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BACKGROUND: Generalizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient's response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient's response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform. METHODS: A single-blinded study was performed using a retrospective database from a single institution (9/2014-12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3 (≥ 99.9% reduction). RESULTS: The cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2- (35%), HR-/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r = 0.53, p = 1.3 × 10-7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TS n = 28; Path n = 27; RD: TS n = 52; Path n = 53), for an overall accuracy of 91.2% (95% CI: 82.8% - 96.4%; Clopper-Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): - 1.99; 95% CI [- 3.96, - 0.02]; p = 0.043) and clinically assessed pCR (HR: - 1.76; 95% CI [- 3.75, 0.23]; p = 0.054). CONCLUSION: We demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Pronóstico , Receptor ErbB-2/análisisRESUMEN
The polo-like kinase (Plk) family is comprised of five different members (Plk1-5), each with their own distinct functions. Plk family members participate in pivotal cell division processes as well as in non-mitotic roles. Importantly, Plk expression has been correlated with various disease states, including cancer. Multiples therapies, which primarily target Plk1, are currently being investigated alone or in combination with other agents for clinical use in different cancers. As the role of Plks in disease progression becomes more prominent, it is important to outline their functions as cell cycle regulators and more. This review summarizes the structure and both mitotic and non-mitotic functions of each of the five Plk family members, sequentially. Additionally, the proposed mechanisms for how Plks contribute to tumorigenesis and the therapeutics currently under investigation are outlined.
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Proteínas de Ciclo Celular , Neoplasias , Carcinogénesis , Proteínas de Ciclo Celular/genética , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
OPINION STATEMENT: Recurrent and second primary head and neck cancers represent a clinical challenge due to frequently unresectable and/or locally advanced disease. Given that many of these patients have received definitive doses of radiation previously, reirradiation is associated with significant morbidity. Use of modern approaches such as conformal photon-based planning and charged particle therapy using protons or carbon ions allows for greater sparing of normal tissues while maintaining or escalating doses to tumor volumes. While the reirradiation data has consistently shown benefits to local control and even survival from escalation of radiotherapy dose, excessive cumulative doses can result in severe toxicities, including fatal carotid blowout syndrome. For all modalities, appropriate patient selection is of utmost importance. Large-scale trials and multi-institutional registry data are needed to standardize treatment modalities, and to determine optimal doses and volumes for reirradiation.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Primarias Secundarias , Reirradiación , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/radioterapia , Dosificación Radioterapéutica , Reirradiación/efectos adversosRESUMEN
BACKGROUND: Human papillomavirus has been implicated in the carcinogenesis of squamous cell carcinoma of the anal canal. p16 expression and the presence of human papillomavirus DNA have been used to define human papillomavirus-positive patients, but neither approach has been validated against the standard of human papillomavirus E6/7 mRNA expression at this disease site. OBJECTIVE: This study aimed to evaluate the acceptability of p16 immunohistochemistry as a surrogate to E6/7 mRNA expression in identifying human papillomavirus-mediated squamous cell carcinoma of the anal canal. DESIGN: This was a retrospective analysis of a previously constructed tissue microarray. SETTINGS: