Publications by authors named "Dong M Shin"

214 Publications

Association of epigenetic age acceleration with risk factors, survival, and quality of life in patients with head and neck cancer.

Int J Radiat Oncol Biol Phys 2021 Apr 18. Epub 2021 Apr 18.

Emory University School of Nursing.

Purpose: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy.

Methods And Materials: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy-HNC.

Results: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to <0.001). A non-linear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (when BMI<35,p=0.04) or increased BMI (when BMI≥35,p=0.01), was linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio (HR)=1.11,95% CI=[1.03,1.18],p=0.004; HR=1.10,95% CI=[1.01,1.19], p=0.02, for EAA at 6-months and 12-months post-treatment, respectively), PFS (HR=1.10, 95% CI=[1.02,1.19], p=0.02; HR=1.14, 95% CI=[1.06,1.23], p<0.001; HR=1.08,95% CI=[1.02,1.14], p=0.01, for EAA before, end, and 6-months post-radiotherapy, respectively), and QOL over time (β=-0.61,p=0.001). An average of 3.25-3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrences compared to those who did not (all p<0.001).

Conclusion: Compared to demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.002DOI Listing
April 2021

Combination of resveratrol and green tea epigallocatechin gallate induces synergistic apoptosis and inhibits tumor growth in head and neck cancer models.

Oncol Rep 2021 May 13;45(5). Epub 2021 Apr 13.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.

Despite widespread interest in chemoprevention and therapy due to the high margin of safety of dietary natural compounds, clinical intervention with single agents has failed to yield the expected outcomes, mostly due to poor bioavailability and low potency. Combinations of natural agents with synergistic effects are gaining increasing attention. In the present study, and antitumor effects of a combination of two natural dietary agents, green tea epigallocatechin gallate (EGCG) and resveratrol were investigated. It was revealed that their combination at low doses (at which single agents induce minimal apoptosis) synergistically increased apoptosis (combination index < 1) in head and neck cancer cell lines. Synergistic apoptosis was also supported by caspase‑3 and PARP cleavage. The combination also significantly inhibited growth of xenografted head and neck tumors in nude mice as supported by significant inhibition of tumor volume, tumor weight and Ki67 expression, and increase in TUNEL‑positive cells. Mechanistic studies revealed that the combination inhibited AKT‑mTOR signaling both and . In addition, overexpression of constitutively active AKT protected cells from apoptosis induced by the combination of EGCG and resveratrol. Collectively, the present results for the first time suggest that the combination of EGCG and resveratrol has synergistic growth inhibitory effects and provide an important rationale for future clinical development for chemoprevention and treatment of head and neck cancer.
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http://dx.doi.org/10.3892/or.2021.8038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025073PMC
May 2021

Co-expression of fibroblast growth factor receptor 3 with mutant p53, and its association with worse outcome in oropharyngeal squamous cell carcinoma.

PLoS One 2021 24;16(2):e0247498. Epub 2021 Feb 24.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America.

Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. However, information on its correlation with other relevant cancer related proteins stratified by p16 status and its prognostic significance in OPSCC is limited. We examined FGFR3 expression and its correlation with clinical characteristics, p16 status, and mutant p53 (mp53) among 220 retrospectively collected OPSCC cases and 40 prospectively collected SCCHN cases, including a majority of OPSCC. Correlations of FGFR3 Weighted Index (WI) with p16 status and mp53 WI as well as its association with disease-free survival (DFS) and overall survival (OS) were evaluated. FGFR3 expression was detected in 61% and 70% of cases in cohorts 1 and 2, respectively. FGFR3 level was significantly higher in p16-negative tumors in both cohorts (p<0.001 and 0.006). FGFR3 expression was highly correlated with mp53 expression in both p16 + and p16- OPSCC (p<0.0001 and p = 0.0006, respectively). In cohort 1, univariate analysis showed that FGFR3 was associated with DFS but not OS. Kaplan-Meier analysis showed that higher FGFR3 and mp53 level correlated with worse DFS (p = 0.025) and OS (p = 0.009). As expected, p16 positive status was associated with improved OS and DFS (p<0.001 for both). Our results suggest that high FGFR3 expression is associated with p16 negative status and mp53 expression in OPSCC and correlates with a worse clinical outcome. The biological relationship between FGFR3 and mp53 in OPSCC deserves further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247498PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904228PMC
February 2021

Socioeconomic Factors Influence the Impact of Tumor HPV Status on Outcome of Patients With Oropharyngeal Squamous Cell Carcinoma.

JCO Oncol Pract 2021 Mar 12;17(3):e313-e322. Epub 2021 Jan 12.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA.

