An Integrated Genomic Strategy to Identify CHRNB4 as a Diagnostic/Prognostic Biomarker for Targeted Therapy in Head and Neck Cancer

Although many studies have shown the association between smoking and the increased incidence and adverse prognosis of head and neck squamous cell carcinoma (HNSCC), the mechanisms and pharmaceutical targets involved remain unclear. Here, we integrated gene expression signatures, genetic alterations, and survival analyses to identify prognostic indicators and therapeutic targets for smoking HNSCC patients, and we discovered that the FDA-approved drug varenicline inhibits the target for cancer cell migration/invasion. We first identified 18 smoking-related and prognostic genes for HNSCC by using RNA-Seq and clinical follow-up data. One of these genes, CHRNB4 (neuronal acetylcholine receptor subunit beta-4), increased the risk of death by approximately threefold in CHRNB4-high expression smokers compared to CHRNB4-low expression smokers (log rank, p = 0.00042; hazard ratio, 2.82; 95% CI, 1.55–5.14), former smokers, and non-smokers. Furthermore, we examined the functional enrichment of co-regulated genes of CHRNB4 and its 246 frequently occurring copy number alterations (CNAs). We found that these genes were involved in promoting angiogenesis, resisting cell death, and sustaining proliferation, and contributed to much worse outcomes for CHRNB4-high patients. Finally, we performed CHRNB4 gene editing and drug inhibition assays, and the results validate these observations. In summary, our study suggests that CHRNB4 is a prognostic indicator for smoking HNSCC patients and provides a potential new therapeutic drug to prevent recurrence or distant metastasis.

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The National Cancer Database: Survival Between Head and Neck Melanoma and Melanoma of Other Regions

Otolaryngology ◽

10.1177/01945998211053204 ◽

2021 ◽

pp. 019459982110532

Author(s):

Claudia I. Cabrera ◽

Shawn Li ◽

Rosalynn Conic ◽

Brian R. Gastman

Keyword(s):

Head And Neck ◽

Survival Data ◽

Controlled Trial ◽

Additional Patient ◽

National Cancer Database ◽

Risk Of Death ◽

Increased Risk ◽

Head And Neck Melanoma ◽

Over Time

Objective Primary site is considered an important prognostic factor for cutaneous malignant melanoma (CMM); however, opinions vary regarding its influence on survival. This study compares overall survival between head and neck melanoma (HNM) and melanoma of other regions (MOR), as well as between melanoma of the scalp and neck (MSN) and melanoma of other head regions (MOHR). Study Design Level III retrospective cohort study. Setting Patients from Commission on Cancer–accredited cancer programs affiliated to the National Cancer Database (NCDB). Methods Patients with HNM (MSN and MOHR included) and MOR, stages I to IV (n = 39,754), and their linked survival data using the NCDB were identified. Survival was analyzed using propensity score matching methods. Results After matching using propensity scores, allowing this observational study to mimic a randomized controlled trial, subjects with HNM showed a 22% increased mortality when compared to MOR ( P < .01). Among those with HNM, hazard was not proportional over time. Overall, subjects with MSN in the first 3.5 years of follow-up (75% of subjects) showed a 15% increased mortality when compared to MOHR ( P < .01); however, after 3.5 years, no difference in survival was noted ( P = .5). Conclusion Patients with HNM showed a higher mortality when compared to MOR. The risk of death of primary sites within the head and neck varies over time, showing a higher risk of mortality for scalp and neck during the first 3.5 years of follow-up. This increased risk was not evident after the 3.5-year threshold. Further research is needed to evaluate additional patient factors or differences in treatment approaches.

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Clinical Implications of Human Papillomavirus in Head and Neck Cancers

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.1291 ◽

2006 ◽

Vol 24 (17) ◽

pp. 2606-2611 ◽

Cited By ~ 317

Author(s):

