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OBJECTIVES: Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC. MATERIALS AND METHODS: Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months. CONCLUSION: Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.
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Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Piridinas , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Anilidas/uso terapéutico , Anilidas/administración & dosificación , Masculino , Cetuximab/uso terapéutico , Cetuximab/administración & dosificación , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: We encountered a cervical lymphoepithelial carcinoma (LEC) possessing a predominantly solid architecture with deficient mismatch repair (dMMR) and loss of expression of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex subunit. This is the first case report of LEC with dMMR and loss of SWI/SNF complex subunit. CASE PRESENTATION: A 34-year-old woman presented at our hospital with menstrual irregularities and abnormal vaginal bleeding. Magnetic resonance imaging revealed an exophytic mass in the posterior uterine cervix. Biopsy specimens confirmed squamous cell carcinoma with a 2018 International Federation of Gynecology and Obstetrics (FIGO) uterine cervical cancer stage of IB2. In a subsequent conization specimen, the tumor appeared exophytic. Microscopically, the tumor cells formed a predominant solid architecture. Abundant lymphocytic infiltration was observed. The pathological diagnosis indicated human papillomavirus (HPV)-associated squamous cell carcinoma with LEC pattern and pT1b2. Immunohistochemically, high programmed death-ligand 1 (PD-L1) expression, dMMR, and loss of the switch/sucrose non-fermentable family-related, matrix-associated, actin-dependent regulator of chromatin subfamily member 4 (SMARCA4)/BRG1, an SWI/SNF complex subunit, were observed. The patient underwent a radical hysterectomy and is alive without disease one year and five months later. Our analysis of five additional LEC cases revealed a consistent association with high-risk HPV and elevated PD-L1 expression. In addition to the present case, another patient exhibited dMMR. The SWI/SNF complex was retained except in the present case. The prognosis was favorable in all cases. CONCLUSIONS: This unique case of LEC with dMMR suggests a distinct clinical entity with potential immunotherapy implications. Analysis of the other five LEC cases revealed that LEC was immune hot, and immune checkpoint inhibitors may be effective. The two dMMR cases showed loss of MLH1 and PMS2 expressions, and prominently high tumor PD-L1 expression. In those cases, dMMR might have contributed to the morphological characteristics of LEC.
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Carcinoma de Células Grandes , Carcinoma de Células Escamosas , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Adulto , Antígeno B7-H1/metabolismo , Reparación de la Incompatibilidad de ADN , Carcinoma de Células Escamosas/patología , Sacarosa , Biomarcadores de Tumor/metabolismo , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
The incidence of adenocarcinoma of the cervix in pregnancy is exceptionally rare, and thus there is no consensus on its management. Here, we report two cases of adenocarcinoma of the cervix diagnosed in the context of pregnancy. In our first case, a patient referred to colposcopy for atypical glandular cells of undetermined significance was subsequently diagnosed with well differentiated endocervical adenocarcinoma on cone biopsy. Just prior to the cone biopsy, she was incidentally found to have a first trimester pregnancy loss. The patient subsequently underwent a radical hysterectomy and bilateral sentinel lymph node dissection. Final pathology revealed a stage 1B1 (FIGO 2009) well differentiated adenocarcinoma of the cervix. Interestingly, the tumour was positive for estrogen receptor, which is unusual for cervical adenocarcinoma. In our second case, a patient presented with a pedunculated, exophytic cervical neoplasm at 31 weeks GA with self-limiting antepartum hemorrhage. The primary lesion measured 52 mm in diameter on MRI and was amputated at the base during the patient's elective repeat cesarean section. Final pathology revealed a stage IB2 (FIGO 2009) mucinous adenocarcinoma of the cervix. The patient subsequently underwent a radical hysterectomy and bilateral pelvic lymph node dissection 17 weeks after initial presentation. The depth of invasion was 2.2 mm, restricted to the inner third of the cervical wall, and there was no lymphovascular space invasion in the surgical specimen. Surgical margins, parametria, and lymph nodes were all negative for adenocarcinoma. This tumour was also found to be estrogen receptor/progesterone receptor (ER/PR) positive, again unusual for cervical adenocarcinoma. P16 was strongly positive and HPV DNA studies were also positive for human papilloma virus 18. The patient received adjuvant external beam radiotherapy to the pelvis and currently remains in remission.