Purpose: Human papilloma virus (HPV) association remains one of the most important predictors of clinical outcome in oropharyngeal squamous cell carcinoma (OPSCC). We aimed to determine whether the relationship between HPV status and overall survival was influenced by socioeconomic factors.

Materials And Methods: Using the National Cancer Database, we examined the relationship between socioeconomic status and overall survival, controlling for demographics and socioeconomic variables (age at diagnosis, race, sex, clinical stage, facility type, facility location, insurance status, median-income quartiles, percent of no high-school education quartiles, rural-urban dwelling, Charlson-Deyo score, primary site, and treatment type).

Results: HPV-positive patients with private insurance have improved overall survival compared with HPV-positive patients who are uninsured (hazard ratio [HR], 0.51, 95% CI, 0.41 to 0.63, < .001). HPV-negative patients with private insurance have improved overall survival compared with HPV-negative patients who were uninsured (HR, 0.62, 95% CI, 0.53 to 0.73, < .001). HPV-positive patients living in the south had improved overall survival compared with HPV-positive patients living in the west (HR, 0.83, 95% CI, 0.72 to 0.96, = .013). As assessed through interaction, relationships between survival and insurance ( = .004), rural-urban status ( = .009), and facility location ( = .021) statistically differed between HPV-positive and HPV-negative patients.

Conclusion: HPV status impact on overall survival for patients with OPSCC is influenced by socioeconomic factors including insurance status and treatment facility. A deeper understanding of these interactions is needed to improve equity of care for patients with OPSCC.
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http://dx.doi.org/10.1200/OP.20.00671DOI Listing
March 2021

Combinatorial approaches targeting the EGFR family and c-Met in SCCHN.

Oral Oncol 2021 01 2;112:105074. Epub 2020 Nov 2.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, United States. Electronic address:

Objective: We aimed to develop novel combinations of inhibitors targeting EGFR family members and c-Met for the treatment of recurrent SCCHN.

Materials And Methods: Three different c-Met inhibitors in combination with a pan-HER inhibitor (crizotinib/afatinib, tivantinib/afatinib and cabozantinib/afatinib) were investigated for their anti-tumor effects on SCCHN cell lines in vitro. In vivo activity of the combinations was tested in SCCHN cell line xenografts and patient-derived xenograft (PDX) animal models generated from patients with recurrent SCCHN.

Results: Western blot assay indicated that activation of EGFR, HER2, HER3, and c-Met was blocked by all three combinations and the downstream PI3K/AKT and ERK signaling pathways were inhibited. Sulforhodamine B colorimetric assay revealed SCCHN cell growth was more effectively inhibited by the combinations than by single agents, particularly in cell lines with high c-Met expression. Furthermore, the combinations were more potent in inducing apoptosis than each of the single agents. In the PDX models, the combination treatments exhibited significantly better efficacy in tumor growth inhibition compared to the respective single agents.

Conclusion: In conclusion, we demonstrated that the simultaneous targeting of EGFR, HER2, and c-Met is more effective than the individual inhibition of these targets in vitro and in SCCHN cell line xenograft and PDX models. Our findings pave the way for further clinical investigation of such combinations in SCCHN.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105074DOI Listing
January 2021

Parenteral Bevacizumab for the Treatment of Severe Respiratory Papillomatosis in an Adult Population.

Laryngoscope 2021 03 27;131(3):E921-E928. Epub 2020 Oct 27.

Division of Medical Oncology, Department of Medicine, Emory University, Atlanta, Georgia, U.S.A.

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a rare, potentially life-threatening, disease that impacts the voice, breathing, and quality of life of patients. Frequent surgical interventions may be needed to control symptoms. We examined the safety and efficacy of utilizing parenteral bevacizumab in the management of severe RRP in adults.

Study Design: This is a retrospective review of clinical management approaches in a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or tracheobronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3-week intervals. Bevacizumab dosing and frequency was then individually titrated down.

Results: Fourteen adults received a median of 8.5 (range 2-17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional tracheobronchial lesions. Patients required a median of 4 (range 2-11) procedures in the year prior to treatment. Only 3/10 (30%) patients who continued therapy required any additional procedures. Bevacizumab administration was generally well tolerated, with four patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus. Common side effects included hypertension (grade 2), headache (grades 1-2), elevated creatinine (grades 1-2), and epistaxis (grade 3).

Conclusions: Intravenous bevacizumab for the primary treatment of severe RRP in adults appears clinically effective and safe. Expected and typically mild side effects related to bevacizumab were observed. Continued investigation of bevacizumab through a prospective clinical trial is warranted.

Level Of Evidence: 4. Laryngoscope, 131:E921-E928, 2021.
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http://dx.doi.org/10.1002/lary.29133DOI Listing
March 2021

Corrigendum to "FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway" [Canc. Lett. 363 (2015) 166-175].

