Oncological and functional outcomes of partial or total laryngopharyngectomy for hypopharyngeal cancer with thyroid or cricoid cartilage invasion.

BACKGROUND: Patients with cartilage invasion in hypopharyngeal squamous cell carcinoma (HPSCC) would benefit from partial laryngopharyngectomy (PLP). AIMS/OBJECTIVES: The purpose of this study was to examine the treatment outcomes of PLP for HPSCC with cartilage invasion, with a focus on the oncological safety and the function preservation. MATERIALS AND METHODS: We performed a retrospective review of 28 patients with HPSCC with thyroid or cricoid cartilage invasion who had undergone upfront surgery and were followed for more than one year between 1993 and 2019. RESULTS: Twelve patients treated with PLP (42.9%) and 16 patients treated with total laryngopharyngectomy (TLP) for cartilage invasion in HPSCC were identified. There was no significant difference in recurrence between the PLP group (7/12, 58.3%) and the TLP group (8/16, 50.0%) (p = .718). PLP was not associated with decreased five-year disease free survival (p = .662) or disease specific survival (p = .883) rates compared to TLP. Nine patients receiving PLP could be decannulated and retained intelligible speech (9/12, 75%). Gastrostomy tubes were placed in the PLP group (5/12, 42.9%) and TLP group (1/16, 6.2%) (p = .057). CONCLUSIONS AND SIGNIFICANCE: PLP appears to be a feasible option for the treatment of thyroid or cricoid cartilage invasion in HPSCC.

Predictive factors of distant metastasis in surgically treated HPV-positive tonsil cancer.

BACKGROUND: Human papilloma virus (HPV)-related tonsil cancer is associated with favorable outcomes. OBJECTIVE: The purpose of this study was to define factors affecting distant metastasis in patients with surgically treated HPV-positive tonsil cancer. METHODS: The present study enrolled 76 patients diagnosed with HPV-positive tonsil cancer who underwent primary surgery between January 2010 and December 2021. RESULTS: Twelve (15.7%) patients experienced a distant failure with a median follow-up time of 43 months. Sites of distant metastasis included the lung (n = 10), liver (n = 1), and brain (n = 1). Upon multivariate analysis, an advanced T stage (odds ratio [OR]: 13.94, 95% confidence interval [CI]: 1.29-149.863, p = 0.003) and margin involvement (OR: 5.96, 95% CI: 1.33-26.76, p = 0.02) were independent predictors of distant metastases. The five-year disease-specific survival for the entire cohort was 85%. The multivariate analysis confirmed that distant metastasis (hazard ratio [HR]: 12.688, 95% CI: 3.424-47.016; p < 0.001) and margin involvement (HR: 6.243; 95% CI: 1.681-23.191; p = 0.006) were significant factors associated with the five-year disease-specific survival. CONCLUSION: HPV-positive tonsil cancer patients with an advanced T stage and a positive surgical margin have a substantial risk of distant metastases. Distant metastasis and margin involvement are factors that affect their survival.

Role of local flaps in the prevention of soft tissue necrosis after transoral robotic surgery for tonsillar cancer.

OBJECTIVE: Soft tissue necrosis (STN) can occur after transoral robotic surgery (TORS) with radiation therapy (RT). We investigated the usefulness of local flap reconstruction for preventing STN after TORS in patients with tonsillar cancer. METHODS: This case-control study retrospectively reviewed clinicopathological data of patients who underwent TORS for tonsillar cancer at a tertiary referral center. The incidence of STN was compared in patients who underwent secondary intention healing or local flap reconstruction, and factors predicting STN were identified. RESULTS: STN occurred in 20 (25%) of 80 patients in the study. The incidence of STN was higher in the secondary intention healing than the flap reconstruction group. Mucositis grade (odds ratio [OR] 3.694, p = 0.02), RT dose (OR 4.667, p = 0.001), and secondary intention healing (OR 14.985, p = 0.035) were predictive factors for STN. CONCLUSION: Flap reconstruction can prevent STN after TORS with RT in patients with tonsillar cancer. The use of local flaps preserves the minimally invasive nature of TORS.

