The clinical outcome of pembrolizumab for patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a single center, real world study in China.

Background: The KEYNOTE-048 and KEYNOTE-040 study have demonstrated the efficacy of pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), we conducted this real-world study to investigate the efficacy of pembrolizumab in patients with R/M HNSCC. Methods: This is a single-center retrospective study conducted in the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Between December 2020 and December 2022, a total of 77 patients with R/M HNSCC were included into analysis. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR)and toxicity.Efficacy was assessed according to RECIST version 1.1.SPSS 27.0 and GraphPad Prism 8.0 software were utilized to perform the statistical analysis. Results: By the cut-off date (February 28, 2023), the median OS,PFS and ORR were 15.97 months,8.53 months and 48.9% in patients treated with the pembrolizumab regimen in the first line therapy. Among these patients, 17 patients received pembrolizumab with cetuximab,and 18 received pembrolizumab with chemotherapy.We observed no significant differences between two groups neither in median OS (13.9 vs 19.4 months, P=0.3582) nor PFS (unreached vs 8.233 months, P= 0.2807). In the ≥2nd line therapy (n=30), the median OS, PFS and ORR were 5.7 months, 2.58 months and 20% respectively. Combined positive score (CPS) was eligible from 54 patients. For first line therapy, the median OS and PFS were 14.6 and 8.53 months in patients with CPS ≥1, and median OS and PFS were 14.6 and 12.33 months in patients with CPS ≥20. The immune-related adverse events (irAEs) were occurred in the 31 patients (31/77, 40.26%), and the most common potential irAEs were hypothyroidism (25.97%), and pneumonitis (7.79%). Conclusion: Our real-world results indicated that pembrolizumab regimen is a promising treatment in patients with R/M HNSCC.

A pilot study of camrelizumab with docetaxel and cisplatin for the first line treatment in recurrent/metastatic oral squamous cell carcinoma.

Pembrolizumab with cisplatin and 5-fluorouracil showed survival benefit but relatively high occurrence of treatment-related adverse events (TRAEs) for recurrent/metastatic oral squamous cell carcinoma (R/M OSCC). A more tolerable regime is needed. This trial enrolled 20 R/M OSCC patients with previously untreated and PD-L1 positive. Patients were administered camrelizumab with docetaxel and cisplatin every 3 weeks for six cycles, followed by camrelizumab monotherapy every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was occurrence of grade ≥ 3 TRAEs, secondary endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). 45% patients experienced grade ≥ 3 TRAEs, which the most common were anemia (15%), stomatitis (15%), and neutropenia (10%). The most common potential immune-related adverse events were reactive cutaneous capillary endothelial proliferation (RCCEP; 60%), hypothyroidism (35%), and pneumonitis (15%). No treatment-related deaths occurred. The median OS, PFS, and ORR was 14.4 months, 5.35 months, and 40.0% respectively. The study also found RCCEP occurrence, lower FOXP3+ cells, and higher density of intratumor tertiary lymphoid structure were associated with improved efficacy. Our data suggest that camrelizumab with docetaxel/cisplatin as first-line therapy was well tolerable and had potentially favorite efficacy in PD-L1-positive patients with R/M OSCC.

Chemotherapy in combination with anti-PD-1 agents as adjuvant therapy for high-risk oral mucosal melanoma.

BACKGROUND: Adjuvant therapy plays a critical role in the treatment of oral mucosal melanoma (OMM). Anti-programmed cell death-1 (PD-1) agents are recommended as front-line therapy for metastatic melanoma, but their efficacy as adjuvant therapy for high-risk OMM remains unclear. PATIENTS AND METHODS: A single-center, retrospective cohort study was conducted in 193 nodular-type oral mucosal melanoma (NOMM) patients who received chemotherapy alone or in combination with high-dose interferon-α2b (HDI) or anti-PD-1 agents as adjuvant therapy. Multivariate analysis was performed to identify significant prognostic factors for the 2-year overall survival (OS) and progression-free survival (PFS). RESULTS: Tumor thickness, ulceration and invasion level were found to be independent prognostic factors for both 2-year OS and PFS, while T-stage was only associated with OS. The 2-year OS and PFS were 43.5% and 10.9% in patients who received only chemotherapy. In comparison, the 2-year OS was improved, albeit not significantly (47.4%; p > 0.05), and PFS was significantly improved (43.6%; p = 0.0028) in patients who received chemotherapy plus HDI; and both 2-year OS (71.0%; p = 0.0118) and PFS (53.6%; p = 0.0001) were significantly improved in patients received chemotherapy plus anti-PD-1. The serious adverse event (SAE) (p < 0.0001) and discontinued treatment due to SAE (p < 0.0001) were significantly lower in patients who received anti-PD-1 than in patients who received HDI. CONCLUSIONS: Invasion level and tumor thickness are independent prognostic factors for NOMM. Chemotherapy plus anti-PD-1 agents seem to be the adjuvant therapy of choice for NOMM, as it is safer and more tolerable than HDI and, more importantly, it can significantly improve the OS and PFS.