Cancer Lett 2021 Feb 20;498:249-250. Epub 2020 Oct 20.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2020.07.039DOI Listing
February 2021

The role of the gut microbiome in cancer-related fatigue: pilot study on epigenetic mechanisms.

Support Care Cancer 2021 Jun 20;29(6):3173-3182. Epub 2020 Oct 20.

School of Nursing, Emory University, 1520 Clifton Road NE, Atlanta, 30322, USA.

Purpose: Recent evidence supports a key role of gut microbiome in brain health. We conducted a pilot study to assess associations of gut microbiome with cancer-related fatigue and explore the associations with DNA methylation changes.

Methods: Self-reported Multidimensional Fatigue Inventory and stool samples were collected at pre-radiotherapy and one-month post-radiotherapy in patients with head and neck cancer. Gut microbiome data were obtained by sequencing the 16S ribosomal ribonucleic acid gene. DNA methylation changes in the blood were assessed using Illumina Methylation EPIC BeadChip.

Results: We observed significantly different gut microbiota patterns among patients with high vs. low fatigue across time. This pattern was characterized by low relative abundance in short-chain fatty acid-producing taxa (family Ruminococcaceae, genera Subdoligranulum and Faecalibacterium; all p < 0.05), with high abundance in taxa associated with inflammation (genera Family XIII AD3011 and Erysipelatoclostridium; all p < 0.05) for high-fatigue group. We identified nine KEGG Orthology pathways significantly different between high- vs. low-fatigue groups over time (all p < 0.001), including pathways related to fatty acid synthesis and oxidation, inflammation, and brain function. Gene set enrichment analysis (GSEA) was performed on the top differentially methylated CpG sites that were associated with the taxa and fatigue. All biological processes from the GSEA were related to immune responses and inflammation (FDR < 0.05).

Conclusions: Our results suggest different patterns of the gut microbiota in cancer patients with high vs. low fatigue. Results from functional pathways and DNA methylation analyses indicate that inflammation is likely to be the major driver in the gut-brain axis for cancer-related fatigue.
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http://dx.doi.org/10.1007/s00520-020-05820-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055716PMC
June 2021

Phase Ib Study of Chemoprevention with Green Tea Polyphenon E and Erlotinib in Patients with Advanced Premalignant Lesions (APL) of the Head and Neck.

Clin Cancer Res 2020 Nov 17;26(22):5860-5868. Epub 2020 Sep 17.

Department of Hematology and Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia.

Purpose: On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR-tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx.

Patients And Methods: Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation.

Results: Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment.

Conclusions: Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016407PMC
November 2020

Gut Microbiome Associated with the Psychoneurological Symptom Cluster in Patients with Head and Neck Cancers.

Cancers (Basel) 2020 Sep 6;12(9). Epub 2020 Sep 6.

School of Nursing, Yale University, New Haven, CT 06477, USA.

Cancer patients experience a cluster of co-occurring psychoneurological symptoms (PNS) related to cancer treatments. The gut microbiome may affect severity of the PNS via neural, immune, and endocrine signaling pathways. However, the link between the gut microbiome and PNS has not been well investigated in cancer patients, including those with head and neck cancers (HNCs). This pilot study enrolled 13 patients with HNCs, who reported PNS using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (CTCAEs). Stool specimens were collected to analyze patients' gut microbiome. All data were collected pre- and post-radiation therapy (RT). Associations between the bacterial abundances and the PNS clusters were analyzed using the linear discriminant analysis effect size; functional pathway analyses of 16S rRNA V3-V4 bacterial communities were conducted using Tax4fun. The high PNS cluster had a greater decrease in microbial evenness than the low PNS cluster from pre- to post-RT. The high and low PNS clusters showed significant differences using weighted UniFrac distance. Those individuals with the high PNS cluster were more likely to have higher abundances in phylum , order , class , and four genera (, and ), while the low PNS cluster had higher abundances in family and three genera (, and ). Both glycan metabolism (Lipopolysaccharide biosynthesis) and vitamin metabolism (folate biosynthesis and lipoic acid metabolism) were significantly different between the high and low PNS clusters pre- and post-RT. Our preliminary data suggest that the diversity and abundance of the gut microbiome play a potential role in developing PNS among cancer patients.
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http://dx.doi.org/10.3390/cancers12092531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563252PMC
September 2020

Association Among Glucocorticoid Receptor Sensitivity, Fatigue, and Inflammation in Patients With Head and Neck Cancer.