This study was conducted at a tertiary academic center. PATIENTS: Biopsies and resection specimens from patients diagnosed with squamous cell carcinoma of the anal canal at the study institution from 2005 to 2015 were reviewed for sample adequacy. MAIN OUTCOME MEASURES: Concordance between p16 positivity by immunohistochemistry and E6/7 mRNA expression by in situ hybridization was evaluated. Sensitivity, specificity, and positive predictive value were assessed. RESULTS: Among the 25 patients evaluated, p16 and E6/7 mRNA results were concordant in 24 of 25 specimens (96%). Of the 24 concordant samples, there were 23 true positives (p16+ and E6/7+) and 1 true negative (p16- and E6/7-). One specimen was discordant (p16- and E6/7+) between p16 and E6/7 mRNA (4%). This resulted in a sensitivity of 96% and a specificity of 100%. Positive predictive value of p16 immunohistochemistry for E6/7 mRNA expression was 100%. LIMITATIONS: This study was limited by its retrospective nature and small sample size. It only assessed diagnostic parameters rather than prognostic implications. CONCLUSIONS: In this study, the clinically prevalent method of p16 immunohistochemistry showed excellent concordance with the standard of E6/7 mRNA expression and demonstrated its potential to serve as a surrogate for identifying human papillomavirus-induced squamous cell carcinoma of the anal canal. See Video Abstract at http://links.lww.com/DCR/B448. EVALUANDO LA CONFIABILIDAD Y EL VALOR PREDICTIVO POSITIVO DE P, COMO SUSTITUTO DE LA EXPRESIN DE ARNM DE E / , MEDIADA POR EL VIRUS DEL PAPILOMA HUMANO, EN CARCINOMA DE CLULAS ESCAMOSAS DEL CANAL ANAL: ANTECEDENTES:El virus del papiloma humano se ha relacionado en la carcinogénesis del carcinoma de células escamosas del canal anal. La expresión de p16 y la presencia de ADN del virus del papiloma humano, se han utilizado para definir a los pacientes positivos al virus del papiloma humano. Pero ninguno de estos enfoques, han sido validados frente al estándar de oro de la expresión del ARNm del virus del papiloma humano E6 / 7, en este sitio de la enfermedad.OBJETIVO:El estudio tuvo como objetivo, evaluar la aceptabilidad de la inmunohistoquímica del p16, como sustituto de la expresión de ARNm de E6 / 7, en la identificación del carcinoma de células escamosas del canal anal, mediada por virus del papiloma humano.DISEÑO:Fue un análisis retrospectivo de un microarreglo de tejido previamente construido.AJUSTE:El estudio se realizó en un centro académico terciario.PACIENTES:Se revisaron biopsias y muestras de resección de pacientes diagnosticados con carcinoma de células escamosas del canal anal, en la institución del estudio, entre 2005 y 2015 para determinar la idoneidad de la muestra.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluó la concordancia entre la positividad de p16 por inmunohistoquímica y la expresión de ARNm de E6 / 7 por hibridación in situ. Se evaluaron la sensibilidad, especificidad y valor predictivo positivo.RESULTADOS:Entre los 25 pacientes evaluados, los resultados del ARNm de p16 y E6 / 7 fueron concordantes en 24/25 muestras (96%). De las 24 muestras concordantes, hubo 23 positivos verdaderos (p16 + y E6 / 7 +) y un negativo verdadero (p16- y E6 / 7-). Una muestra fue discordante (p16- y E6 / 7 +) entre p16 y ARNm de E6 / 7 (4%). Esto resultó en una sensibilidad del 96% y una especificidad del 100%. El valor predictivo positivo de la inmunohistoquímica de p16 para la expresión de ARNm de E6 / 7 fue del 100%.LIMITACIONES:El estudio estuvo limitado por su naturaleza retrospectiva y por el tamaño pequeño de la muestra. Solamente evaluó los parámetros de diagnóstico, en lugar de las implicaciones pronosticas.CONCLUSIONES:En este estudio, el método clínico prevalente de inmunohistoquímica p16, mostró una excelente concordancia con el estándar de oro de la expresión de ARNm de E6 / 7 y demostró su potencial para servir, como sustituto para identificar el carcinoma de células escamosas del canal anal, inducido por el virus del papiloma humano. Consulte Video Resumen en http://links.lww.com/DCR/B448.