MicroRNA-769-3p Acts as a Prognostic Factor in Oral Squamous Cell Cancer by Modulating Stromal Genes.

miR-769-3p expression is suppressed in the stromal subtype of head and neck squamous cell carcinoma (HNSCC); however, its role in stromal HNSCC has not been fully elucidated. To investigate the biological relevance of miR-769-3p in the stromal phenotype, we established oral squamous cell cancer (OSCC) cell lines, namely CAL27, HSC3, and YD8, overexpressing miR-769-3p. miR-769-3p expression was positively and negatively correlated with interferon-gamma-related genes and MYC target gene sets, respectively. miR-769-3p decreased OSCC cell migration and invasion as well as mesenchymal marker expression and increased epithelial marker expression. Moreover, miR-769-3p enhanced OSCC cell sensitivity to 5-fluorouracil. High miR-769-3p expression was associated with good prognosis of HNSCC patients. Collectively, these results suggest that miR-769-3p suppression enhances stromal gene expression and promotes the epithelial-to-mesenchymal transition. Therefore, miR-769-3p may be a potential biomarker of the miRNA phenotype in OSCC patients.

Close Surgical Margins in Oral and Oropharyngeal Cancer: Do They Impact Prognosis?

Introduction. Mucosal margins exhibit a mean shrinkage of 30−40% after resection of oral and oropharyngeal cancers, and an adequate in situ surgical margin frequently results in a pathological close margin. However, the impact on prognosis remains unclear. We investigated the impact of a pathological close margin on disease-free survival (DFS) and overall survival (OS). Methods. We retrospectively reviewed the clinicopathological data of 418 patients diagnosed with squamous cell carcinomas of the oral cavity or oropharynx who underwent initial surgery (with curative intent) at our institute between 2010 and 2016. Results. Of the total population, the pathological marginal status of 290 (69.4%) patients was reported as clear (>5 mm), 61 (14.6%) as close (>1 mm, ≤5 mm), and 67 (16.0%) as positive (≤1 mm). The 5-year DFSs were 79.3%, 65.1%, and 52% in patients in the negative margin (group 1), close margin (group 2), and positive margin (group 3) groups, respectively. The difference between groups 1 and 2 was not significant (p = 0.213) but the difference between groups 2 and 3 was (p = 0.034). The 5-year OSs were 79.4%, 84%, and 52.3% in groups 1, 2, and 3, respectively. The difference between groups 1 and 2 was not significant (p = 0.824) but the difference between groups 2 and 3 was (p = 0.001). In multivariate analysis, older age, advanced T stage, and a positive margin were independently prognostic of the 5-year DFS and OS. Conclusion. In conclusion, the OS of patients with close margins was no different than that of others when appropriate postoperative adjuvant and/or salvage treatment were/was prescribed. However, we could not determine the impact of close margins on locoregional recurrence given various biases in our study setting. A future prospective study is needed.

Prophylactic contralateral neck dissection has no advantage in patients with early stage HPV-positive tonsil cancer.

BACKGROUND: Patients with locally advanced HPV-positive tonsil cancer would benefit from prophylactic contralateral neck dissection (pCND). AIMS/OBJECTIVES: The aim of this study was to analyze rates of contralateral lymph node metastases (LNM) and their prognostic effects on locally advanced HPV-positive tonsillar squamous cell carcinoma. MATERIALS AND METHODS: Medical records of 54 patients who underwent upfront primary surgery and pCND were retrospectively reviewed. RESULTS: Six (11.1%) patients had contralateral LNM in 54 locally advanced HPV-positive tonsil cancer. Of these, five patients had contralateral level II LNM and one patient had contralateral level II and III LNM. Contralateral LNM showed significant positive correlations with advanced T stage (p = .017) and the presence of extracapsular spread (p = .007). Contralateral lymph node metastasis had no significant association with five-year disease-specific survival. CONCLUSIONS AND SIGNIFICANCE: This study demonstrated no advantage in performing pCND in early stage HPV-positive tonsil cancer.

Prognostic impact of resection margin involvement in surgically managed HPV-positive tonsil cancer.