Psychosom Med 2020 06;82(5):508-516

From the School of Nursing (Xiao, Knobf), Yale University, Orange, Connecticut; and School of Nursing (Eldridge, Chico, Bruner), School of Medicine (Beitler, Higgins, Saba, Shin), and Department of Psychiatry and Behavioral Sciences, School of Medicine (Felger, Wommack, Miller), Emory University, Atlanta, Gerogia.

Objective: Fatigued cancer patients often have high peripheral inflammation; however, the biological mechanisms of this association remain unclear. We examined whether decreased sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids may contribute to inflammation and fatigue in head and neck cancer (HNC) patients during treatment.

Methods: HNC patients without distant metastasis and with curative intent (n = 77) were studied 1 week before intensity-modulated radiotherapy (IMRT) and 1 month after IMRT. At each time point, fatigue was measured by the Multidimensional Fatigue Inventory-20 along with plasma inflammation markers and glucocorticoid receptor (GR) sensitivity as determined by in vitro dexamethasone suppression of lipopolysaccharide-induced interleukin 6. Linear regression models were used.

Results: In contrast to our hypothesis, GR sensitivity increased during treatment; however, increased fatigue was associated with a lesser increase in GR sensitivity from baseline to 1 month after IMRT (unstandardized estimate = 4.07, p = .02). This effect was more prominent in human papillomavirus-unrelated HNCs (unstandardized estimate = 8.22, p = .002). Lower increases in GR sensitivity were also associated with increased inflammation at 1 month after IMRT as represented by C-reactive protein, interleukin 6, and tumor necrosis factor α. Addition of inflammation markers to models of GR sensitivity predicting fatigue indicated that these inflammation markers were stronger predictors of fatigue than GR sensitivity.

Conclusions: Lower increases in GR sensitivity during HNC treatment were significantly predictive of increased fatigue and inflammation markers. Inflammation markers in turn predicted fatigue above and beyond levels of GR sensitivity. Our findings indicate that HNC patients with cancer-related fatigue may exhibit a decreased capacity for glucocorticoids to regulate inflammatory processes, as evidenced by a lower increase in GR sensitivity. Larger studies are necessary to verify the findings.
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http://dx.doi.org/10.1097/PSY.0000000000000816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905992PMC
June 2020

Tumor Membrane Vesicle Vaccine Augments the Efficacy of Anti-PD1 Antibody in Immune Checkpoint Inhibitor-Resistant Squamous Cell Carcinoma Models of Head and Neck Cancer.

Vaccines (Basel) 2020 Apr 14;8(2). Epub 2020 Apr 14.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Immune checkpoint inhibitor (ICI) immunotherapy improved the survival of head and neck squamous cell carcinoma (HNSCC) patients. However, more than 80% of the patients are still resistant to this therapy. To test whether the efficacy of ICI therapy can be improved by vaccine-induced immunity, we investigated the efficacy of a tumor membrane-based vaccine immunotherapy in murine models of HNSCC. The tumors, grown subcutaneously, are used to prepare tumor membrane vesicles (TMVs). TMVs are then incorporated with glycolipid-anchored immunostimulatory molecules GPI-B7-1 and GPI-IL-12 by protein transfer to generate the TMV vaccine. This TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. The tumor-free mice survived for several months, remained tumor-free, and were protected following a secondary tumor cell challenge, suggesting that the TMV vaccine induced an anti-tumor immune memory response. However, no synergy with anti-PD1 mAb was observed in this model. In contrast, the TMV vaccine was effective in inhibiting MOC1 and MOC2 murine oral cancer models and synergized with anti-PD1 mAb in extending the survival of tumor-bearing mice. These observations suggest that tumor tissue based TMV vaccines can be harnessed to develop an effective personalized immunotherapy for HNSCC that can enhance the efficacy of immune checkpoint inhibitors.
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http://dx.doi.org/10.3390/vaccines8020182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348725PMC
April 2020

Outcomes and Predictive Value of Post-adjuvant Therapy PET/CT for Locally Advanced Oral Squamous Cell Carcinoma.

Laryngoscope 2020 12 14;130(12):E850-E857. Epub 2020 Feb 14.

Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.

Objectives/hypothesis: For locally advanced oral squamous cell carcinoma (OSCC) treated by surgery and adjuvant therapy, consensus has yet to be reached on whether the optimal time to initiate surveillance positron emission tomography/computed tomography (PET/CT) scan is before or after adjuvant therapy. In this study, we characterize the utility of PET/CT scans obtained 3 months after adjuvant therapy.

Study Design: PET/CT scans were obtained for 220 patients with stage III, IVA, or IVB OSCC who underwent resection followed by adjuvant radiotherapy or chemoradiotherapy.