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Alphapapillomavirus/genética , Neoplasias del Ano/patología , Carcinoma de Células Escamosas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , ARN Mensajero/genética , Adulto , Anciano , Canal Anal/patología , Biopsia/métodos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/virología , Femenino , Humanos , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To determine the optimal dose-volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck. MATERIALS AND METHODS: Thirty patients with stage II-IVA oropharynx cancers received definitive radiotherapy with split-field IMRT (SF-IMRT) to the bilateral neck between 2008 and 2013. Each case was re-planned using whole-field IMRT (WF-IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage. RESULTS: Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF-IMRT than SF-IMRT (22.1 vs 25.8 Gy; P < 0.01). The MDACC larynx mean dose was 17.5 Gy ± 5.4 Gy with no differences between the 3 techniques. WF-IMRT and VMAT plans were associated with lower mean doses to the supraglottic larynx (42.1 vs 41.2 vs 54.8 Gy; P < 0.01) and esophagus (18.1 vs 18.2 vs 36 Gy; P < 0.01). CONCLUSIONS: Modern whole field techniques can provide effective laryngeal sparing in patients receiving radiotherapy to the bilateral neck for advanced oropharyngeal cancers. SUMMARY: We evaluated laryngeal dose in patients with locally advanced oropharyngeal cancer treated to the bilateral neck using split-field IMRT (SF-IMRT), whole-field IMRT (WF-IMRT) and volumetric arc therapy (VMAT). All three techniques provided good sparing of laryngeal structures and were able to achieve a mean larynx dose < 33 Gy. There were no significant differences in dose to target structures or non-laryngeal organs at risk among techniques.
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Laringe , Neoplasias Orofaríngeas , Radioterapia de Intensidad Modulada , Humanos , Órganos en Riesgo , Neoplasias Orofaríngeas/radioterapia , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
BACKGROUND: The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC. METHODS: Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000 mg, 2550 mg, and 3000 mg daily in divided doses in addition to cisplatin (at a dose of 100 mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56 years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5 days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19 months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy. CONCLUSIONS: To the authors' knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Neoplasias de Cabeza y Cuello/terapia , Metformina/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Anciano , Anemia/inducido químicamente , Anemia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Cisplatino/efectos adversos , Diarrea/inducido químicamente , Diarrea/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Leucopenia/inducido químicamente , Leucopenia/epidemiología , Masculino , Dosis Máxima Tolerada , Metformina/efectos adversos , Persona de Mediana Edad , Mucositis/inducido químicamente , Mucositis/epidemiología , Náusea/inducido químicamente , Náusea/epidemiología , Estadificación de Neoplasias , Supervivencia sin Progresión , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Tasa de Supervivencia , Vómitos/inducido químicamente , Vómitos/epidemiologíaRESUMEN
PURPOSE: This study evaluates the prognostic significance of MST1R (RON) expression in breast cancer with respect to disease progression, long-term survival, subtype, and association with conventional prognostic factors. METHODS: The approach includes interrogation of survival and tumor staging with paired MST1R RNA expression from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Protein expression evaluation was performed using immunohistochemistry (IHC) staining of MST1R on breast cancer tissue samples from the Cancer Diagnosis Program Breast Cancer Progression tissue microarray and locally obtained breast tumor tissue samples analyzed with paired survival, metastasis, and subtype. RESULTS: Data from TCGA (n = 774) show poorer relapse-free survival (RFS) in patients with high MST1R expression (P = 0.32) and no difference in MST1R expression based on tumor stage (P = 0.77) or nodal status (P = 0.94). Patients in the GEO-derived Kaplan-Meier Plotter microarray dataset demonstrate the association of MST1R and poorer overall survival (n = 1402, P = 0.018) and RFS in patients receiving chemotherapy (n = 798, P = 0.041). Patients with high MST1R