OBJECTIVES: To find out the role of resection margin involvement in surgically managed HPV-positive tonsil cancer. MATERIALS AND METHODS: The study included 94 subjects with HPV-positive tonsil cancer undergoing surgical treatment. We evaluated the relationships between the resection margin status, clinicopathological factors, and oncological outcome. RESULTS: The rate of resection margin involvement was 22.3% (21/94) after ablative surgery. Margin involvement, lymphatic invasion, and extracapsular spread were associated with the 5-year disease-free survival (DFS) and disease-specific survival (DSS) rate in univariate analysis. Multivariate Cox regression analysis confirmed a significant association between the margin involvement and 5-year DFS rate (HR = 4.602; 95% CI = 1.202-17.620; p = 0.026) and 5-year DSS rate (HR = 12.826; 95% CI = 1.399-117.593; p = 0.024). The incidence of resection margin involvement was significantly higher in patients with larger tumors (35.19 ± 15.07 mm vs. 25.53 ± 10.32 mm, p = 0.011) and more invasive tumors (17.84 ± 7.90 mm vs. 13.46 ± 6.88 mm, p = 0.037). The cutoff value of tumor size and depth of invasion for resection margin involvement was 29.5 mm (74% sensitivity and 63% specificity) and 14.5 mm (74% sensitivity and 61% specificity), respectively. CONCLUSION: Resection margin involvement was significantly correlated with tumor size and the depth of invasion in HPV-positive tonsil cancer. Furthermore, resection margin involvement was associated with adverse outcomes.

Characterization of FaDu-R, a radioresistant head and neck cancer cell line, and cancer stem cells.

OBJECTIVES: The aim of this study was to evaluate the impact of CSC on insensitivity to radiotherapy in HNSCC. METHODS: A radioresistant cell line, FaDu-R, was established using fractionated ionizing radiation. Cells with high and low CD44/ALDH activity were isolated. RESULTS: FaDu-R cells demonstrated significantly increased cell viability after radiation exposure compared with parental cells. CD44high/ALDHhigh FaDu-R cells demonstrated significantly faster wound closure (p<0.05) and more efficient invasion (p<0.05) compared to the CD44high/ALDHhigh FaDu cells or the CD44low/ALDHlow FaDu-R cells. There was a significant difference in tumor volume between the CD44high/ALDHhigh FaDu-R cells and the CD44high/ALDHhigh FaDu cells (p<0.05) as well as the CD44low/ALDHlow FaDu-R cells (p<0.05). CONCLUSION: Cancer stem cells (CSC) were associated with invasion and tumorigenesis in a radioresistant head and neck squamous cell carcinoma (HNSCC) cell line. This concept might help to improve the understanding of these mechanisms and to develop drugs that can overcome radioresistance during radiotherapy.

Oral siRNA Delivery to Treat Colorectal Liver Metastases.

Convenient multiple dosing makes oral administration an ideal route for delivery of therapeutic siRNA. However, hostile GI environments and nonspecific biological trafficking prevent achieving appropriate bioavailability of siRNA. Here, an orally administered AuNP-siRNA-glycol chitosan-taurocholic acid nanoparticle (AR-GT NPs) was developed to selectively deliver Akt2 siRNA and treat colorectal liver metastases (CLM). AR-GT NPs are dual padlocked nonviral vectors in which the initially formed AuNP-siRNA (AR) conjugates are further encompassed by bifunctional glycol chitosan-taurocholic acid (GT) conjugates. Covering the surface of AR with GT protected the Akt2 siRNA from GI degradation, facilitated active transport through enterocytes, and enhanced selective accumulation in CLM. Our studies in CLM animal models resulted in the reduction in Akt2 production, followed by initiation of apoptosis in cancer cells after oral administration of Akt2 siRNA-loaded AR-GT. This therapeutic siRNA delivery system may be a promising approach in treating liver-associated diseases.

Oral delivery of a therapeutic gene encoding glucagon-like peptide 1 to treat high fat diet-induced diabetes.

The number of people suffering from insulin-independent type 2 diabetes mellitus (T2DM) is ever increasing on a yearly basis. Current anti-diabetic medications often result in adverse weight gain and hypoglycemic episodes. Hypoglycemia can be avoided with glucagon-like peptide (GLP)-1 receptor agonists, which are expensive and require daily injections that may result immune activation. This study demonstrates the use of non-viral vector based oral delivery of GLP-1 gene through enterohepatic recycling pathways of bile acids. Oral administration of the plasmid DNA (pDNA) encoding GLP-1 decreased diabetic glucose levels to the normoglycemic range with significant weight reduction in a high-fat diet (HFD) induced diabetic mouse model and a genetically engineered T2DM rat model. This novel oral GLP1 delivery system is an attractive alternative to treat late-stage T2DM conditions that require repeated insulin injection and can potentially minimize the occurrence of hypoglycemic anomalies.

