Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials.

Purpose: In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Materials and Methods: We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed. Results: In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and 3 patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6, 12.4, and 18.1 months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor. Conclusion: Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.

Current Status and Future Direction in the Treatment of Advanced Adrenocortical Carcinoma.

PURPOSE OF REVIEW: To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease. RECENT FINDINGS: Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a predictive biomarker for axitinib in adenoid cystic carcinoma.

BACKGROUND: This study analyzed the predictive value of artificial intelligence (AI)-powered tumor-infiltrating lymphocyte (TIL) analysis in recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC) treated with axitinib. METHODS: Patients from a multicenter, prospective phase II trial evaluating axitinib efficacy in R/M ACC were included in this study. H&E whole-side images of archival tumor tissues were analyzed by Lunit SCOPE IO, an AI-powered spatial TIL analyzer. RESULTS: Twenty-seven patients were included in the analysis. The best response was stable disease, and the median progression-free survival (PFS) was 11.1 months (95% CI, 9.2-13.7 months). Median TIL densities in the cancer and surrounding stroma were 25.8/mm2 (IQR, 8.3-73.0) and 180.4/mm2 (IQR, 69.6-342.8), respectively. Patients with stromal TIL density >342.5/mm2 exhibited longer PFS (p = 0.012). CONCLUSIONS: Cancer and stromal area TIL infiltration were generally low in R/M ACC. Higher stromal TIL infiltration was associated with a longer PFS with axitinib treatment.

Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors.

BACKGROUND AIMS: Human telomerase reverse transcriptase (hTERT) is an attractive target for anti-cancer therapies. We developed an effective method for generating hTERT-specific CD8+ T cells (hTERT-induced natural T cells [TERTiNTs]) using peripheral blood mononuclear cells (PBMCs) from patients with solid cancers and investigated their feasibility and safety. METHODS: This was a single-center phase 1 trial using a 3 + 3 dose escalation design to evaluate six dose levels of TERTiNTs. PBMCs from each patient were screened using an hTERT peptide panel to select those that stimulated CD8+ T cells. The four most stimulatory peptides were used to produce autologous CD8+ T cells from patients refractory or intolerant to standard therapies. Eligible patients received a single intravenous infusion of TERTiNTs at different dose levels (4 × 108 cells/m2, 8 × 108 cells/m2 and 16 × 108 cells/m2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion. RESULTS: From January 2014 to October 2019, a total of 24 patients with a median of three prior lines of therapy were enrolled. The most common adverse events were lymphopenia (79.2%), nausea (58.3%) and neutropenia (54.2%), mostly caused by pre-conditioning chemotherapy. The TERTiNT infusion was well tolerated, and dose-limiting toxicities were not observed. None of the patients showed objective responses. Seven patients (30.4%) achieved stable disease with a median progression-free survival of 3.9 months (range, 3.2-11.3). At the highest dose level (16 × 108 cells/m2), four of five patients showed disease stabilization. CONCLUSIONS: The generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.

A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: This open-label, single-arm, phase II study evaluated the vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) rivoceranib in patients with recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). PATIENTS AND METHODS: Eligible patients had confirmed disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) with ≥20% increase in radiologically or clinically measurable lesions or appearance of new lesions within the preceding 6 months. Patients received oral rivoceranib 700 mg once daily. Primary outcomes were objective response rate (ORR) by investigator review and by blinded independent review committee (BIRC). RESULTS: Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9-25.7] and 9.7% (95% CI, 4.0-19.0); median duration of response was 14.9 months (95% CI, 4.9-17.3) and 7.2 months (95% CI, 3.5-8.4); and median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5). Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity. CONCLUSIONS: In patients with progressing R/M ACC, rivoceranib demonstrated antitumor activity and a manageable safety profile consistent with other VEGFR TKIs.

A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17-11).