Candidate therapeutic agents in a newly established triple wild-type mucosal melanoma cell line.

BACKGROUND: Mucosal melanoma has characteristically distinct genetic features and typically poor prognosis. The lack of representative mucosal melanoma models, especially cell lines, has hindered translational research on this melanoma subtype. In this study, we aimed to establish and provide the biological properties, genomic features and the pharmacological profiles of a mucosal melanoma cell line that would contribute to the understanding and treatment optimization of molecularly-defined mucosal melanoma subtype. METHODS: The sample was collected from a 67-year-old mucosal melanoma patient and processed into pieces for the establishment of cell line and patient-derived xenograft (PDX) model. The proliferation and tumorigenic property of cancer cells from different passages were evaluated, and whole-genome sequencing (WGS) was performed on the original tumor, PDX, established cell line, and the matched blood to confirm the establishment and define the genomic features of this cell line. AmpliconArchitect was conducted to depict the architecture of amplified regions detected by WGS. High-throughput drug screening (HTDS) assay including a total of 103 therapeutic agents was implemented on the established cell line, and selected candidate agents were validated in the corresponding PDX model. RESULTS: A mucosal melanoma cell line, MM9H-1, was established which exhibited robust proliferation and tumorigenicity after more than 100 serial passages. Genomic analysis of MM9H-1, corresponding PDX, and the original tumor showed genetic fidelity across genomes, and MM9H-1 was defined as a triple wild-type (TWT) melanoma subtype lacking well-characterized "driver mutations". Instead, the amplification of several oncogenes, telomerase reverse transcriptase (TERT), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), melanocyte Inducing transcription factor (MITF) and INO80 complex ATPase subunit (INO80), via large-scale genomic rearrangement potentially contributed to oncogenesis of MM9H-1. Moreover, HTDS identified proteasome inhibitors, especially bortezomib, as promising therapeutic candidates for MM9H-1, which was verified in the corresponding PDX model in vivo. CONCLUSIONS: We established and characterized a new mucosal melanoma cell line, MM9H-1, and defined this cell line as a TWT melanoma subtype lacking well-characterized "driver mutations". The MM9H-1 cell line could be adopted as a unique model for the preclinical investigation of mucosal melanoma.

Evaluation of Safety of Treatment With Anti-Epidermal Growth Factor Receptor Antibody Drug Conjugate MRG003 in Patients With Advanced Solid Tumors: A Phase 1 Nonrandomized Clinical Trial.