Carole Fakhry ◽

Maura L. Gillison

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Head And Neck ◽

Sexual Behaviors ◽

Hpv Infection ◽

Genetic Alterations ◽

Sufficient Evidence ◽

Clinical Implications ◽

Risk Of Death ◽

Increased Risk

Human papillomavirus (HPV) is now recognized to play a role in the pathogenesis of a subset of head and neck squamous cell carcinomas (HNSCCs), particularly those that arise from the lingual and palatine tonsils within the oropharynx. High-risk HPV16 is identified in the overwhelming majority of HPV-positive tumors, which have molecular-genetic alterations indicative of viral oncogene function. Measures of HPV exposure, including sexual behaviors, seropositivity to HPV16, and oral, high-risk HPV infection, are associated with increased risk for oropharyngeal cancer. HPV infection may be altering the demographics of HNSCC patients, as these patients tend to be younger, nonsmokers, and nondrinkers. There is sufficient evidence to conclude that a diagnosis of HPV-positive HNSCC has significant prognostic implications; these patients have at least half the risk of death from HNSCC when compared with the HPV-negative patient. The HPV etiology of these tumors may have future clinical implications for the diagnosis, therapy, screening, and prevention of HNSCC.

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Impact of age on treatment effect in locally advanced head and neck cancer (HNC): Two individual patient data meta-analyses

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5501 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5501-5501 ◽

Cited By ~ 18

Author(s):

J. Bourhis ◽

A. Le Maı̂tre ◽

J. Pignon ◽

K. Ang ◽

J. Bernier ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Treatment Effect ◽

Cox Model ◽

Meta Analysis ◽

Performance Status ◽

Locally Advanced ◽

Risk Of Death

5501 Background: The Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck (MARCH; Bourhis J, ASTRO 2002) showed that altered fractionation radiotherapy (Alt-RT) could improve survival as compared to standard RT in patients with locally advanced HNC (pooled hazard ratio - HR -: 0.92, 95% confidence interval: 0.86–0.97). The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC; Bourhis J, ASCO 2004) demonstrated that concomitant chemotherapy (CT), added to RT, improved survival (HR: 0.82, 95% CI: 0.78–0.86). This study considers age as a potential modifier of the treatment effect. Methods: 15 randomized trials with 6,515 patients were included in MARCH (median follow up: 6.0 years), and 50 with 9,471 patients in concomitant part of MACH-NC (median follow up: 5.6 years). The interaction between age and treatment effect, using HR of death, was tested with heterogeneity test. Effect of prognostic factors on the interaction was analysed using Cox model. Results: The effect of Alt-RT in MARCH and of concomitant CT in MACH-NC on overall survival decreased with increased age ( table ). Patients aged 71+ had a lower performance status, less advanced stage, and more often laryngeal cancer than the younger patients; there were more women in the oldest patients group. However, adjusting on covariates did not modify the results. Causes of death was available in MARCH and in recent (1994–2000) trials of MACH-NC. The proportion of deaths not due to HNC increased with age, from 18% at age 50 to 41% at age 71+ in MARCH, and from 15% to 39% in MACH-NC. Conclusions: Treatment benefit decreases with increasing age. Patients aged 71+ did not benefit from Alt- RT nor from concomitant CT. The increasing risk of death from other causes with age may explain part of these observations. Supported by PHRC, ARC, LNCC [Table: see text] No significant financial relationships to disclose.

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D-Dimer as a Prognostic Indicator in Critically Ill Patients Hospitalized With COVID-19 in Leishenshan Hospital, Wuhan, China

Frontiers in Pharmacology ◽

10.3389/fphar.2020.600592 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jinpeng Li ◽

Zeming Liu ◽

Gaosong Wu ◽

Meilin Yi ◽

Yongfeng Chen ◽

...

Keyword(s):