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OBJECTIVES: Human papillomavirus (HPV) positivity is a favorable prognostic factor in the general population of head and neck squamous cell carcinoma (HNSCC) patients. However, its impact on the survival of metastatic HNSCC of pharynx (mHNSC-P) patients is unclear. This study aims to investigate the associations between HPV status and survival in mHNSC-P patients. METHODS: 735 mHNSC-P patients diagnosed at first presentation from 2010 to 2016 were retrieved from the Surveillance, Epidemiology and End Result database (SEER). Chi-Squared test, univariate and multivariate cox proportional hazards model, Kaplan-Meier analysis, and log-rank test were applied to compare HPV-positive and -negative mHNSC-P patients. RESULT: Using univariate cox proportional hazards analysis, HPV status, primary site, T stage, treatment and distant metastatic site correlate with the overall survival (OS) and disease-specific survival (DSS) in mHNSC-P patients. Multivariate cox regression analysis shows that HPV-positive mHNSC-P patients experienced significantly better OS (HR: 0.62 CI: 0.51-0.76, p < 0.001) and DSS (HR: 0.73 CI: 0.58-0.91, p < 0.01) as compared to HPV-negative mHNSC-P patients. Subgroup analysis indicates that HPV-associated OS and DSS benefits exist in patients with metastatic HNSCC of oropharynx (mHNSC-OP) but not in patients with metastatic HNSCC of non-oropharynx (mHNSC-non-OP). Among mHNSC-OP patients, HPV positivity confers disease-specific survival benefit in patients with oligometastatic rather than polymetastatic patients. Furthermore, HPV associated OS and DSS advantages in mHNSC-OP with lung metastasis was observed. CONCLUSION: HPV-positive mHNSC-OP patients with lung metastasis show better survival than HPV-negative mHNSC-OP patients, providing key information to guide patient treatment approaches.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/complicaciones , Humanos , Faringe/patología , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/complicacionesRESUMEN
OBJECTIVES: Human papillomavirus (HPV)-associated cancers account for about 9% of the cancer mortality burden in the United States; however, survival differs among sociodemographic factors. We determine sociodemographic and clinical variables associated with HPV-associated cancer survival. METHODS: Data derived from the Surveillance, Epidemiology, and End Results 18 cancer registry were analyzed for a cohort of adult patients diagnosed with a first primary HPV-associated cancer (anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancers), between 2007 and 2015. Multivariable Fine and Gray proportional hazards regression models stratified by anatomic site estimated the association of sociodemographic and clinical variables and cancer-specific survival. RESULTS: A total of 77 774 adults were included (11 216 anal, 27 098 cervical, 30 451 oropharyngeal, 2221 penile, 1176 vaginal, 5612 vulvar; average age = 57.2 years). The most common HPV-associated cancer was cervical carcinoma (58%) for females and oropharyngeal (81%) for male. Among patients diagnosed with anal/rectal squamous cell carcinoma (SCC), males had a higher risk of death than females. NonHispanic (NH) blacks had a higher risk of death from anal/rectal SCC, oropharyngeal SCC, and cervical carcinoma; and Hispanics had a higher risk of death from oropharyngeal SCC than NH whites. Marital status was associated with risk of death for all anatomic sites except vulvar. Compared to nonMedicaid insurance, patients with Medicaid and uninsured had higher risk of death from anal/rectal SCC, oropharyngeal SCC, and cervical carcinoma. CONCLUSIONS: There exists gender (anal) and racial and insurance (anal, cervical, and oropharyngeal) disparities in relative survival. Concerted efforts are needed to increase and sustain progress made in HPV vaccine uptake among these specific patient subgroups, to reduce cancer incidence.