Importance: The antibody drug conjugate drug MRG003 comprises an anti-epidermal growth factor receptor (EGFR) humanized immunoglobulin G1 monoclonal antibody that is conjugated with monomethyl auristatin E via a valine-citrulline linker. There is currently insufficient evidence of this drug's safety and efficacy. Objective: To evaluate the safety and maximum tolerated dose of MRG003 in a phase 1a study and investigate the preliminary antitumor activity in EGFR-expressing patients in a phase 1b study. Design, Setting, and Participants: This nonrandomized open-label, single-arm, phase 1, multicenter study of solid tumors was divided into 2 parts, phase 1a dose escalation and phase 1b dose expansion. Patients with advanced or metastatic solid tumors who had failed outcomes from or were not able to receive standard treatment were enrolled in phase 1a without EGFR prescreening. Phase 1b recruited EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). This study was conducted at 7 Chinese centers between April 11, 2018, and March 29, 2021 (data cutoff date). Data analysis took place between April 2021 and June 2021. Interventions: An intravenous dose of 0.1 to 2.5 mg/kg of MRG003 was administered every 3 weeks during phase 1a. During phase 1b, patients were administered the recommended dose identified in phase 1a. Main Outcomes and Measures: The primary end points were dose-limiting toxic effects in phase 1a and objective response rate in phase 1b. The safety, tolerability, immunogenicity, and pharmacokinetics of MRG003 were assessed. Tumor assessment was evaluated by RECIST 1.1. Results: Twenty-two patients (mean [range] age, 54.5 [32.0-67.0] years; 9 women [41%]) were enrolled in phase 1a and 39 patients (mean [range] age, 50.4 [27.0-75.0] years; 8 women [21%]) in phase 1b. The recommended dose was identified as 2.5 mg/kg. Eighty-nine percent of adverse events (AEs) were associated with MRG003 treatment, and most AEs were grade 1 to 2. Nineteen patients (31%) reported grade 3 or greater treatment-related AEs, including hyponatremia, leukocytopenia, neutropenia, increased aspartate aminotransferase levels, and febrile neutropenia. In phase 1a, 1 patient (5%) achieved a partial response, and 5 (23%) achieved stable disease. In phase 1b, 8 patients (21%) achieved a confirmed partial response, and 12 (31%) achieved stable disease. The objective response rates for SCCHN, NPC, and CRC were 40%, 44%, and 0%, and the disease control rates were 100%, 89%, and 25%, respectively. Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that MRG003 showed a manageable safety profile and promising antitumor activity in patients with EGFR-positive NPC and SCCHN. Trial Registration: Clinicaltrials.gov Identifier: NCT04868344.

A multicenter randomized phase II trial of hyperthermia combined with TPF induction chemotherapy compared with TPF induction chemotherapy in locally advanced resectable oral squamous cell carcinoma.

BACKGROUND: Hyperthermia has been reported to cause cancer stage regression, thus providing surgical opportunities in patients with unresectable tumors and improving the quality of life of patients by preserving certain organs. METHODS: A prospective open-label phase II trial was conducted to evaluate the efficacy of hyperthermia combined with induction chemotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). Patients received hyperthermia combined with two cycles of 5-fluorouracil, cisplatin, and docetaxel (TPF) induction chemotherapy regimens or TPF induction chemotherapy alone, followed by radical surgery with postoperative radiotherapy. The primary endpoint was the clinical response rate of the induction chemotherapy. The secondary endpoints were overall survival (OS), disease-free survival (DFS), and toxicity. RESULTS: A total of 120 patients were enrolled, and 115 patients were included in the clinical response analysis. The clinical response rate was significantly higher in the experimental arm than in the control arm (65.45% vs. 40.00%, p = 0.0088). There were no unexpected toxicities, and hyperthermia and induction chemotherapy did not increase the perioperative morbidity rate. Moreover, there was a significant improvement in DFS, but no significant difference in OS between the two arms. In the subgroup analysis, increased OS and DFS rates were associated with patients with favorable clinical response after induction chemotherapy in the total population, experimental arm, and control arm. CONCLUSIONS: Our study demonstrates that hyperthermia combined with induction chemotherapy is associated with a high response rate and provides a new treatment option for patients with resectable stage III or IVA OSCC.

A bibliometric analysis on studies of nanomedicine applications in head and neck squamous cell carcinoma.

BACKGROUND: Bibliometric analysis highlights the pivotal studies and topics that have shaped the understanding and management of a disease in its designated field. Herein, original articles on the applications of nanotechnology in head and neck squamous cell carcinoma (HNSCC) were characterized and analyzed. METHODS: A comprehensive search was carried out using a bibliometric methodology, and eligible articles on nanomedicine research in HNSCC were retrieved from the Scopus database. RESULTS: A total of 309 eligible articles were retrieved, and the total citation count was 7,468. An ascending trend in citation count was observed since 2004, which increased substantially between 2014 and 2019. There were 144 (52.7%) original articles on oral cavity carcinomas. Chemotherapy (n=53, 19.4%), chemoprevention (n=35, 11.3%), and photodynamic therapy (n=23, 8.4%) were the three most published topics on the applications of nanotechnology in the therapy of HNSCC. Sentinel node detection (n=25, 9.2%) and noninvasive cancer diagnosis (n=22, 8.1%) were the two most published topics in the diagnostic area of HNSCC. A vast majority of these articles were preclinical studies, and only four articles (1.5%) were phase I/II clinical studies on chemotherapy and radiotherapy. CONCLUSIONS: To the best of our knowledge, this is the first study to analyze the bibliometric characteristics of original articles on nanomedicine in HNSCC. The results of this study not only provide a historical perspective on the scientific evolution in this field, but also revealed the trends and key topics within it that may help facilitate further research.