Prognostic implication of ERCC1 protein expression in resected oropharynx and oral cavity cancer.

BACKGROUND: Excision repair cross complement group 1 (ERCC1) expression is a predictive biomarker for platinum-containing treatment in squamous cell carcinoma of head and neck (SCCHN). However, the prognostic significance after surgical resection is not well understood. METHODS: Oropharynx (n=143) or oral cavity (n=61) SCCHN patients undergoing surgery were included. ERCC1 protein expression and HPV status were assessed by ERCC1 and p16 immunohistochemistry. RESULTS: The ERCC1, over-expressed in 66.7% of patients, was associated with oral cavity cancer (P<0.001), well differentiation (P=0.036), and HPV negativity (P<0.001). In TCGA database, ERCC1 mRNA upregulation was enriched in HPV-negative and oral cavity cancers, and associated with HRAS mutation (P<0.001). The prognostic role of ERCC1 was not different according to HPV status. High ERCC1 expression showed a trend toward poor prognosis in patients with an advanced stage (P=0.079) with marginal significance. CONCLUSIONS: The ERCC1 expression was not prognostic in surgically resected oropharynx/oral cavity SCCHN, irrespective of HPV status. However, it could provide additional prognostic information for advanced stage patients.

Prognostic impact of perineural invasion in hypopharyngeal squamous cell carcinoma.

OBJECTIVES: The aim of this study was to evaluate the role of PNI in HPSCC. METHODS: The medical records of 105 patients who underwent surgery-based treatment for HPSCC were reviewed. Clinicopathologic parameters including disease-specific survival were correlated with PNI. RESULTS: PNI was identified in 27 of the 105 (25.7%) cases of HPSCC. Correlation analysis demonstrated that PNI in HPSCC was significantly correlated with pN classification (10.3% in N0/N1 vs 34.8% in N2/N3, p = 0.006). Patients with PNI had decreased 5-year disease-specific survival with borderline significance (p = 0.065). In a sub-set of 31 patients who did not receive post-operative radiotherapy, PNI was determined to be a significant prognostic predictor (p = 0.033). In multivariate analysis, extracapsular invasion was the only independent prognostic factor for disease-specific survival (p = 0.001). CONCLUSION: Perineural invasion (PNI) should be considered an independent predictor for cervical lymph node involvement. PNI status in primary hypopharyngeal squamous cell carcinoma (HPSCC) specimens should be considered in decisions concerning adjuvant radiotherapy.

Chromosomal aberrations and prognosis in patients with concomitant chemoradiotherapy for resected head and neck cancer.

Although concomitant chemoradiotherapy (CCRT) has recently become a mainstay of a primary treatment modality in advanced head and neck squamous cell carcinoma (HNSCC), some of the patients experience CCRT failure. If we can predict the CCRT outcomes, we can reduce unnecessary CCRT avoiding risk of CCRT­related complication. We aimed to identify genetic alteration markers related to treatment failure in HNSCC patients who underwent radical surgery and CCRT. Genome­wide copy number alterations (CNAs) were analyzed in 18 HNSCC patients with (n=9) or without (n=9) recurrence using oligoarray­comparative genomic hybridization and candidate CNAs were validated by quantitative RT­PCR. A total of 15 recurrently altered regions (RARs) were identified in the 18 HNSCC cases. Among them, two RARs were significantly associated with CCRT­failure: copy number gained RARs of 7p11.2 harboring EGFR (P=0.029) and 18p11.32 harboring TYMS gene (P=0.029). Three RARs (7p11.2, 9p21.3 and 18p11.32) were significantly associated with poor disease­specific survival in univariate analysis, and 7p11.2 was consistently significant in the multivariate analysis (HR 40.68, P=0.003). In conclusion, we defined novel genomic alterations associated with CCRT­failure: 7p11.2 (EGFR) and 18p11.32 (TYMS). Our results provide useful clues for the elucidation of the molecular pathogenesis of HNSCC and to predict CCRT­failure.

Prognostic impact of lymph node micrometastasis in oral and oropharyngeal squamous cell carcinomas.