expression display worse overall survival (P = 0.01) and receiver operator characteristic (ROC) analysis demonstrate the predictive capacity of increased MST1R with early death (P = 0.0017) in IHC-stained samples. Paired IHC-stained breast tumor samples from the primary versus metastatic site show MST1R expression is associated with metastatic progression (P = 0.032), and ROC analysis supports the predictive capacity of MST1R in metastatic progression (P = 0.031). No associations of MST1R with estrogen receptor (ER), progesterone receptor (PR), both ER and PR, HER2 positivity, or triple-negativity were found (P = 0.386, P = 0.766, P = 0.746, P = 0.457, P = 0.947, respectively). CONCLUSIONS: MST1R expression has prognostic value in breast cancer with respect to survival and metastatic progression. MST1R expression is not associated with tumor stage, nodal status, or subtype.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma Basocelular/secundario , Recurrencia Local de Neoplasia/patología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/terapia , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , TranscriptomaRESUMEN
PURPOSE: Although a standard cutoff value of less than 35 mm in the maximum mouth opening (MMO) has been used to diagnose trismus, this value does not account for natural demographic variations. The present cross-sectional study investigated the effects of age, weight, height, body mass index (BMI), and gender on the MMO in a healthy, heterogeneous population. MATERIALS AND METHODS: A volunteer sample from multiple sites in Cincinnati, Ohio, without any reported head and neck pathologies or current dental prostheses and with intact natural incisors were included. The main outcome measure was the average MMO. Key demographic information was collected from each participant. Multivariate regression analysis was completed on the factors of age, gender, weight, and height. One-way analysis of variance was completed for binned categories of BMI. RESULTS: Data from 330 participants (age range, 18 to 86 years; mean, 42.13 ± 18.53 years; 171 men, 159 women) were collected. The range of MMO was 31 to 71 mm. Age, height, and weight were significant predictors of the MMO, and the final model accounted for â¼20% of the variation in the MMO [adjusted r2, 0.208; F(3,326) = 29.731; P = .001]. On average, individuals with a greater BMI had a greater MMO (BMI, ≤25 kg/m2, 50.57 ± 7.16 mm; BMI >25 but ≤30 kg/m2, 51.58 ± 7.13 mm; BMI >30 kg/m2, 53.53 ± 9.84 mm). CONCLUSIONS: In a heterogeneous population of healthy adults, natural variations in age, height, and weight significantly affected the MMO.
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Estatura , Boca , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Peso Corporal , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ohio , Estados Unidos , Adulto JovenRESUMEN
In patients with pituitary adenomas (PA) who are unable to undergo complete surgical resection, radiation therapy (RT), specifically stereotactic radiosurgery (SRS), results in excellent local control. However, the utility of radiosurgery may be limited by the proximity of the lesion to the optic chiasm (OC). We evaluate the efficacy of debulking surgery in increasing the PA-OC separation to convert patients into SRS candidates. From 2007 to 2015, 31 patients with PA < 2 mm from the OC underwent debulking surgery followed by RT within 2 years of resection. Coronal and sagittal T1-pre- and post-contrast sequences were used to determine PA-OC separation. Time interval between postoperative and pre-radiotherapy MRI scans and type of radiation therapy were analyzed. Functional tumor status, tumor characteristics [cavernous sinus (CS) or suprasellar (SS) involvement, chiasm/nerve encasement (NE)], and presence of ≥ 2 of these characteristics (multiple factors, MF) was also noted. Surgery converted 9 of 31 patients (29%) to SRS candidates. Median time from surgery to pre-RT planning MRI was 8 months (range 2-20). Of the 31 patients initially ineligible for SRS, 6 became eligible immediately after surgery, and another 3 were deemed eligible on follow-up. Mean PA-OC separation was 0.3 mm preoperative, 1.4 mm postoperative, and 2.1 mm at time of SRS (p = 0.002). Preoperative SS, NE, and MF involvement predicted pre-RT separation < 2 mm. Debulking surgery of unresectable pituitary tumors is a successful strategy for converting select radiosurgery-ineligible patients to radiosurgery candidates. Absence of preoperative SS, NE, and MF predicts for successful conversion.