TLR4 activation leads to anti-EGFR therapy resistance in head and neck squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and related to cancer progression. The resistance to anti-EGFR therapy remains a major clinical problem in HNSCC. In this study, we found that TOLL-like receptor 4 (TLR4) was highly expressed in 50% of EGFR overexpressed HNSCC biopsies, which correlated to worse prognosis in patients. In HNSCC cell lines, activation of TLR4 reversed cetuximab-induced the inhibition of proliferation, migration and invasion. LPS induced of TLR4 signaling was potentiated under cetuximab treatment, showing increased activation of downstream NF-κB and MAPK pathways. Accordingly, cetuximab treatment also increased expression of TNF-α, COX2, and other molecules involved in TLR4 induced tumor inflammation. Mechanistically, we found inhibition of EGFR by cetuximab led to decreased phosphorylation of Src and sequentially Src-medicated activation of Cbl-b. This inhibited Cbl-b-mediated degradation of the key TLR4 adaptor protein MyD88 and activated TLR4 signaling. TLR4 or MyD88 overexpressed CAL27 and SCC4 cells grew faster and were more resistant to cetuximab and gefitinib both in vitro and in vivo. Out study delineates a crosstalk between EGFR and TLR4 pathways and identified TLR4 as a potential biomarker as well as a therapeutic target in overcoming the resistance to anti-EGFR therapy of HNSCC.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in the oromaxillofacial head and neck region: A retrospective analysis of 105 patients.

BACKGROUND: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the oromaxillofacial head and neck region is rare, with limited data available. This retrospective study explored the clinical features, stage, treatment, and prognosis of this disease. METHODS: Overall, 105 patients with MALT lymphomas in the oromaxillofacial head and neck region were included in this retrospective analysis. SPSS 22.0 software package was used for data analysis and a two-tailed P value of ≤.05 was considered statistically significant. Primary endpoints of the study were the complete response (CR) rate, overall survival (OS), and progression-free survival (PFS). RESULTS: About 52% of the patients had long-term xerostomia, autoimmune diseases, or chronic parotitis and 81% had diseases involving the large salivary glands. Ann Arbor staging of the patients was as follows: stages I/II, 73 patients and stages III/IV, 32 patients. In the 97 patients followed up, CR rate after initial treatment was 80%. Tumor progression was observed in 12 patients and 14 patients died. There was a significant difference between the rate of CR in localized (87%) and disseminated (67%) lymphoma patients (P = .02). The 5- and 10-year PFS of the localized lymphoma patients were both 91%, whereas those of the disseminated lymphoma patients were 83% and 65%, respectively (P = .03). The 5-year PFS rates of the chemotherapy and non-chemotherapy groups in the disseminated lymphoma patients were 85% and 73% (P = .04). Meanwhile, the 5-year PFS rates of the rituximab and non-rituximab groups in the disseminated lymphoma patients were 100% and 70% (P = .03). In multivariate analysis, MALT Lymphoma International Prognostic Index (MALT-IPI) was an independent prognostic factor affecting OS, whereas Ann Arbor staging affected PFS. CONCLUSIONS: This study suggests that the outcome after initial treatment of MALT lymphomas in the oromaxillofacial head and neck region is satisfactory and that this disease progresses slowly. The CR rate and PFS of localized lymphoma patients are better than those of disseminated lymphoma patients. Systemic treatment (chemotherapy or rituximab) may improve PFS in disseminated disease patients. MALT-IPI and Ann Arbor staging are independent prognostic factors.

Cisplatin based induction chemotherapy modified by ERCC1 improved the outcome of young adults with locally advanced oral squamous cell carcinoma.