Methods: Using the Neck Imaging Reporting and Data System, PET/CT scans were dichotomized as suspicious (primary or neck category ≥3, or distant lesion present) versus nonsuspicious. We then computed differences in locoregional progression, distant progression, and overall survival; positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity; and success rate of salvage.

Results: Sixty-seven patients (30%) had suspicious PET/CT scans, which were significantly associated with local failure (hazard ratio [HR] 14.0, 95% confidence interval [CI] 7.3-26.6), distant failure (HR 18.4, 95% CI 9.6-35.3), and poorer overall survival (HR 9.5, 95% CI 5.0-17.9). Overall PPV, locoregional PPV, NPV, sensitivity, and specificity were 85%, 79%, 73%, 58%, and 92%, respectively. Among those with biopsy-confirmed progression, 37 patients (65%) underwent salvage therapy; four (11%) were without evidence of disease at last follow-up.

Conclusions: For locally advanced OSCC, PET/CT scan 3 months after adjuvant therapy is strongly predictive of disease recurrence and survival, demonstrating improved performance over postoperative imaging in previous studies. Following a suspicious post-adjuvant therapy PET/CT scan, cure of locoregional recurrence is possible but unlikely.

Level Of Evidence: 4 Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.28509DOI Listing
December 2020

Demographic and Socioeconomic Factors Associated With Metastases at Presentation in HPV-Related Squamous Cell Carcinoma of the Head and Neck: An NCDB Analysis.

JCO Oncol Pract 2020 06 27;16(6):e476-e487. Epub 2020 Jan 27.

Department of Hematology and Medical Oncology, Emory University, Atlanta, GA.

Purpose: Human papillomavirus (HPV)-related squamous cell carcinomas of the head and neck (SCCHNs) tend to have a distinct prognosis. Socioeconomic and demographic factors associated with metastatic disease at presentation and diagnosis in patients with HPV-related SCCHN tumors were examined.

Methods: The National Cancer Database (NCDB) was queried to assess patients with HPV-related oropharyngeal carcinomas (HPVOPCAs) and HPV-related nonoropharyngeal carcinomas (HPVNOPCAs) diagnosed between 2010 and 2014. Rate of metastases at presentation was analyzed using clinical M stage. Multivariable analysis was performed evaluating race, ethnicity, sex, age, facility location, facility type, insurance status, income, education, and tumor and nodal stage using logistic regression.

Results: A total of 12,857 patients with HPVOPCA and 952 patients with HPVNOPCA were included. Private insurance was carried by 64% and 47% of patients with HPVOPCA and HPVNOPCA, respectively. HPVOPCA was located in the tonsil in 56% of patients. For both HPVOPCA and HPVNOPCA, there was no meaningful difference in distant metastasis at presentation based on facility type or location, sex, race, Hispanic ethnicity, or urban or rural location. For HPVOPCA, there were significantly lower odds of metastasis in privately insured patients compared with uninsured patients (odds ratio [OR], 0.37; 95% CI, 0.21 to 0.64; < .001) and higher odds of metastasis for patients living in census tracts with the lowest rates of high school graduates compared with the highest rates (OR, 1.81; 95% CI, 1.02 to 3.19; = .041) and for patients with higher tumor stage (OR, 3.67, 95% CI, 2.25 to 5.99; < .001) and nodal stage (OR, 3.34; 95% CI, 2.11 to 5.29; < .001). For HPVNOPCA, neither higher T or N stage nor any demographic features were found to be associated with metastasis at presentation.

Conclusion: This large retrospective analysis identifies likely modifiable risk factors for metastatic presentation in HPVOPCA. Educational interventions may result in modifications of these patterns.
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http://dx.doi.org/10.1200/JOP.19.00400DOI Listing
June 2020

Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation.

J Clin Invest 2019 10;129(10):4110-4123

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia, USA.

Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers.
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http://dx.doi.org/10.1172/JCI125963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763259PMC
October 2019

Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance.

J Clin Invest 2019 05 13;129(6):2431-2445. Epub 2019 May 13.

Winship Cancer Institute, Department of Hematology and Medical Oncology, and.