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Neoplasias/epidemiología , Neoplasias/etiología , Infecciones por Papillomavirus/complicaciones , Factores Sociodemográficos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Neoplasias/virología , Infecciones por Papillomavirus/virología , Estudios Retrospectivos , Programa de VERF , Factores Sexuales , Estados Unidos/epidemiología , Adulto JovenRESUMEN
In 1989, two NFX1 protein products were identified as nuclear proteins with the ability to bind to X-box cis-elements. Since that publication, the NFX1 gene and its homologs have been identified, from yeast to humans. This review article summarizes what is known about the NFX1 gene across species. We describe the gene and protein motifs of NFX1 homologs and their functions in cellular biology, then turn to NFX1 in human biology and disease development. In that, we focus on more recent literature about NFX1 and its two splice variants protein products (NFX1-91 and NFX1-123) that are expressed in epithelial cells. We describe new evidence of conserved protein motifs, direct and indirect gene expression regulation, and critical protein-protein interactions. Finally, we stress the emerging roles of these NFX1 splice variants in high-risk human papillomavirus-associated cancers, and the increased expression of the longer splice variant, NFX1-123, found in these cancers.
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INTRODUCTION: The objective of this study is to evaluate locoregional and distant failure for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) using American Joint Committee on Cancer eighth edition (AJCC 8) staging. MATERIALS AND METHODS: Retrospective cohort study of 457 patients with HPV + OPSCC, treated with platinum-based chemoradiation from 2002 to 2018, followed for a median of 4.3 years. Time to locoregional failure (TTLRF) and distant failure (TTDF) were estimated by Kaplan-Meier method. Log-rank, recursive partitioning analysis (RPA), and multivariable Cox proportional hazards were used to evaluate associated factors and stratify risk. RESULTS: Rates of five-year locoregional control (LRC) and distant control (DC) were 92% (95% CI, 90-95%) and 89% (95% CI, 85-92%), respectively. Smoking, T4, N3, and stage III were associated with significantly worse TTLRF. RPA identified three distinct locoregional failure groups: cT1-3 and <19 pack-years vs. cT1-3 with ≥19 pack-years vs. cT4 (five-year LRC: 97% vs. 90% vs. 82%, P < .0001). The only factor associated with significantly worse TTDF was smoking status, while stage was not correlated. RPA identified two prognostic groups: former or never smokers vs. current smokers (five-year DC: 92% vs. 77%, P = .0003). DISCUSSION: In the largest evaluation of HPV + OPSCC after platinum-based chemoradiation using AJCC 8, risk for locoregional recurrence was stratified by smoking, T category, N category, and overall stage. Risk of distant recurrence was only stratified by smoking status and not related to stage. This has implications for surveillance and clinical trial design.
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Recurrencia Local de Neoplasia/patología , Neoplasias Orofaríngeas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Adulto , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/efectos adversos , Antineoplásicos/uso terapéutico , Quimioradioterapia/métodos , Ex-Fumadores/estadística & datos numéricos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/virología , Estadificación de Neoplasias/métodos , Neoplasias Orofaríngeas/etnología , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virología , Papillomaviridae , Compuestos de Platino/uso terapéutico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Riesgo , Fumadores/estadística & datos numéricos , Fumar/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/etnología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/virologíaRESUMEN
This article outlines the ways that transoral robotic surgery and transoral laser microsurgery relate to treatment de-escalation in the treatment of head and neck cancer. Treatment de-escalation has particular importance in context of human papillomavirus-related oropharynx squamous cell carcinoma, which responds well to therapy but leaves many survivors with decades of treatment-related sequelae. We compare these less invasive transoral approaches with previously used open approaches to the oropharynx. We discuss the topic of treatment de-escalation in human papillomavirus-related disease and outline completed and ongoing clinical trials investigating the choice of primary treatment modality and de-escalation of adjuvant therapy.