Objective: To evaluate the efficacy of induction chemotherapy in young adults with locally advanced oral squamous cell carcinoma (OSCC) and the usefulness of ERCC1 as a prognostic indicator. Methods: A total of 156 young adults with locally advanced OSCC were retrospectively analyzed from May 2007 to May 2017. Cisplatin based induction chemotherapy followed by surgery and upfront surgery were the primary treatment options for locally advanced OSCC. ERCC1 was evaluated by immunohistochemistry. Multivariate analysis was performed to identify significant prognostic factors for the overall survival (OS) in young adults with locally advanced OSCC. Results: Extracapsular spread (ECS) (p<0.0001) and UICC staging (p<0.0001) were critical prognostic factors for OS in young adults with locally advanced OSCC. The 5-year OS was 83.2% in N0 patients received induction chemotherapy and 61.7% in N0 patients received upfront surgery (p<0.05). Patients with a low ERCC1 expression were more likely to benefit from induction chemotherapy, as the 5-year OS was 22.4% in patients with a high ERCC1 expression and 84.7% in patients with a low ERCC1 expression, respectively (p<0.0001). However, induction chemotherapy resulted in a higher 5-year OS (84.7%) than upfront surgery (59.1%) in patients with a low ERCC1 expression (p=0.03). Conclusions: Induction chemotherapy can improve the outcome of N0 patients. However, the ERCC1 expression should be determined in young patients with locally advanced OSCC prior to induction chemotherapy, as it is a useful biomarker for predicting the outcome after induction chemotherapy.

Long non-coding RNA ANRIL promotes tumorgenesis through regulation of FGFR1 expression by sponging miR-125a-3p in head and neck squamous cell carcinoma.

ANRIL (CDKN2B antisense RNA 1, CDKN2B-AS1) is involved in the progression of various cancers. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, we found that ANRIL expression was upregulated in HNSCC and correlated with tumor progression. Further functional analysis showed that knockdown of ANRIL significantly inhibited proliferation in vivo and in vitro. ANRIL functioned as a ceRNA (competing endogenous RNAs) for miR-125a-3p and upregulated FGFR1 (fibroblast growth factor receptor-1), which could promote tumor growth. Moreover, we confirmed that ANRIL promoted HNSCC activity via FGFR1 with a FGFR1 inhibitor in vivo and in vitro. Thus, it could be concluded that ANRIL promoted the progression of HNSCC via miR-125a-3p/FGFR1/MAPK signaling, which might provide a new target for the diagnosis and treatment of HNSCC.

The existence of early stage oral mucosal melanoma: A 10-year retrospective analysis of 170 patients in a single institute.

BACKGROUND: Oral mucosal melanoma (OMM) is an aggressive tumor with an extremely low incidence, and the current TNM Staging System has classified all OMMs as high stage. However, controversy remains regarding the existence of early stage OMMs. PATIENTS AND METHODS: The clinical and pathological features, treatments and outcomes of 170 OMM patients treated in a single institution from January 2007 to July 2017 were retrospectively analyzed. Multivariate analysis was performed to identify significant prognostic factors for overall survival (OS). RESULTS: Multivariate analysis identified positive cervical lymph nodes (p < 0.0001), nodular OMMs (p < 0.0001), ulceration (p = 0.002), and level III or level IV invasion (p < 0.0001) as independent poor prognostic factors for OS. Nodular OMM patients with a tumor size ≤1 cm had a better outcome than those with a tumor size >1 cm (p < 0.0001). Twenty-two patients with superficial invasion had a favorable survival without the need of adjuvant therapy (postoperative chemotherapy or radiotherapy), and the current TNM Staging System was not suitable for those patients. Patients with deep invasion were more likely to suffer from recurrence and distant metastasis. CONCLUSIONS: Tumor size ≤1 cm and OMM in situ, although extremely rare, do exist. It is advisable for AJCC to consider tumor size ≤1 cm and OMM in situ as the early stage of OMM when updating the new Oral Melanoma Staging System.

Ultrasound hyperthermia enhances chemo-sensitivity in oral squamous cell carcinoma by TRIF-mediated pathway.

BACKGROUND: Hyperthermia is currently used as an alternative to surgery or in combination with chemotherapy and/or radiation therapy in the treatment of oral squamous cell carcinoma. However, little has been known about the change in chemo-sensitivity after hyperthermia and the mechanism underlie it in oral squamous cell carcinoma. METHODS: The aim of this study was to explore the influence of chemo-sensitivity of CAL-27 and SCC-4 cells by histoculture drug response assay after the animal model treated by the ultrasound hyperthermia. Then, we conducted a microarray between xenograft after hyperthermia at 42°C for 45 minutes and that with no treatment. We further confirmed the expression of TRIF in hyperthermia by immunohistochemistry, RT-PCR and Western blot. RESULTS: The chemo-sensitivity to five kinds of drugs demonstrated ultrasound hyperthermia performed in 42°C for 45 minutes would reach the highest inhibition rate in CAL-27 and SCC-4 cells. The microarray dataset revealed that 847 mRNA were upregulated and 1031 were downregulated. GO and pathway analyses indicated that they play an important role in translational initiation, nucleoplasm, and poly (A) RNA binding in the hyperthermia process. We further confirmed the expression of TRIF was downregulated in hyperthermia along with inactivation of NF-κB pathway. CONCLUSIONS: The experiments confirms the rationality of synchronous combination of hyperthermia and chemotherapy and may provide a better treatment that the use of sensitivity testing in such cases may lead to individualized, more effective therapy.