PURPOSE: Although programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are promising agents for recurrent or metastatic nasopharyngeal carcinoma (NPC), PD-1/PD-L1 inhibitor monotherapy has shown modest efficacy. This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with NPC who failed prior platinum-based chemotherapy. PATIENTS AND METHODS: This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. To identify potential biomarkers, whole-exome sequencing, whole-transcriptome sequencing, and immune phenotype analysis based on Lunit SCOPE IO, an artificial intelligence-powered spatial tumor-infiltrating lymphocyte analyzer, were performed. RESULTS: Thirty-six patients were enrolled between June 2018 and June 2019. The ORR was 36.1% and disease control rate was 97.2%. With median follow-up of 22.0 months, median PFS was 13.8 months [95% confidence interval (CI), 8.6-16.8 months]. Median OS was not reached, and OS rate at 6 months was 97.0% (95% CI, 80.4%-99.6%). The grade ≥3 treatment-related adverse events were hypertension (2.8%) and anemia (2.8%). In multivariate analysis of mutation of chromatin modifier gene, tumor mutational burden (≥ 2.1 mut/Mb), and somatic copy-number alteration (SCNA) level, the group with high SCNA (> 3 points; HR, 7.0; 95% CI, 1.3-37.9; P = 0.02) had independently associated with poor PFS. Immune phenotype analysis showed that tumors with high proportion of immune-excluded immune phenotype was significantly correlated with poor PFS (HR, 4.4; 95% CI, 1.2-16.2; P = 0.018). CONCLUSIONS: Nivolumab plus gemcitabine showed promising efficacy with favorable toxicity profiles in patients with advanced NPC in whom platinum-based combination chemotherapy failed.

Randomized Phase II Study of Axitinib versus Observation in Patients with Recurred or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: The role of chemotherapy in adenoid cystic carcinoma (ACC) is controversial because ACC is usually stable without chemotherapy and the lack of randomized trials. Here, we conducted the first randomized trial to evaluate the efficacy of axitinib as compared with observation in ACC. PATIENTS AND METHODS: In this multicenter, prospective phase II trial, we enrolled patients with recurrent or metastatic ACC whose cancer had progressed within the past 9 months. Patients were randomly assigned to either axitinib (5 mg twice daily) or observation at a 1:1 ratio. Crossover from observation to axitinib was permitted after progression. The primary endpoint was a 6-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), overall survival (OS), PFS, duration of response, and adverse events. RESULTS: Sixty patients were allocated to the axitinib or observation group, with response evaluation conducted in 54 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.0% with axitinib and 23.0% with observation. Median PFS was longer in the axitinib arm (10.8 months vs. 2.8 months, P < 0.001). The ORR of axitinib was 0.0%, but the disease control rate was 100.0% with axitinib and 51.9% with observation. Median OS was not reached with axitinib, but was 27.2 months with observation (P = 0.226). The most frequently reported adverse events for axitinib were oral mucositis and fatigue. CONCLUSIONS: In this first randomized trial in patients with ACC, axitinib significantly increased the 6-month PFS rate as compared with observation. (ClinicalTrials.gov number, NCT02859012).

Guidelines for Cancer Care during the COVID-19 Pandemic in South Korea.

At the end of 2019, the cause of pneumonia outbreaks in Wuhan, China, was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In February 2020, the World Health Organization named the disease cause by SARS-CoV-2 as coronavirus disease 2019 (COVID-19). In response to the pandemic, the Korean Cancer Association formed the COVID-19 task force to develop practice guidelines. This special article introduces the clinical practice guidelines for cancer patients which will help oncologists best manage cancer patients during the COVID-19 pandemic.

Spatial ecology of little egret (Egretta garzetta) in Hong Kong uncovers preference for commercial fishponds.

Many natural wetlands have been converted to human-influenced wetlands. In some instances, human-influenced wetlands could provide complementary habitats for waterbirds, compensating for the loss of natural wetlands. Inner Deep Bay in Hong Kong is composed of both natural and human-influenced wetlands and is under immense development pressure. From an ecology perspective, we need to understand if different wetland types play the same ecological role. To achieve this, we tracked nine little egrets (Egretta garzetta) using GPS loggers for 14 months to study their spatial ecology, home range, movement and habitat use. We found that over 88% of the home range of all individuals comprised of wetlands (commercial fishponds, mangrove, gei wai, channel, and intertidal mudflat). Among these wetland types, nearly all (seven of nine) individuals preferred commercial fishponds over other habitats in all seasons. Little egrets exhibited seasonal movement and habitat use among seasons, with largest home range, greatest movement, and most frequent visits to commercial fishponds in winter compared to spring and autumn. Our results highlight the significant role of commercial fishponds, providing a feeding ground for little egrets. However, other wetland types cannot be ignored, as they were also used considerably. These findings underscore the importance of maintaining a diversity of wetland types as alternative foraging and breeding habitats.

