the index hospitalization. We used classification and regression tree modeling to inform a multivariable Cox-regression model predicting reintervention after EVR. RESULTS: We studied 12,911 patients treated from 2003 to 2015. Mean age was 75.5 ±â€Š7.3 years, 79.9% were male, and 89.1% of operations were elective. The 3-year reintervention rate was 15%, and the 10-year rate was 33%. Five factors predicted reintervention: operative time ≥3.0 hours, aneurysm diameter ≥6.0 cm, an iliac artery aneurysm ≥2.0 cm, emergency surgery, and a history of prior aortic surgery. Patients with no risk factors had a 3-year reintervention rate of 12%, and 10-year rate of 26% (n = 7310). Patients with multiple risk factors, such as prior aortic surgery and emergent surgery, had a 3-year reintervention rate 72%, (n = 32). Modifiable factors including EVR graft manufacturer or supra-renal fixation were not associated with reintervention (P = 0.76 and 0.79 respectively). CONCLUSIONS: All patients retain a high likelihood of reintervention after EVR, but clinical factors at the time of repair can predict those at highest risk.

Five-year reintervention after endovascular abdominal aortic aneurysm repair in the Vascular Quality Initiative.

OBJECTIVE: Patients who undergo endovascular abdominal aortic aneurysm repair (EVR) remain at risk for reintervention and rupture. We sought to define the 5-year rate of reintervention and rupture after EVR in the Vascular Quality Initiative (VQI). METHODS: We identified all patients in the VQI who underwent EVR from 2003 to 2015. We linked patients in the VQI to Medicare claims for long-term outcomes. We stratified patients on baseline clinical and procedural characteristics to identify those at risk for reintervention. Our primary outcomes were 5-year rates of reintervention and late aneurysm rupture after EVR. We assessed these with Kaplan-Meier survival estimation. RESULTS: We studied 12,911 patients who underwent EVR. The mean age was 75.5 years, 79.9% were male, 3.9% were black, and 89.1% of operations were performed electively. The 5-year rate of reintervention for the entire cohort was 21%, and the 5-year rate of late aneurysm rupture was 3%. Reintervention rates varied across categories of EVR urgency. Patients who underwent EVR electively had the lowest 5-year rate of reintervention at 20%. Those who underwent surgery for symptomatic aneurysms had higher rates of reintervention at 25%. Patients undergoing EVR emergently for rupture had the highest rate of reintervention, 27% at 4 years (log-rank across the three groups, P < .001). Black race and aneurysm size of 6.0 cm or greater were associated with significantly elevated reintervention rates (black, 31% vs white, 20% [log-rank, P < .001]; aneurysm size 6.0 cm or greater, 27% vs all others, <20% [log-rank, P < .001]). There were no significant associations between age or gender and the 5-year rate of reintervention. CONCLUSIONS: More than one in five Medicare patients undergo reintervention within 5 years after EVR in the VQI; late rupture remains low at 3%. Black patients, those with large aneurysms, and those who undergo EVR urgently and emergently have a higher likelihood of adverse outcomes and should be the focus of diligent long-term surveillance.

Traditional Processed Meat Products Re-designed Towards Inulin-rich Functional Foods Reduce Polyps in Two Colorectal Cancer Animal Models.