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Adenoma/terapia , Procedimientos Quirúrgicos de Citorreducción , Procedimientos Neuroquirúrgicos , Neoplasias Hipofisarias/terapia , Radiocirugia , Adenoma/diagnóstico por imagen , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos , Neoplasias Hipofisarias/diagnóstico por imagen , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The purpose of this study was to investigate the setup and positioning uncertainty of a custom cushion/mask/bite-block (CMB) immobilization system and determine PTV margin for image-guided head and neck stereotactic ablative radiotherapy (HN-SABR). We analyzed 105 treatment sessions among 21 patients treated with HN-SABR for recurrent head and neck cancers using a custom CMB immobilization system. Initial patient setup was performed using the ExacTrac infrared (IR) tracking system and initial setup errors were based on comparison of ExacTrac IR tracking system to corrected online ExacTrac X-rays images registered to treatment plans. Residual setup errors were determined using repeat verification X-ray. The online ExacTrac corrections were compared to cone-beam CT (CBCT) before treatment to assess agreement. Intrafractional positioning errors were determined using prebeam X-rays. The systematic and random errors were analyzed. The initial translational setup errors were -0.8 ± 1.3 mm, -0.8 ± 1.6 mm, and 0.3 ± 1.9 mm in AP, CC, and LR directions, respectively, with a three-dimensional (3D) vector of 2.7 ± 1.4 mm. The initial rotational errors were up to 2.4° if 6D couch is not available. CBCT agreed with ExacTrac X-ray images to within 2 mm and 2.5°. The intrafractional uncertainties were 0.1 ± 0.6 mm, 0.1 ± 0.6 mm, and 0.2 ± 0.5 mm in AP, CC, and LR directions, respectively, and 0.0° ± 0.5°, 0.0° ± 0.6°, and -0.1° ± 0.4° in yaw, roll, and pitch direction, respectively. The translational vector was 0.9 ± 0.6 mm. The calculated PTV margins mPTV(90,95) were within 1.6 mm when using image guidance for online setup correction. The use of image guidance for online setup correction, in combination with our customized CMB device, highly restricted target motion during treatments and provided robust immobilization to ensure minimum dose of 95% to target volume with 2.0 mm PTV margin for HN-SABR.
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Neoplasias de Cabeza y Cuello/cirugía , Inmovilización , Posicionamiento del Paciente , Radiocirugia , Planificación de la Radioterapia Asistida por Computador/métodos , Errores de Configuración en Radioterapia/prevención & control , Humanos , Imagenología Tridimensional/métodos , Dosificación Radioterapéutica , Radioterapia Guiada por Imagen , Radioterapia de Intensidad Modulada/métodos , ReirradiaciónRESUMEN
Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves both fluid secretion and abnormal proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK). Metformin, a drug in wide clinical use, is a pharmacological activator of AMPK. We find that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. In addition, metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD. Our results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD.
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Proteínas Quinasas Activadas por AMP/metabolismo , Proliferación Celular , Células Epiteliales/enzimología , Riñón Poliquístico Autosómico Dominante/enzimología , Proteínas Quinasas Activadas por AMP/genética , Animales , Línea Celular , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Modelos Animales de Enfermedad , Perros , Células Epiteliales/patología , Humanos , Hipoglucemiantes/farmacología , Metformina/farmacología , Ratones , Ratones Transgénicos , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/patología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
INTRODUCTION: Stereotactic body radiation therapy (SBRT) is a treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC). Surveillance guidelines vary after treatment. While patients are more likely to locally recur within 2 years of treatment, there remains a paucity of data on the benefit of frequent and long-term surveillance. We evaluated a cohort of NSCLC patients to evaluate surveillance patterns and outcomes. MATERIALS AND METHODS: Patients with ES-NSCLC treated with SBRT were retrospectively evaluated. Imaging was reviewed after SBRT for evidence of recurrence or new malignancy. The median scan interval (MSI) was calculated as the median number of months between surveillance scans. The MSI between patients with or without new disease was compared by t-test. New disease development and survival between patients with
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Radiocirugia , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirugía , Radiocirugia/métodos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Persona de Mediana Edad , Estudios de Seguimiento , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Guías de Práctica Clínica como Asunto , Tasa de Supervivencia , AdultoRESUMEN
Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell-cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.
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OBJECTIVE(S): To assess the influence of treatment package time (TPT) on overall survival (OS) and event free survival (EFS) in oral cavity cancer (OCC) patients treated with surgery and adjuvant radiation therapy (RT) with or without concurrent chemotherapy (CHT). MATERIALS/METHODS: 354 adult OCC patients treated at a single, high-volume center between 2012-2022 with various pathologic risk features were included. TPT was defined as days from surgery to RT completion. Kaplan-Meier estimates, log-rank p-values, univariable (UVA) and multivariable (MVA) Cox regression analyses were performed to determine the impact of TPT on OS and EFS, and the optimal TPT cutoff. RESULTS: The optimal TPT cutoff was 105 days. TPT < 105 days was significantly associated with improved OS and EFS (p = 0.002 and p = 0.027, respectively) compared to TPT ≥ 105 days. On UVA, factors significantly associated with OS were TPT < 105 days, former/current smoker status, pathologic stage IV, positive perineural invasion (PNI), and extranodal extension (ENE) (all p < 0.05). On MVA for OS, TPT < 105 days, former/current smoker status, pathologic stage IV, and positive PNI (all p < 0.05) remained significant. Factors significantly associated with EFS on UVA were TPT < 105 days, former/current smoker status, pathologic stage IV, positive PNI or ENE, and concurrent CHT (all p < 0.05). On MVA, TPT < 105 days, pathologic stage IV, and positive PNI (all p < 0.05) remained significant. CONCLUSIONS: In a large, homogenous cohort of OCCs, optimal TPT was <105 days, with TPT ≥ 105 days significantly associated with worse OS and EFS. Multidisciplinary coordination should analyze factors potentially contributing to treatment delay.