Disease Severity ◽

Early Warning ◽

Prognostic Indicator ◽

Underlying Disease ◽

Protein Fragment ◽

Risk Of Death ◽

Increased Risk ◽

High Flow Oxygen ◽

D Dimer

Background: D-dimer is a small protein fragment and high levels of D-dimer have been associated with increased mortality in patients presenting to emergency departments with infection. Previous studies have reported increased levels of D-dimer in COVID-19; however, it is unclear whether an increased D-dimer level provides early warning of poor prognosis. Therefore, this study aimed to assess the usefulness of D-dimer as an early indicator of prognosis in patients with coronavirus disease (COVID-19).Methods: We conducted a retrospective study of patients with COVID-19 admitted to Leishenshan Hospital in Wuhan, China, from February 15 to March 30, 2020. The final date of follow-up was April 11, 2020.Results: Of the 1,643 patients with COVID-19, 691 had elevated D-dimer levels. Their median age was 65 years. Of the patients with elevated D-dimer levels, 45% had comorbidities, with cardiovascular disease (205 [29.7%]) being the most common. Patients with elevated D-dimer were more likely to require treatment with high-flow oxygen, anticoagulation, antibiotics, and admission to the intensive care unit They were also more likely to have increased interleukin-6, monocytes, and lymphocytes. Patients with elevated D-dimer levels had significantly higher mortality than those with normal or low D-dimer levels.Conclusion: In patients with COVID-19, elevated D-dimer was associated with abnormal immunity, underlying disease, increased disease severity, and increased mortality. Taken together, D-dimer may be a marker for the early warning of disease severity and increased risk of death. These findings provide insights into the potential risk of elevated D-dimer in patients with COVID-19.

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Perceived Physical Fatigability Predicts All-Cause Mortality in Older Adults

The Journals of Gerontology Series A ◽

10.1093/gerona/glab374 ◽

2021 ◽

Author(s):

Nancy W Glynn ◽

Theresa Gmelin ◽

Sharon W Renner ◽

Yujia Susanna QiaoScM ◽

Robert M Boudreau ◽

...

Keyword(s):

Older Adults ◽

Prognostic Indicator ◽

Underlying Disease ◽

Registration System ◽

Civil Registration ◽

Risk Of Death ◽

Validated Questionnaire ◽

Patient Reported ◽

Cox Proportional Hazard Models

Abstract Background Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults. Methods Participants (N = 2,906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study were assessed at Visit 2 (2014-2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0-50, higher=greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by: family members notifying field centers, reporting during another family member’s annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates. Results Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared to alive (12.2, [SE, 0.4]) overall, as well as across age strata (P<.001), except for those 60-69 years (P=.79). Participants with the most severe fatigability (PFS Physical scores ≥25) were over twice as likely to die (HR, 2.33 [95% CI, 1.65 to 3.28]) compared to those with less severe fatigability (PFS Physical scores <25) after adjustment. Conclusions This work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death.

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Part I. DNA Flow Cytometry as a Prognostic Indicator in Head and Neck Cancer

Otolaryngology ◽

10.1177/019459988709600402 ◽

1987 ◽

Vol 96 (4) ◽

pp. 307-318 ◽

Cited By ~ 58

Author(s):

Manning M. Goldsmith ◽

David H. Cresson ◽

Larry A. Arnold ◽

Duncan S. Postma ◽

Frederic B. Askin ◽

...

Keyword(s):

Flow Cytometry ◽

Head And Neck Cancer ◽

Head And Neck ◽

Prognostic Indicator ◽

Squamous Cell Carcinomas ◽

Dna Flow Cytometry ◽

Dna Amount ◽

Favorable Prognosis ◽

Dna Amounts

The prognostic significance of deoxyribonucleic acid (DNA) flow cytometry has been investigated for many solid tumors, but few data have been accumulated for squamous cell carcinomas of the head and neck. To our knowledge, we report the largest number of patients (69) with head and neck primary carcinomas to be studied by DNA flow cytometry. In the first part of this study, we reviewed 109 consecutive patients with laryngeal or hypopharyngeal primary carcinomas which were treated at North Carolina Memorial Hospital during the period of 1981 to 1984. The final analysis comprised 139 DNA histograms (mean coefficient of variation: 8.02) on paraffin-embedded specimens from 48 patients. Of the 48 patients with primary carcinomas, 24 had glottic, 18 had supraglottic, and 6 had carcinomas from the piriform sinus. Patients had follow-up for a minimum of 12 months, with a mean follow-up period of 23 months. Twenty-three of the 48 primary carcinomas (48%) were clearly aneuploid, and the remaining 52% were tetraploid (22%) or diploid (30%). We have concluded that patients with clearly aneuploid primary carcinomas had significantly better prognoses than those with diploid tumors ( p = 0.008). High DNA amounts (greater than 40% of cells beyond the diploid peak, DNA G1GO) also correlated with a favorable prognosis when compared with low DNA amounts ( p <0.01), and this remained significant when the clinical outcome was adjusted for staging of the primary site (T), nodal status, and stage of disease. Ploidy was the most significant prognostic variable for the laryngeal group of patients. In the second part of the study, twenty-one patients with oral cavity squamous cell carcinomas were studied in a similar fashion as the group with laryngeal carcinomas. In this group, a low DNA amount, with 40% as the cutoff point, was associated with a favorable prognosis ( p = 0.024), and this remained significant while controlling for I, nodal status, and stage of disease. Numbers were too small to permit evaluation of the impact of ploidy in this group, but there was a slight trend toward aneuploidy and tetraploidy, correlating with a poor treatment outcome ( p = 0.228). DNA amount was the most significant prognostic variable for the group of patients with oral cavity carcinomas. We conclude that DNA flow cytometry may be a powerful prognostic indicator in malignant conditions of the head and neck. The implications of these data for the management of head and neck cancer are discussed.