Inulin-rich foods exert a prebiotic effect, as this polysaccharide is able to enhance beneficial colon microbiota populations, giving rise to the in situ production of short-chain fatty acids (SCFAs) such as propionic and butyric acids. These SCFAs are potent preventive agents against colorectal cancer due to their histone deacetylases inhibitory properties, which induce apoptosis in tumor colonocytes. As colorectal cancer is the fourth most common neoplasia in Europe with 28.2 new cases per 100,000 inhabitants, a cost-effective preventive strategy has been tested in this work by redesigning common porcine meat products (chorizo sausages and cooked ham) consumed by a substantial proportion of the population towards potential colorectal cancer preventive functional foods. In order to test the preventive effect of these inulin-rich meat products against colorectal cancer, an animal model (Rattus norvegicus F344) was used, involving two doses of azoxymethane (10 mg/kg) and two treatments with dextran sodium sulfate (DSS) during a 20-week assay period. Control feed, control sausages, functional sausages (15.7% inulin), control cooked ham and functional cooked ham (10% inulin) were used to feed the corresponding animal cohorts. Then, the animals were sacrificed and their digestive tract tissues were analyzed. The results showed a statistically significant 49% reduction in the number of colon polyps in the functional meat products cohorts with respect to the control meat products animals, as well as an increase in the cecum weight (an indicator of a diet rich in prebiotic fiber), a 51.8% increase in colon propionate production, a 39.1% increase in colon butyrate concentrations, and a reduction in the number of hyperplastic Peyer's patches. Metagenomics studies also demonstrated colon microbiota differences, revealing a significant increase in Bacteroidetes populations in the functional meat products (mainly due to an increase in Bacteroidaceae and Prevotellaceae families, which include prominent propionate producers), together with a reduction in Firmicutes (especially due to lower Lachnospiraceae populations). However, functional meat products showed a remarkable increase in the anti-inflammatory and fiber-fermentative Blautia genus, which belongs to this Lachnospiraceae family. The functional meat products cohorts also presented a reduction in important pro-inflammatory bacterial populations, such as those of the genus Desulfovibrio and Bilophila. These results were corroborated in a genetic animal model of CRC (F344/NSlc-Apc1588/kyo) that produced similar results. Therefore, processed meat products can be redesigned towards functional prebiotic foods of interest as a cost-effective dietary strategy for preventing colorectal cancer in human populations.

A comparative analysis of long-term mortality after carotid endarterectomy and carotid stenting.

BACKGROUND: The value of carotid intervention is predicated on long-term survival for patients to derive a stroke prevention benefit. Randomized trials report no significant difference in survival after carotid endarterectomy (CEA) vs carotid artery stenting (CAS), whereas observational studies of "real-world" outcomes note that CEA is associated with a survival advantage. Our objective was to examine long-term mortality after CEA vs CAS using a propensity-matched cohort. METHODS: We studied all patients who underwent CEA or CAS within the Vascular Quality Initiative from 2003 to 2013 (CEA, n = 29,235; CAS, n = 4415). Long-term mortality information was obtained by linking patients in the registry to their respective Medicare claims file. We assessed the long-term rate of mortality for CEA and CAS using Kaplan-Meier estimation. We assessed the crude, adjusted, and propensity-matched (total matched pairs, n = 4261) hazard ratio (HR) of mortality for CEA vs CAS using Cox regression. RESULTS: The unadjusted Kaplan-Meier estimated 5-year mortality was 14.0% for CEA and 18.3% for CAS. The crude HR of all-cause mortality for CEA vs CAS was 0.75 (95% confidence interval [CI], 0.70-0.81), indicating that patients who underwent CEA were 25% less likely to die before those who underwent CAS. This survival advantage persisted after adjustment for age, sex, and comorbidities (adjusted HR, 0.75; 95% CI, 0.69-0.82). This effect was confirmed on a propensity-matched analysis, with an HR of 0.76 (95% CI, 0.69-0.85). Finally, these findings were robust to subanalyses that stratified patients by presenting symptoms and were more pronounced in symptomatic patients (adjusted HR, 0.69; 95% CI, 0.61-0.79) than in asymptomatic patients (adjusted HR, 0.80; 95% CI, 0.71-0.90). CONCLUSIONS: During the last 15 years, patients who underwent CEA in the Vascular Quality Initiative have a long-term survival advantage over those who underwent CAS in real-world practice. Despite no difference in long-term survival in randomized trials, our observational study demonstrated a survival benefit for CEA that did not diminish with risk adjustment.

Correlation of focal adhesion kinase expression with nodal metastasis in patients with head and neck cutaneous squamous cell carcinoma.

BACKGROUND: Focal adhesion kinase (FAK) and cortactin overexpression is frequently detected in a variety of cancers, and has been associated with poor clinical outcome. However, there are no data in cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To investigate the relationship of FAK and cortactin expression with the clinicopathologic features and the impact on the prognosis of cSCC patients. METHODS: FAK and cortactin expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 100 patients with cSCC, and correlated with the clinical data. RESULTS: FAK overexpression was a significant risk factor for nodal metastasis with crude and adjusted ratios (HRs) of 2.04, (95% CI [1.08-3.86], [P = 0.029]) and 2.23 (95% CI [1.01-4.91], [P = 0.047]), respectively. Cortactin expression was not a significant risk factor for nodal metastasis. CONCLUSION: These findings demonstrate that FAK overexpression is an independent predictor of nodal metastasis that might be helpful for risk stratification and management of patients with cSCC.

Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Binding of tumor-expressed programmed cell death ligand 1 (PD-L1) to the programmed cell death 1 (PD-1) surface receptor blocks T-cell activation thereby leading to immune evasion. Tumor PD-L1 expression has been associated with poor outcome in a wide variety of cancers; however, data in cutaneous squamous cell carcinoma (cSCC) are scarce and conflicting. OBJECTIVE: To investigate the relationship of tumor PD-L1 expression with the clinicopathologic features and prognosis of cSCC. METHODS: PD-L1 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 100 patients with cSCC. Cumulative/dynamic receiver operating characteristic curve was used to determine the optimal PD-L1 threshold. Kaplan-Meier estimators and Cox proportional hazards regression models were also used. RESULTS: On the basis of cumulative/dynamic receiver operating characteristic curves, we defined the cut-off score for PD-L1 expression as ≥25% of tumor cells positively stained. PD-L1 expression was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios of 3.39 (1.71-6.65) and 6.54 (2.28-18.78), respectively. LIMITATIONS: This is a retrospective study limited to cSCC of the head and neck. CONCLUSION: These findings indicate that tumor PD-L1 expression predicts increased risk for nodal metastasis in patients with cSCC.

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure.

Cisplatin, one of the most extensively used metallodrugs in cancer treatment, presents the important drawback of patient resistance. This resistance is the consequence of different processes including those preventing the formation of DNA adducts and/or their quick removal. Thus, a tool for the accurate detection and quantitation of cisplatin-induced adducts might be valuable for predicting patient resistance. To prove the validity of such an assumption, highly sensitive plasma mass spectrometry (ICP-MS) strategies were applied to determine DNA adduct levels and intracellular Pt concentrations. These two metal-relative parameters were combined with an evaluation of biological responses in terms of genomic stability (with the Comet assay) and cell cycle progression (by flow cytometry) in four human cell lines of different origins and cisplatin sensitivities (A549, GM04312, A2780 and A2780cis), treated with low cisplatin doses (5, 10 and 20 µM for 3 hours). Cell viability and apoptosis were determined as resistance indicators. Univariate linear regression analyses indicated that quantitation of cisplatin-induced G-G intra-strand adducts, measured 1 h after treatment, was the best predictor for viability and apoptosis in all of the cell lines. Multivariate linear regression analyses revealed that the prediction improved when the intracellular Pt content or the Comet data were included in the analysis, for all sensitive cell lines and for the A2780 and A2780cis cell lines, respectively. Thus, a reliable cisplatin resistance predictive model, which combines the quantitation of adducts by HPLC-ICP-MS, and their repair, with the intracellular Pt content and induced genomic instability, might be essential to identify early therapy failure.

The adverse prognostic effect of tumor budding on the evolution of cutaneous head and neck squamous cell carcinoma.

BACKGROUND: Tumor budding is a readily detectable histopathologic feature that has been recognized as an adverse prognostic factor in several human cancers. OBJECTIVE: We sought to assess the correlation of tumor budding with the clinicopathologic features and the prognostic value of tumor budding in cutaneous squamous cell carcinoma (cSCC). METHODS: Forty-nine primary nonmetastatic and 49 primary metastatic cSCCs to regional lymph nodes were retrospectively studied. Statistical analyses were carried out to assess the relationship between tumor budding, clinicopathologic parameters, and patient survival. RESULTS: Tumor budding was observed in 45 cases of 98 (46%). High-intensity budding (≥5 tumor buds) was observed in 20 tumors. Presence of tumor buds was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios (HRs) of 8.92 (95% CI, 4.39-18.1) and 6.93 (95% CI, 3.30-14.5), respectively, and for reduced overall survival time (crude and adjusted HRs of 2.03 [95% CI, 1.26-3.28] and 1.72 [95% CI, 1.05-2.83], respectively). LIMITATIONS: This was a retrospective study limited to cSCCs of the head and neck. Examined tumors were >2 mm thick, and all were from a primary excision. CONCLUSION: These results indicate an increased frequency of nodal metastasis and risk of death in patients with tumor buds.