BACKGROUND: The purpose of this study was to determine the role of lymph node micrometastasis in oral and oropharyngeal cancers. METHODS: We investigated the presence of micrometastases by cytokeratin immunohistochemical staining in 54 patients with node-negative oral and oropharyngeal carcinomas. RESULTS: The positive rate of cytokeratin expression was 13.0% (7 of 54 patients). The incidence of micrometastasis was significantly higher in patients with more invasive tumors (p < .001) and larger tumor size (p = .034). The 5-year disease-specific (DS) survival rate significantly correlated with micrometastasis, margin involvement, and depth of invasion in the univariate analyses. Multivariate Cox regression analysis confirmed a significant association between the 5-year DS survival rate and micrometastasis (hazard ratio [HR] = 7.89; 95% confidence interval [CI] = 1.09-57.14; p = .041) and margin involvement (HR = 11.68; 95% CI = 1.22-111.75; p = .033). CONCLUSION: Micrometastasis was significantly correlated with the depth of invasion and tumor size in oral and oropharyngeal cancers. Furthermore, micrometastasis was associated with adverse outcomes. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1777-E1782, 2016.

Efficacy of 18F-fluorodeoxyglucose positron emission tomography/CT imaging for extracapsular spread of laryngeal squamous cell carcinoma.

BACKGROUND: We evaluated the use of fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT for the identification of extracapsular spread (ECS) with supporting histologic correlations in laryngeal cancer. METHODS: We reviewed the medical records of 89 patients with laryngeal cancer who underwent FDG PET/CT before surgery. RESULTS: ECS was present in 38.2% (18 of 47) of dissected necks and in 32.2% (20 of 62) of dissected cervical levels. There was a significant difference in the standardized uptake value maximum (SUVmax ) between cervical lymph nodes with and without ECS (6.39 ± 4.53 vs 1.21 ± 1.70; p < .001); the cutoff value for differentiating nodes with ECS from those without ECS was 2.8, with a sensitivity of 85.7% and specificity of 85.6%. CONCLUSION: A median SUVmax cutoff value >2.8 was associated with an increased risk of cervical lymph node metastasis and ECS in patients with laryngeal cancer.

Swallowing function in patients with vertical hemipharyngolaryngectomy for hypopharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to evaluate the long-term swallowing function in patients with vertical hemipharyngolaryngectomy (VHPL) for hypopharyngeal cancer. METHODS: A retrospective review of 30 patients followed for more than 2 years with VHPL between 1998 and 2011 was performed. RESULTS: Five patients (16.7%) experienced gastrostomy tube placement, 4 patients (13%) had pharyngoesophageal stricture, and 13 patients (45%) had aspiration pneumonia. There was a significant difference in the fraction of gastrostomy tube placement among type II VHPL (35.7%), type I VHPL (0%), and type III VHPL (0%; p = .014). Gastrostomy tube dependence was significantly associated with flap size (larger than 70 cm(2) ; p = .043) and aspiration pneumonia (p = .009). A significant positive correlation was found between current smokers and aspiration pneumonia (p = .030). CONCLUSION: Type II VHPL, large flap reconstruction, and aspiration pneumonia had predictable values for gastrostomy tube dependence. Smoking status correlated with aspiration pneumonia. Better counseling and vigilance concerning swallowing difficulties may be possible.

Establishment of a novel human papillomavirus-negative and radiosensitive head and neck squamous cell carcinoma cell line.

BACKGROUND: The purpose of this study was to develop a CMCSCC-1 cell line for head and neck cancer research into new therapies for head and neck squamous cell carcinoma (HNSCC). METHODS: The CMCSCC-1 cell line was isolated from a primary oral tongue tumor specimen of a female patient. Tumor cells were evaluated for biomarkers expression by Western blots, reverse transcriptase-polymerase chain reaction (RT-PCR), fluorescence activated cell sorter, and immunostaining. Cell proliferation in response to radiation was measured by the WST-8 assay. RESULTS: The characterization analyses revealed a typical epithelial morphology; a doubling time of approximately 24 hours, high tumorigenicity in immunodeficient mice, and upregulated biomarkers. CMCSCC-1 cells were negative for human papillomavirus (HPV) infection, but more sensitive to radiation compared with those FaDu cell lines. CONCLUSION: CMCSCC-1, a novel oral tongue SCC cell line, was established. It will help in the elucidation of the molecular pathogenesis of HPV-negative radiosensitive tumors. © 2015 Wiley Periodicals, Inc. Head Neck 38: E542-E551, 2015.