The clinical significance of c-Kit mutations in metastatic oral mucosal melanoma in China.

c-Kit mutations are frequently detected in mucosal melanomas, but their clinical significance in metastatic oral mucosal melanomas (OMM) remains unclear. The main purpose of this study was to investigate the clinical and pathological features of metastatic OMMs with c-Kit mutations and the efficiency of the tyrosine kinase inhibitor imatinib in treating metastatic OMMs. We found thatresidual primary lesion and neck lymph nodes could act as independent prognostic factors in metastatic OMM patients. c-Kit mutations were detected in 22 out of 139 (15.8%) metastatic OMM patients. Under chemotherapy, the overall survival (OS) of c-Kit mutant patients was significantly shorter than that of wild-type patients. The Ki67 expression was significantly higher in c-Kit mutant patients than in wild-type patients. In distant metastatic OMM patients with c-Kit mutations, the treatment with c-Kit inhibitor resulted in a better OS. In conclusion, residual primary lesion, cervical lymph nodes and c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The Kit inhibitor imatinib could benefit metastatic OMM patients with c-Kit mutations.

Ki67 Proliferation Index as a Histopathological Predictive and Prognostic Parameter of Oral Mucosal Melanoma in Patients without Distant Metastases.

Background: To investigate the relationship between clinical and histopathological characteristics and overall survival of patients with oral mucosal melanoma (OMM) without distal metastasis in order to provide predictive prognostic information of OMM. Methods: Ki67 expression was assessed by immunohistochemistry in 123 patients with OMM without distant metastases. The associations between Ki67 expression and clinical features and overall survival (OS) of patients were statistically analyzed. The Ki67 levels of the primary and recurrent lesions from 14 OMM patients were compared. Results: Univariate analysis showed that tumor type and cervical lymph node (CLN) status, as well as Ki67 expression, were all correlated with survival. Cox proportional hazards regression analysis identified Ki67 expression and CLN status as independent prognostic factors in OMM patients. Further, we found that Ki67 expression was associated with clinical tumor type of OMM. Moreover, with a cut-off point of 20%, patients with lower Ki67 scores showed a survival advantage over those with higher Ki67 scores. Conclusions: Ki67 expression may be a useful pathological predictor of survival of OMM patients without distant metastases.

Loss of nuclear BAP1 expression is associated with poor prognosis in oral mucosal melanoma.

Oral mucosal melanoma (OMM) is an aggressive neoplasm with an extremely poor prognosis. BAP1 is a tumor suppressor that has been associated with the outcome of melanomas and other malignancies. In this study, we investigated the genetic alterations in BAP1 and the prognostic potential of BAP1 protein expression in oral mucosal melanoma. DNA sequence analysis of BAP1 from 12 OMM patient samples revealed missense mutations in the tissues from four patients. Based on immunohistochemical staining, loss of nuclear BAP1 expression was associated with poor overall survival (P < 0.001, Log-rank = 21.308) and distant metastasis (P = 0.034, OR = 0.320). Multivariate analysis showed BAP1 to be an independent prognostic factor (P = 0.027, HR = 0.479). It thus appears that loss of nuclear BAP1 expression is an independent prognostic factor of poor overall survival and associated with distant metastasis in OMM.

Mutation scanning of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma: a study of 57 cases.

BACKGROUND: Recent advances in novel targeted therapies have created the need for molecular characterization of cancer to allow accurate personalized treatments. In this study, our aim was to investigate the incidence of activating mutations of oncogenes BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma. METHODS: We analyzed a cohort of 57 oral mucosal melanoma samples, including 27 frozen samples and 30 formalin-fixed paraffin-embedded samples. The tumors were screened for hotspot mutations of BRAF (exon 15), NRAS (exons 2 and 3), KIT (exons 9, 11, 13, and 17), and GNAQ/GNA11 (exon 5) by high-resolution melting and direct sequencing. RESULTS: In oral mucosal melanoma, 7.0% of tumors harbored KIT mutations and 3.5% harbored BRAF mutations, while classic BRAF V600E mutation was not detected. We found no mutations of NRAS or GNAQ/GNA11 in oral mucosal melanoma. CONCLUSION: We demonstrated that driver mutations are rare in mutational hotspots of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma. The majority of patients will not benefit from KIT and BRAF inhibitors.