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Neoplasias de la Boca , Humanos , Neoplasias de la Boca/terapia , Neoplasias de la Boca/patología , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/radioterapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Resultado del Tratamiento , Anciano de 80 o más Años , Estudios Retrospectivos , Radioterapia AdyuvanteRESUMEN
High-risk human papillomavirus (hrHPV) is an emerging risk factor for sinonasal squamous cell carcinoma (SNSCC). The goal of this study was to assess the prevalence of hrHPV and subtype distribution in SNSCC and correlation with patient and clinical characteristics. This retrospective cohort study included 43 cases diagnosed with incident primary SNSCC at the University of Cincinnati Medical Center from 2010 to 2015. The prevalence of hrHPV was interrogated using a multi-assay approach that included p16 immunohistochemistry (IHC), RNA in-situ hybridization (ISH), and hrHPV DNA sequencing. The association of hrHPV with 5-year overall survival (OS) and 2-year disease-free survival (DFS) was assessed. Fourteen cases (32.6â¯%) were classified as hrHPV positive, based on the a priori definition of having either a positive RNAScope™ ISH test or hrHPV DNA and p16-positive IHC; 9 cases (20.9â¯%) were positive for all three tests. All cases that arose from an inverted sinonasal papilloma (ex-ISP) were negative for hrHPV. HPV16 was the most common subtype among hrHPV positive cases (58.8â¯%), followed by HPV18 (17.6â¯%). No significant association was observed between hrHPV and OS or DFS after adjusting for potential confounding. hrHPV is prevalent in a sizable fraction of SNSCC. Additional studies are needed to better elucidate the relationship with patient survival outcomes and determine the optimal testing modality for prognostication.
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Virus del Papiloma Humano , Infecciones por Papillomavirus , Neoplasias de los Senos Paranasales , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Virus del Papiloma Humano/genética , Virus del Papiloma Humano/aislamiento & purificación , Inmunohistoquímica , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/mortalidad , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Neoplasias de los Senos Paranasales/mortalidad , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/virología , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidadRESUMEN
Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers.
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Biomarcadores de Tumor , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/sangre , Biomarcadores de Tumor/sangre , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/sangre , Estados Unidos , Sociedades Médicas , Neoplasias Primarias Secundarias/diagnóstico por imagenRESUMEN
Purpose/Objectives: The purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT for recurrent head and neck squamous cell cancer (HNSCC). Materials/Methods: Patterns of LRR for 61 patients treated consecutively between 2003 and 2014 who received post-operative IMRT reirradiation to ≥ 60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR. Results: A total of 55 patients were eligible for analysis and 23 (42 %) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the most significant predictor of LRR after post-operative reirradiation with salvage rate of 67 % for lymphatic vs. 33 % for mucosal sites (p = 0.037). Physician classification of LRR yielded 14 (61 %) in-field failures, 3 (13 %) marginal failures, and 6 (26 %) out-of-field failures, while DIR yielded 10 (44 %) in-field failures, 4 (17 %) marginal failures, and 9 (39 %) out-of-field failures. Most failures (57 %) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56 % of failures occurred within 1 cm of the surgical flap. Conclusion: Our study highlights the role of DIR in enhancing the accuracy and consistency of POF analysis. Compared to traditional visual inspection, DIR reduces interobserver variability and provides more nuanced insights into dose-specific and spatial parameters of locoregional recurrences. Additionally, the study identifies the location of the initial recurrence as a key predictor of subsequent locoregional recurrence after salvage surgery and re-IMRT.