Prognostic significance of smoking and alcohol history in young age oral cavity cancer.

OBJECTIVE: To assess prognostic factors of patients with operable oral cavity squamous cell carcinoma (OSCC), focusing on the associations with smoking/alcohol exposure and age. MATERIALS AND METHODS: A total of 247 patients with OSCC who received curative surgery ± adjuvant radiotherapy were analyzed. The patient subgroups were divided according to pretreatment smoking/alcohol exposure. Individuals aged 45 years or less were classified as younger patients. RESULTS: The median follow-up was 52.2 months. The 5-year locoregional progression-free survival (LRFFS), distant metastasis-free survival (DMFS), overall survival (OS), and cancer-specific survival (CSS) rates were 85.2%, 88.3%, 78.1%, and 83.5%, respectively. An advanced stage, differentiation, and lympho-vascular space invasion were significantly associated with lower OS and CSS. In a subgroup analysis of younger patients (n = 49), more smoking/alcohol exposure was significantly associated with better OS (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.05-0.95, p = .043). With increasing age, the HR for smoking/alcohol exposure with respect to OS increased up to 11.59 (95% CI: 1.49-89.84, p = .019) in older patients. CONCLUSION: Younger OSCC patients with non- or less smoking/alcohol exposure showed unfavorable outcomes. The prognostic significance of pretreatment smoking/alcohol exposure changed from favorable to detrimental with increasing age in operable OSCC.

Targeting TJP1 attenuates cell-cell aggregation and modulates chemosensitivity against doxorubicin in leiomyosarcoma.

Tight junction protein 1 (TJP1) is a membrane-associated cytosolic protein important for cell-cell communication in intercellular barriers in epithelial and non-epithelial cells. Here, we explored the functional involvement of TJP1 in non-epithelial tumors such as soft tissue sarcoma, especially in leiomyosarcoma (LMS). TJP1 expression in soft tissue sarcoma was analyzed in normal and tumor tissues as well as from public datasets such as the TCGA provisional dataset, in which TJP1 expression was compared with other subtypes such as undifferentiated sarcomas, and myxofibrosarcomas. SK-LMS-1 cell lines with reduced TJP1 expression showed attenuated anchorage-independent colony formation as well as reduced intercellular aggregation on non-coated culture plates compared with control as well as parental SK-LMS-1 cells. Transcriptome profiling following TJP1 knockdown in SK-LMS-1 cells suggested the involvement of several signaling pathways, including NF-κB pathway and growth factor receptor signaling. In addition, TJP1 downregulation induced enhanced response against anti-cancer agents, doxorubicin and gefitinib. Taken together, these results suggest that TJP1 contributes to sarcoma genesis and might be useful therapeutic target. KEY MESSAGES: • TJP1 expression at RNA level higher in tumor than in normal tissues of sarcoma. • Targeting TJP1 attenuates cell-cell aggregation and anchorage-independent growth. • Targeting TJP1 is beneficial in anti-cancer therapy in LMS.

Phase I and pharmacokinetic study of the vascular-disrupting agent CKD-516 (NOV120401) in patients with refractory solid tumors.

We report a phase I pharmacological study of an oral formulation of CKD-516, a vascular-disrupting agent, in patients with refractory solid tumors. Twenty-seven patients (16 in the dose-escalation cohort and 11 in the expansion cohort) received a single daily dose (5-25 mg) of CKD-516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment-related adverse events. The recommended phase II dose of oral CKD-516 was 20 mg/d (15 mg/d with a body surface area (BSA) <1.65 m2 ). Notably, S-516 half-lives in patients receiving 15-20 mg CKD-516/d significantly differed between patients with and without splenomegaly that is suggestive of portal hypertension associated with liver cirrhosis (6.1 vs 4.6 hours, respectively). Of 11 patients without splenomegaly who completed at least one cycle of a daily CKD-516 dose of either 15 or 20 mg, only one patient (9.1%) suffered from any dose-limiting toxicity. We conclude that a daily oral dose of 15 or 20 mg CKD-516 five days per week could be tolerable in patients without liver cirrhosis.

Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. MATERIALS AND METHODS: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. RESULTS: Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)-negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). CONCLUSION: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

Primary Malignant Melanoma of the Breast: A Report of Two Cases.

Primary malignant melanoma of the breast (PMMB) is a rare tumor with only a few case reports available in the literature. We report two cases of PMMB, one derived from the breast parenchyma and the other from the breast skin. The first case consisted of atypical epithelioid cells without overt melanocytic differentiation like melanin pigments. The tumor cells showed diffuse positivity for S100 protein, tyrosinase, and BRAF V600E. However, the tumor cells were negative for cytokeratin, epithelial membrane antigen, and HMB-45. The second case showed atypical melanocytic proliferation with heavy melanin pigmentation. The tumor cells were positive for S100 protein, HMB-45, tyrosinase, and BRAF V600E. These two cases represent two distinct presentations of PMMB in terms of skin involvement, melanin pigmentation, and HMB-45 positivity. Although PMMB is very rare, the possibility of this entity should be considered in malignant epithelioid neoplasms in the breast parenchyma.

Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16.

Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of 94.3× for WES and 35.3× for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC. [BMB Reports 2018; 51(11): 584-589].

Integrated molecular characterization of adult soft tissue sarcoma for therapeutic targets.

BACKGROUND: Several studies have investigated the molecular drivers and therapeutic targets in adult soft tissue sarcomas. However, such studies are limited by the genomic heterogeneity and rarity of sarcomas, particularly in those with complex and unbalanced karyotypes. Additional biomarkers are needed across sarcoma types to improve therapeutic strategies. To investigate the molecular characteristics of complex karyotype sarcomas (CKSs) for therapeutic targets, we performed genomic profiling. RESULTS: The mutational landscape showed that TP53, ATRX, and PTEN genes were highly mutated. CKS samples were categorized into three groups based on copy number variations that were associated with CDK4 and RB1 signatures. Integrated analysis of genomic and transcriptomic data revealed several pathways related to PDGFR, which could be a strategic target for anti-sarcoma therapy. CONCLUSIONS: This study provides a detailed molecular classification of CKSs and proposes several therapeutic targets. Targeted or combinational therapies for treating CKS should be considered before chemotherapy.

Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas.

Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC.

Prognostic role of the neutrophil-to-lymphocyte ratio in patients with primary central nervous system lymphoma.

Neutrophil-to-lymphocyte ratio (NLR) is one of the parameters of a complete blood cell count (CBC) test and has been reported to be an easily accessible prognostic marker in aggressive cancer, including non-Hodgkin lymphoma (NHL). Primary central nervous system lymphoma (PCNSL) is an extranodal NHL with highly aggressive features. However, the importance of the NLR has never been assessed in PCNSL. This retrospective study enrolled 62 biopsy-proven patients whose baseline NLR was available, and reviewed their medical records to compare both high (≥2.0) and low NLR (<2.0) groups, in terms of clinical characteristics and outcomes. The low NLR group showed significantly better response rates to induction chemotherapy compared to the high NLR group (p=0.041). At a median follow-up of 41.5 months, the high NLR group revealed a significantly worse 3-year overall survival (OS) (42.5 vs. 71.2%; p=0.031) and a worse 3-year progression-free survival (PFS) (37.3 vs. 60.1%; p=0.028). Univariable Cox analysis results showed that a high NLR at diagnosis was a poor prognostic factor for both 3-year OS (HR 2.64, 95% CI 1.06-6.60; p=0.038) and 3-year PFS (HR 2.41, 95% CI 1.07-5.42; p=0.034). However, multivariable analyses adjusting for International Extranodal Lymphoma Study Group (IELSG) score and induction chemotherapy regimen with rituximab, which were strongly prognostic in this study, showed no statistical significance even with the high NLR group's tendency towards a worse 3-year OS (HR 2.36, 95% CI 0.84-6.62, p=0.102) and a worse 3-year PFS (HR 2.28, 95% CI 0.93-5.63, p=0.073). In conclusion, given that NLR is simple and easily obtainable, it might play a potentially prognostic role in PCNSL from early disease onset.

Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status. MATERIALS AND METHODS: Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D). RESULTS: Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities. CONCLUSION: Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.