Primary Malignant Melanoma of the Lip: A Report of 48 Cases.

PURPOSE: Lip melanoma (LM) is a rare malignant tumor and well-established treatment protocols for it are in short supply. The objective of this study was to evaluate the outcome of treatment modalities and explore the prognostic factors. PATIENTS AND METHODS: A retrospective chart review was performed on 48 patients with primary LM treated in the authors' hospital from January 1992 to November 2013. The clinical characteristics and treatment modalities were identified and correlated with the outcomes. RESULTS: The 5-year overall survival (OS) rate was 56.1%, and the rate of cervical lymph node (CLN) metastasis was 46% (22 of 48). A tumor of at least 4 cm (P = .001), nodular types (P = .003), and CLN (P < .0001) were independent prognostic factors for OS. Twenty-five patients died during follow-up, mainly from to neck recurrence (14 of 25). Chemotherapy significantly improved the 5-year OS rate in patients with stage IV LM (P = .03), but not in those with stage III (P = .8). CONCLUSIONS: LM has a lower CLN and distant metastasis rate and a better prognosis than other oral mucosal melanomas. A long history of melanin pigmentation is a dangerous sign for all patients, and smoking seems to be associated with LM in male patients. Tumor size (≥4 cm), nodular type, and CLN positivity are poor prognostic factors. A wide excision with close observation is advocated as the primary treatment for stage III LM. Adjuvant chemotherapy is useful for patients with stage IV cancer, but not for those with stage III.

Prognostic factors of oral mucosal melanoma: histopathological analysis in a retrospective cohort of 82 cases.

AIMS: To investigate the histopathological predictors of overall survival and metastatic failure of oral mucosal melanoma (OMM), of which the histopathological classification and microstaging has not been established. METHODS AND RESULTS: The pathological data, including cell type (CT), level of invasion, ulceration, mitotic rate, pigmentation, necrosis, tumour-infiltrating lymphocyte (TIL) and vascular invasion, of 82 OMM patients from April 2002 to April 2012 were reviewed and analysed retrospectively. CT, ulceration, mitotic rate, pigmentation, necrosis and vascular invasion were found to be of significance in predicting the overall survival of OMM patients. CT was an independent prognostic factor of overall survival in multivariate analysis. In patients with localized OMM, CT, level of invasion, mitotic rate, pigmentation and necrosis were associated with overall survival but none of them proved to be an independent prognostic factor. CT, mitotic rate and TIL were associated with the risk of distant metastasis. TIL was revealed to be an independent factor of distant metastases risk in multivariate analysis. CONCLUSIONS: CT was an independent prognostic factor of overall survival. Patients with epithelioid cell type OMM had a poor prognosis. Patients without TIL had a higher risk of distant metastasis.

Head and neck rhabdomyosarcoma in adults.

AIM: The purpose of this study was to explore the treatment and prognosis of head and neck rhabdomyosarcoma (RMS) in adults. METHODS: Fifty-nine patients with head and neck RMS in adults (AHNRMS) treated in one institution were selected. Multivariate analysis was used to evaluate the various variables related to overall survival (OS). RESULTS: The estimated 5-year OS was 36%. The rate of cervical lymph node (CLN) involvement was 28%. Patients with embryonic RMS who underwent chemotherapy enjoyed a favorable outcome according to the multivariate analysis (P = 0.047). Local recurrence (n = 30) and distant metastasis (n = 17) were the main causes of treatment failure. The rate of local recurrence or distant metastasis in the patients who underwent chemotherapy also decreased. Positive surgical margin (32%) was frequently seen in the AHNRMS. Primary site (P = 0.01), tumor size (P < 0.0001), CLN (P = 0.003), and margin status (P = 0.0002) were significant prognostic factors related to OS. CONCLUSIONS: Head and neck RMS in adults is a rare malignancy with a poor outcome, which is more likely to have CLN involvement compared with other soft tissue sarcomas of the head and neck. Standard treatment for AHNRMS should comprise surgery and chemotherapy.