How altered metabolism contributes to chemotherapy resistance in cancer cells remains unclear. Through a metabolism-related kinome RNAi screen, we identified inositol-trisphosphate 3-kinase B (ITPKB) as a critical enzyme that contributes to cisplatin-resistant tumor growth. We demonstrated that inositol 1,3,4,5-tetrakisphosphate (IP4), the product of ITPKB, plays a critical role in redox homeostasis upon cisplatin exposure by reducing cisplatin-induced ROS through inhibition of a ROS-generating enzyme, NADPH oxidase 4 (NOX4), which promotes cisplatin-resistant tumor growth. Mechanistically, we identified that IP4 competes with the NOX4 cofactor NADPH for binding and consequently inhibits NOX4. Targeting ITPKB with shRNA or its small-molecule inhibitor resulted in attenuation of NOX4 activity, imbalanced redox status, and sensitized cancer cells to cisplatin treatment in patient-derived xenografts. Our findings provide insight into the crosstalk between kinase-mediated metabolic regulation and platinum-based chemotherapy resistance in human cancers. Our study also suggests a distinctive signaling function of IP4 that regulates NOX4. Furthermore, pharmaceutical inhibition of ITPKB displayed synergistic attenuation of tumor growth with cisplatin, suggesting ITPKB as a promising synthetic lethal target for cancer therapeutic intervention to overcome cisplatin resistance.
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http://dx.doi.org/10.1172/JCI124550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546469PMC
May 2019

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

Nutr Cancer 2019 12;71(5):772-780. Epub 2019 Mar 12.

a University of Michigan , Ann Arbor , Michigan, USA.

Aim: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial.

Methods: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months.

Results: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes.

Conclusion: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.
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http://dx.doi.org/10.1080/01635581.2019.1577981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513708PMC
May 2020

Concurrent chemoradiotherapy with weekly versus triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck: Comparative analysis.

Head Neck 2019 05 5;41(5):1490-1498. Epub 2019 Mar 5.

Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.

Background: Cisplatin-based chemoradiotherapy is standard of care for locally advanced squamous cell carcinoma of the head and neck. This systemic review compared efficacy and safety of weekly vs triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck.

Methods: Among 1500 prospective studies published from 1970 to 2015, 39 (18 weekly, 21 triweekly) including 3668 patients qualified for inclusion. Clinical outcomes were analyzed using weighted estimates and 2-tailed t test for comparisons; significance level was 0.05.

Results: Locoregional control was 58% (CI 53%-63%) vs 61% (CI 56%-65%; P = .7). The 2-year overall survival (OS) was 74% (CI 66%-80%) for weekly vs 67% (64%-69%) triweekly groups (P = .67). The 2-year progression-free survival (PFS) was 69% (CI 59%-77%) for weekly vs 62% (CI 58%-65%) triweekly groups (P = .9). Grade 3 to 5 toxicities were 36% vs 40% (P = .37) in weekly vs triweekly groups.

Conclusions: Weekly cisplatin was comparable in efficacy and safety to the triweekly regimen. Our analysis supports the use of weekly or triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck, with tolerability being a key factor in selection.
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http://dx.doi.org/10.1002/hed.25379DOI Listing
May 2019

Phase IB Study of Induction Chemotherapy With XELOX, Followed by Radiation Therapy, Carboplatin, and Everolimus in Patients With Locally Advanced Esophageal Cancer.

Am J Clin Oncol 2019 04;42(4):331-336

Radiation Oncology, Vanderbilt University, Nashville, TN.

Purpose: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation.

Materials And Methods: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used.

Results: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively.

Conclusions: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.
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http://dx.doi.org/10.1097/COC.0000000000000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433493PMC
April 2019

A continuous-flow acoustofluidic cytometer for single-cell mechanotyping.

Lab Chip 2019 01;19(3):387-393

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.

The biophysical properties of cells such as their compressibility have been found to be closely related to disease progression such as cancer development and metastasis. As cancer cells are heterogeneous, rapid and high-throughput evaluation of cell biophysical properties at single-cell resolution is needed to assess their potential as biomarkers for cancer staging and prognosis. Acoustofluidics has shown promise as a contactless method for accurately measuring cell biophysical properties; however, previously reported methods had relatively low throughput due to their requirement of no-flow conditions. This work presents a high-throughput continuous flow-based acoustofluidic cell mechanotyping method at single-cell resolution that retains the advantage of simplicity and low-cost.
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http://dx.doi.org/10.1039/c8lc00711jDOI Listing
January 2019

Prognostic implications of peritumoral vasculature in head and neck cancer.

Cancer Med 2019 01 21;8(1):147-154. Epub 2018 Dec 21.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.

Background: There is conflicting evidence regarding the role of peritumoral lymphatic vessel density (LVD) and blood microvessel density (MVD) in the metastasis and prognosis of head and neck squamous cell carcinoma (HNSCC). Existing studies are limited to one or two head and neck subsites and/or small sample sizes. A larger study incorporating multiple sub-sites is needed to address the role of peritumoral LVD and MVD in HNSCC metastasis and prognosis.

Methods: Tissue samples from 200 HNSCC cases were stained simultaneously using immunohistochemistry (IHC) for markers of peritumoral LVD (lymphatic vessel marker D240) and MVD (blood vessel marker CD31). Of the stained slides, 166 and 167 were evaluable for LVD and MVD, respectively. The results were then correlated with clinicopathologic features and patient outcomes.