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T-Cell Subpopulations in Head and Neck Carcinoma

Otolaryngology ◽

10.1177/019459988409200402 ◽

1984 ◽

Vol 92 (4) ◽

pp. 381-385 ◽

Cited By ~ 13

Author(s):

Jonas T. Johnson ◽

Bruce S. Rabin ◽

Barry Hirsch ◽

Patricia B. Thearle

Keyword(s):

T Cells ◽

T Cell ◽

Head And Neck ◽

Cytotoxic T Cells ◽

Head And Neck Carcinoma ◽

Prognostic Indicator ◽

Cell Subpopulation ◽

Cell Subpopulations ◽

T Cell Subpopulations

Peripheral blood T-cell subpopulations were quantitated with monoclonal antibodies in a group of 27 patients with biopsy-proved squamous cell carcinoma of the head and neck. Abnormal quantitative relationships between helper/inducer T cells (Th) and suppressor/cytotoxic T cells (Ts) were encountered in many patients. Short-term follow-up of these patients did not demonstrate a correlation between these immune parameters and clinical course. Longer follow-up and expansion of the data base will be necessary before a determination can be made of the value of quantitative T-cell subpopulation analysis relative to its use as a prognostic indicator in patients with head and neck cancer.

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The Carpentier-Edwards Classic and Physio Mitral Annuloplasty Rings: A Randomized Trial

The Heart Surgery Forum ◽

10.1532/hsf.419 ◽

2006 ◽

Vol 8 (5) ◽

pp. 389 ◽

Cited By ~ 9

Author(s):

Ghada M. M. Shahin ◽

Geert J. M. G. van der Heijden ◽

Michiel L. Bots ◽

Maarten-Jan Cramer ◽

Wybren Jaarsma ◽

...

Keyword(s):

Left Ventricular Function ◽

Ventricular Function ◽

Absolute Risk ◽

Statistical Significance ◽

Nyha Class ◽

Left Ventricular ◽

Mitral Annuloplasty ◽

Risk Of Death ◽

Late Failure

Objective: To evaluate clinical and echocardiographic outcomes for the semi-flexible Carpentier-Edwards Physio and the rigid Classic mitral annuloplasty ring. Methods: Ninety-six patients were randomized for either a Classic (n = 53) or a Physio (n = 43) ring from October 1995 through July 1997. Mean follow-up was 5.1 years (range .1-6.6). We included standard patient characteristics at baseline and during follow-up. Analyses were adjusted for age and gender, and for factors that differed across groups at baseline. In 2002, echocardiography was performed in 74% of the survivors. Results: We found a 16% difference in mortality: 14% in the Physio group (n = 6) and 30% in the Classic group (n = 16) (adjusted P = .41). Life table analysis shows that the absolute risk of death after 30 months is lower in the Physio group. Intra-operative repair failure occurred in 3 patients (6%) of the Classic group, and in 4 (9%) of the Physio group, resulting in mitral valve replacement. Late failure occurred in 1 patient (2%) in the Classic group, and in 4 (9%) in the Physio group. At follow-up, left ventricular function did not differ across groups (ejection fraction 45% and 48% (adjusted P = .65)). The combined NYHA class III-IV had improved for the Classic group in 42% and for the Physio group in 34%. Conclusion: Although the 16% difference in mortality did not reach statistical significance, it is considered clinically important. No differences in morbidity, valve function, and left ventricular function were found. Further research to explain the difference in mortality is required.

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