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Carcinoma de Células Escamosas/cirugía , Terapia por Láser/métodos , Microcirugia/métodos , Neoplasias Orofaríngeas/cirugía , Procedimientos Quirúrgicos Robotizados , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Humanos , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Papillomaviridae/patogenicidadRESUMEN
Previous studies of naturally occurring mouse papillomavirus (PV) MmuPV1-induced tumors in B6.Cg-Foxn1nu/nu mice suggest that T cell deficiency is necessary and sufficient for the development of such tumors. To confirm this, MmuPV1-induced tumors were transplanted from T cell-deficient mice into immunocompetent congenic mice. Consequently, the tumors regressed and eventually disappeared. The elimination of MmuPV1-infected skin/tumors in immunocompetent mice was consistent with the induction of antitumor T cell immunity. This was confirmed by adoptive cell experiments using hyperimmune splenocytes collected from graft-recipient mice. In the present study, such splenocytes were injected into T cell-deficient mice infected with MmuPV1, and they eliminated both early-stage and fully formed tumors. We clearly show that anti-tumor T cell immunity activated during tumor regression in immunocompetent mice effectively eliminates tumors developing in T cell-deficient congenic mice. The results corroborate the notion that PV-induced tumors are strongly linked to the immune status of the host, and that PV antigens are major anti-tumor antigens. Successful anti-PV T cell responses should, therefore, lead to effective anti-tumor immune therapy in human PV-infected patients.
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Modelos Animales de Enfermedad , Inmunidad Celular/inmunología , Papillomaviridae/inmunología , Infecciones por Papillomavirus/complicaciones , Neoplasias Cutáneas/prevención & control , Linfocitos T/inmunología , Animales , Femenino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Desnudos , Infecciones por Papillomavirus/virología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patologíaRESUMEN
Answer questions and earn CME/CNE The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, introduces significant modifications from the prior seventh edition. This article details several of the most significant modifications, and the rationale for the revisions, to alert the reader to evolution of the field. The most significant update creates a separate staging algorithm for high-risk human papillomavirus-associated cancer of the oropharynx, distinguishing it from oropharyngeal cancer with other causes. Other modifications include: the reorganizing of skin cancer (other than melanoma and Merkel cell carcinoma) from a general chapter for the entire body to a head and neck-specific cutaneous malignancies chapter; division of cancer of the pharynx into 3 separate chapters; changes to the tumor (T) categories for oral cavity, skin, and nasopharynx; and the addition of extranodal cancer extension to lymph node category (N) in all but the viral-related cancers and mucosal melanoma. The Head and Neck Task Force worked with colleagues around the world to derive a staging system that reflects ongoing changes in head and neck oncology; it remains user friendly and consistent with the traditional tumor, lymph node, metastasis (TNM) staging paradigm. CA Cancer J Clin 2017;67:122-137. © 2017 American Cancer Society.
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Neoplasias de Cabeza y Cuello/patología , Algoritmos , Carcinoma de Células Escamosas/patología , Humanos , Estadificación de Neoplasias , Neoplasias Primarias Desconocidas/patología , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Guías de Práctica Clínica como Asunto , Estados UnidosRESUMEN
OBJECTIVES/HYPOTHESIS: The purpose of this study was to retrospectively review patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) for the presence of retropharyngeal lymph nodes (RPLNs) prior to treatment using positron emission tomography/computed tomography (PET/CT), and to determine if the presence of RPLNs is of utility in predicting outcomes. STUDY DESIGN: Retrospective review of patient data from a single institution. METHODS: Two hundred thirty patients with a diagnosis of HPV-associated OPSCC were identified from 2002 to 2013. The presence of RPLNs was determined primarily from findings on PET/CT as reviewed in a standardized fashion by two neuroradiologists. RESULTS: Of the 230 patients, 165 had pretreatment PET/CT imaging available for review. There were a total of 16 patients (9.70%) with evidence of RPLNs. Among patients positive for RPLNs pretreatment, with an average follow-up of 2 years, there was a 5.2-times greater odds of having recurrence or death (31.3% vs. 8.1%, P=.004). When T and N stage were adjusted for with multiple regression, there was no significant association between RPLN status and recurrence free survival. CONCLUSIONS: This is a unique investigation utilizing PET/CT to classify RPLN status in HPV-associated OPSCC. RPLNs were relatively common in our HPV-associated OPSCC cohort at 9.70%, at the low end of the quoted positivity of 10% to 27% in all OPSCC. A combination of PET/CT is useful in identifying RPLNs. Prospective investigation will be needed to determine the sensitivity and specificity of PET/CT in identifying RPLNs, and the precise impact of RPLNs on HPV-associated OPSCC treatment and outcomes. LEVEL OF EVIDENCE: 4.