Results: Patients with metastatic disease were more likely to have high peritumoral MVD. Through multivariable analyses, MVD was not significantly related to DFS and OS, while low LVD was related to higher risk of disease progression and poor survival.

Conclusions: Peritumoral MVD was found to be positively associated with metastasis, while LVD was found to be inversely related to both metastasis and progression of HNSCC. These findings may suggest a prognostic role of both peritumoral LVD and MVD in patients with HNSCC.
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http://dx.doi.org/10.1002/cam4.1910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346230PMC
January 2019

Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx.

Cancer 2019 03 11;125(5):704-711. Epub 2018 Dec 11.

NRG Oncology.

Background: With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with human papillomavirus-associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective of this study was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx.

Methods: Under a shared use agreement, 547 patients from Radiation Therapy Oncology Group 0129 and 0522 with nonmetastatic oropharyngeal squamous cell cancers who had a known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. The analyzed factors included the p16 status, sex, T stage, N stage, age, and smoking history.

Results: A multivariate analysis of 547 patients with a median follow-up of 4.8 years revealed that an age ≥ 50 years (hazard ratio [HR], 3.28; P = .003), smoking for more than 0 pack-years (HR, 3.09; P < .001), N3 disease (HR, 2.64; P < .001), T4 disease (HR, 1.63; P = .030), and a negative p16 status (HR, 1.60; P = .044) were all factors associated with an increased risk of distant disease.

Conclusions: Age, smoking, N3 disease, T4 disease, and a negative p16 status were associated with the development of distant metastases in patients with squamous cell cancers of the oropharynx treated definitively with concurrent chemoradiation.
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http://dx.doi.org/10.1002/cncr.31820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463275PMC
March 2019

Differential regulation of NF-kB and IRF target genes as they relate to fatigue in patients with head and neck cancer.

Brain Behav Immun 2018 11 11;74:291-295. Epub 2018 Sep 11.

Division of Hematology-Oncology, UCLA AIDS Institute, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, and Norman Cousins Center, UCLA School of Medicine, Los Angeles, CA 90095, United States.

Previous studies have linked plasma inflammatory markers to elevated fatigue in patients with head and neck cancer (HNC). To identify the molecular mechanisms underlying this association, we conducted promoter-based bioinformatics analyses to determine the relationship between fatigue and specific gene expression profiles associated with inflammation in human papillomavirus (HPV)-related and -unrelated HNC patients undergoing treatment. Patients with newly diagnosed HNC without distant metastasis were assessed at baseline (pre-radiotherapy) and one-month post-radiotherapy. Fatigue was measured by the Multidimensional Fatigue Inventory. Genome-wide gene expression profiles were collected from peripheral blood mononuclear cells (PBMC). Promoter-based bioinformatics analyses were employed to identify transcription control pathways underlying transcriptomic correlates of fatigue in the sample as a whole and in HPV-related and HPV-unrelated HNC patients separately. In transcriptome profiling analyses of PBMC from 44 patients, TELiS bioinformatics analyses linked fatigue to increased nuclear factor-kappa B (NF-kB) transcriptional activity and decreased interferon regulatory factor family (IRF) transcription factor activity. Patients with HPV-related HNC showed lower levels of fatigue-related gene expression profile compared to HPV-unrelated HNC. Fatigue in HNC patients undergoing treatment is associated with gene expression profiles consistent with the conserved transcriptional response to adversity (CTRA) characterized by increased proinflammatory and decreased anti-antiviral transcriptional activity. Interestingly, this CTRA response was mitigated in patients with HPV-related HNC and may explain the lower level of fatigue they experience relative to HPV-unrelated HNC.
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http://dx.doi.org/10.1016/j.bbi.2018.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289813PMC
November 2018

Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma.

Head Neck Pathol 2019 Sep 6;13(3):304-312. Epub 2018 Sep 6.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA, 30322, USA.