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BACKGROUND: Radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. We observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) after radiation. We therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy. METHODS: We performed a retrospective chart review of all patients treated with curative intent in the Department of Radiation Oncology at the MD Anderson Cancer Center from 2008-2011 who received any ixabepilone after completion of external-beam radiation therapy. These patients received adjuvant ixabepilone on one of two protocols, either for locally advanced breast cancer or for metastatic breast cancer. In total, 19 patients were identified and their charts were subsequently reviewed for evidence of ixabepilone-related toxicity. RESULTS: Of the 19 patients identified who received ixabepilone following radiation therapy, three (15.8%) had unexpectedly serious reactions in the months following radiation therapy. Complications included delayed wound closure and drain placement into the seroma, intense erythema, and delayed wound closure and grade 4 chest wall necrosis requiring latissimus flap and skin grafting. The average number of days between the end of radiation therapy and documentation of reaction was 99. CONCLUSIONS: Ixabepilone chemotherapy may induce radiation recall and delayed wound healing when used shortly after the completion of external-beam radiotherapy. Significant clinical interactions have not been previously reported and merit further evaluation.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Epotilonas/uso terapéutico , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Epotilonas/efectos adversos , Femenino , Humanos , Estudios RetrospectivosRESUMEN
Introduction: Iodine-125 loaded Collaborative Ocular Melanoma Study plaques can achieve excellent tumor control for patients diagnosed with uveal melanomas. Our ocular cancer team hypothesized that use of novel, partially loaded COMS plaques could ease and improve accurate plaque placement during treatment of small, posterior tumors while providing equivalent tumor control. Materials/methods: Records of 25 patients treated with custom plaques were compared to 20 patients treated with fully loaded plaques, who had received treatment prior to our institution's adopting the use of these partial plaques. Tumors were matched with regards to location and dimensions as measured by the ophthalmologist. Retrospective analysis of dosing parameters, tumor control and toxicity outcomes were performed. Results: There were no cancer related deaths, local recurrences or metastases in either cohort at an average follow up of 24 months for patients treated with custom plaques and 60.7 months for patients treated with fully loaded plaques. No statistically significant difference was found in regards to post-operative development of cataracts (χ2 = 0.76) or radiation retinopathy (χ2 = 0.22). Patients treated with custom loaded plaques noted significantly less clinical visual loss (χ2 = 0.006) and were more likely to have vision preserved at ≥20/200 (χ2 = 0.006). Conclusion: Treatment of small, posterior uveal melanomas with partially loaded COMS plaques results in equivalent survival and recurrence outcomes as treatment with fully loaded plaques, while exposing the patient to less radiation. Additionally, treatment with partially loaded plaques reduces the incidence of clinically significant visual loss. These promising early results support the use of partially loaded plaques in well-selected patients.
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In vitro studies allow evaluation of normal or cancer cell responses to radiation, either alone or in combination with agents used to modify these biological responses. Ionizing radiation can be produced by a variety of particles and sources, with varying energy spectra, interaction probabilities, linear energy transfer, dose uniformity, dose rates, and delivery methods. Multiple radiation sources have been used to irradiate cells in the published literature. However, the equivalence of response in cell culture models across radiation sources has not been rigorously established. Moreover, current reporting of radiation source parameters lacks consistency and rigor which may impact the reproducibility of pre-clinical data between laboratories. Relevant choices of radiation source are also of high importance due to growing interest in comparing photon versus particle radiation effect on biological responses. Therefore, this study robustly evaluates the cellular response (cell survival, apoptosis, and DNA damage) of three distinct cell lines using four unique photon generating radiation sources. We hypothesize there may be subtle differences across the radiation sources, without an appreciable difference in cellular response. The four photon irradiation energies investigated, 662 keV, 100 kVp, 220 kVp, 6 MV, did produce subtle differences in DNA damage and cell survival when treating three distinct tumor cell lines. These variations in cellular response emphasize the need to carefully consider irradiation source, energy, and dose rate depending on study goal and endpoint.