Lymph node density as an independent prognostic factor in node-positive patients with tonsillar cancer.

BACKGROUND: The purpose of this study was to evaluate the utility of lymph node density for predicting the survival of patients with tonsillar cancer and positive neck nodes. METHODS: We reviewed data for 64 patients diagnosed with tonsillar cancer with lymph node metastasis in a retrospective single center audit. RESULTS: Lymph node density (≥0.05), extracapsular spread (ECS), number of ECS (≥3), vascular invasion, perineural invasion, and N classification (N1/N2a vs N2b/N2c) were significant predictors of 5-year disease-free survival (DFS). Lymph node density (≥0.05), human papillomavirus (HPV) infection, and N classification (N1/N2a vs N2b/N2c) were significant predictors of 5-year overall survival (OS). In the multivariate analysis, categorical lymph node density remained a significant predictor of DFS (p = .025*; hazard ratio [HR] = 6.063) and no parameter was significantly predictive of OS. CONCLUSION: Lymph node density might be useful as an independent predictor of survival in patients with tonsillar cancer and positive lymph nodes. © 2015 Wiley Periodicals, Inc. Head Neck 38: E705-E711, 2016.

Prognostic Significance of Lymph Node Density in Patients with Hypopharyngeal Squamous Cell Carcinoma.

BACKGROUND: Lymph node density (LND) is more useful than the TNM classification in predicting survival after surgery for many cancers. The purpose of this study was to clarify independent prognostic factors for hypopharyngeal squamous cell carcinoma (HPSCC) and broaden the staging system to improve its predictive value. METHODS: The present study included 105 patients with HPSCC treated with hypophagectomy and neck dissection between 1993 and 2014. RESULTS: The median LND in patients with HPSCC was 0.060 (range 0.026-0.620). We found a significant difference in LND values between patients with and without recurrence (0.063 vs. 0.030, respectively; p = 0.001). The cutoff value of LND for recurrence was 0.055, with a sensitivity of 68% and specificity of 71%. Cervical lymph node metastasis, advanced pathologic T stage, lymphovascular invasion, LND ≥0.055, and extracapsular spread had significant adverse effects on 5-year overall and disease-specific survival in a univariate analysis. Multivariate analysis confirmed a significant association between 5-year overall survival and LND ≥0.055 [hazard ratio (HR) 2.19; 95% confidence interval (CI) 1.06-4.51; p = 0.035] and extracapsular spread (HR 2.47; 95% CI 1.09-5.61; p = 0.030). Furthermore, LND ≥0.055 (HR 2.30; 95% CI 1.07-4.93; p = 0.034) and extracapsular spread (HR 2.95; 95% CI 1.20-7.29; p = 0.019) were associated with 5-year, disease-specific survival. CONCLUSIONS: The median LND cutoff values ≥0.055 are associated with a greater risk of recurrence and survival in patients with HPSCC.

A hyaluronic acid nanogel for photo-chemo theranostics of lung cancer with simultaneous light-responsive controlled release of doxorubicin.

The combined delivery of photo- and chemo-therapeutic agents is an emerging strategy to overcome drug resistance in treating cancer, and controlled light-responsive drug release is a proven tactic to produce a continuous therapeutic effect for a prolonged duration. Here, a combination of light-responsive graphene, chemo-agent doxorubicin and pH-sensitive disulfide-bond linked hyaluronic acid form a nanogel (called a graphene-doxorubicin conjugate in a hyaluronic acid nanogel) that exerts an activity with multiple effects: thermo and chemotherapeutic, real-time noninvasive imaging, and light-glutathione-responsive controlled drug release. The nanogel is mono-dispersed with an average diameter of 120 nm as observed by using TEM and a hydrodynamic size analyzer. It has excellent photo-luminescence properties and good stability in buffer and serum solutions. Graphene itself, being photoluminescent, can be considered an optical imaging contrast agent as well as a heat source when excited by laser irradiation. Thus the nanogel shows simultaneous thermo-chemotherapeutic effects on noninvasive optical imaging. We have also found that irradiation enhances the release of doxorubicin in a controlled manner. This release synergizes therapeutic activity of the nanogel in killing tumor cells. Our findings demonstrate that the graphene-doxorubicin conjugate in the hyaluronic acid nanogel is very effective in killing the human lung cancer cell line (A549) with limited toxicity in the non-cancerous cell line (MDCK).