This study addresses the hypothesis that IL-6/STAT3 signaling is of clinical relevance in oropharyngeal squamous cell carcinoma (OPSCC). We evaluated relationships between key components of this pathway in tumors from a unique cohort of n = 59 fully annotated, treatment-naïve patients with OPSCC. The multiplex Opal platform was utilized for immunofluorescence (IF) analysis of tissues to detect IL-6 and phosphorylated STAT3 (pSTAT3), taking into consideration its nuclear versus cytoplasmic localization. Abundant staining for both IL-6 and pSTAT3 was evident in tumor-rich regions of each specimen. IL-6 correlated with cytoplasmic pSTAT3 but not nuclear or total pSTAT3 in this cohort of OPSCC tumors, regardless of p16 status (r = 0.682, p < 0.0001). There was a significant association between increased total pSTAT3, nuclear pSTAT3, cytoplasmic pSTAT3 and IL-6 in p16 negative tumors. Our data indicate STAT3 phosphorylation was a key feature in p16-negative OPSCC tumors. When IL-6 data was stratified by median expression in tumors, there was no association with overall survival. In contrast, both total and nuclear pSTAT3 were significant predictors of poor overall and disease free survival. This strong inverse relationship with overall survival was present in p16 negative tumors for both total and nuclear pSTAT3, but not in p16 positive OPSCC tumors. Together these data indicate that activation of the STAT3 signaling pathway is a marker of p16 negative tumors and relevant to OPSCC prognosis and a potential target for treatment of this more aggressive OPSCC sub-population.
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http://dx.doi.org/10.1007/s12105-018-0962-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684688PMC
September 2019

Chloride Influx of Anion Exchanger 2 Was Modulated by Calcium-Dependent Spinophilin in Submandibular Glands.

Front Physiol 2018 19;9:889. Epub 2018 Jul 19.

Department of Physiology, College of Medicine, Gachon University, Incheon, South Korea.

Secretory glands including salivary glands by many hormonal inputs produce and secrete biological fluids determined by variety of ion transporters. Spinophilin is a multifunctional scaffolding protein, which involved in receptor signaling and regulation of anion exchangers AE2 activity. We found that spinophilin expressed in salivary glands. The role of salivary spinophilin on the modulation of chloride/bicarbonate exchange remains unknown. The spinophilin enhanced AE2 activity and associated with a STE20/SPS1-related kinase and showed an additive effect on the modulation of the activity of AE2. The cholinergic stimulation and subsequent intracellular Ca increase was required for the interaction with AE2 and spinophilin and abrogated the enhanced effect of spinophilin on Cl transporting activity. Ductal chloride/bicarbonate exchange activity was increased in pretreatment with carbachol. The CaMKII inhibitor KN-93 suppressed the chloride/bicarbonate exchange activity of ducts, suggesting that CaMKII was required for ductal chloride/bicarbonate exchange activity. Additionally, microtubule destabilization by nocodazole attenuated the interaction of AE2 and spinophilin and almost abolished the ductal chloride/bicarbonate exchange activity. The treatment of siRNA-spinophilin on the isolated salivary ducts also reduced the ductal chloride/bicarbonate exchange activity. Therefore, role of salivary spinophilin on AE2 may facilitate the Cl influx from basolateral in salivary glands in response to cholinergic inputs.
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http://dx.doi.org/10.3389/fphys.2018.00889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060233PMC
July 2018

MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation.

Cancer Cell 2018 08 19;34(2):315-330.e7. Epub 2018 Jul 19.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models.
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http://dx.doi.org/10.1016/j.ccell.2018.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092215PMC
August 2018

Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent/metastatic head and neck squamous cell carcinoma.

Oral Oncol 2018 07 19;82:83-90. Epub 2018 May 19.

University of Texas M. D. Anderson Cancer Center, Houston, TX, United States. Electronic address:

Objectives: Cixutumumab (CIX) and cetuximab (CET) monoclonal antibodies block ligand-binding to insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) respectively. The objective of this study was to assess the efficacy of CIX alone or combined with CET in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients.

Methods: In this open-label phase II trial, 91 R/M HNSCC patients who progressed within 90 days of platinum-based chemotherapy, were randomized to CIX 10 mg/kg alone or with CET 500 mg/m every 2 weeks. Patients were stratified by prior CET use. The primary endpoint was median progression-free survival (PFS). Exploratory biomarker assessments included relevant markers on archival tumor and serial cytokine/angiogenic-factor profiles in blood.

Results: Forty-seven patients were treated with CIX monotherapy and 44 with combination. The median PFS was 1.9 and 2.0 months and clinical benefit rate (complete or partial responses and stable disease) was 5.9% and 15.3%, respectively. There was no exacerbation of CET toxicity by concurrent CIX exposure. Higher tumor expression of IGF-1 was associated with improved PFS in the CIX + CET arm while increased p-EGFR expression correlated with shorter PFS in patients receiving single agent CIX. Higher serum baseline levels of IGF-1 and IGFBP-3 correlated with improved PFS and overall survival (OS) in the CIX arm. Neither regimen resulted in improved PFS or OS compared to historical data with CET alone.

Conclusion: The results of this study do not support the use of cixutumumab alone or with cetuximab in unselected patients with R/M HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2018.05.014DOI Listing
July 2018