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1.
Cancer ; 128(11): 2193-2204, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35139236

RESUMEN

BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.


Asunto(s)
Alphapapillomavirus , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Alphapapillomavirus/genética , ADN Tumoral Circulante/genética , Neoplasias de Cabeza y Cuello/complicaciones , Humanos , Cinética , Papillomaviridae/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/complicaciones
2.
Eur J Nucl Med Mol Imaging ; 49(8): 2735-2745, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35089375

RESUMEN

PURPOSE: Tumor heterogeneity limits the predictive value of PD-L1 expression and influences the outcomes of the immunohistochemical assay for therapy-induced changes in PD-L1 levels. This study aimed to determine the predictive value of PD-L1 for non-small cell lung carcinoma (NSCLC), thereby developing imaging agents to non-invasively image and examine the effect of the therapeutic response to PD-L1 blockade therapy. METHODS: A cohort of 102 patients with lung cancer was analyzed, and the prognostic significance of PD-L1 expression level was investigated. Recombinant human PD-1 ECD protein (rhPD1) was expressed, purified, and labeled with 64Cu for the evaluation of PD-L1 status in tumors. Mice subcutaneously bearing PD-L1 high-expressing tumor HCC827 and PD-L1 low-expressing tumor A549 were used to determine tracer-target specificity and examine the effect of therapeutic response to PD-L1 blockade therapy. RESULTS: PD-L1 was proved to be a good prognosis marker for NSCLC, and its expression was correlated with the histology of NSCLC. PET imaging revealed high tumor accumulation of 64Cu-NOTA-rhPD1 in HCC827 tumors (9.0 ± 0.5%ID/g), whereas it was 3.2 ± 0.4%ID/g in A549 tumors at 3 h post-injection. The lower tumor uptake (3.1 ± 0.3%ID/g) of 64Cu-labeled denatured rhPD1 in HCC827 tumors at 3 h post-injection (p < 0.001) demonstrated the target specificity of 64Cu-NOTA-rhPD1. Furthermore, PET showed that 64Cu-NOTA-rhPD1 sensitively monitored treatment-related changes in PD-L1 expression, and seemed to be superior to [18F]FDG. CONCLUSION: We identified PD-L1 as a good prognosis marker for surgically resected NSCLC and developed the PET tracer 64Cu-NOTA-rhPD1 with high target specificity for PD-L1.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Receptor de Muerte Celular Programada 1
3.
Am J Otolaryngol ; 43(3): 103457, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35453094

RESUMEN

Most human papillomavirus (HPV)-positive carcinomas of unknown primary (CUP) in the cervical lymph nodes are ultimately found to arise from the oropharynx, which has by far the highest prevalence of HPV-positivity among head and neck tumors. However, HPV is also detected in a subset of tumors from other sites. In this case report, we describe the first reported instance of a lacrimal sac carcinoma presenting as an HPV-positive CUP. A 64-year-old male presented with isolated right-sided neck swelling, found on core biopsy to be HPV-positive squamous cell carcinoma (SCC). Initial diagnostic workup did not reveal a primary site, and he was treated for T0N1M0 oropharyngeal SCC with chemoradiation. Shortly afterwards he developed epiphora and was found to have an FDG-avid lesion along his inferior right orbit. Biopsy revealed HPV-positive SCC, presumed to be the true primary site of his previously diagnosed CUP. He was treated with surgical resection, proton-beam radiation, and carboplatin-paclitaxel. He had an excellent outcome with no evidence of disease 18 months following treatment completion. This case underscores the importance of continued vigilance and thorough investigation for a primary tumor site even when cervical nodal metastases are HPV-positive. While the vast majority of HPV-positive head and neck tumors arise in the oropharynx, other anatomical sites may also harbor HPV-positive malignancies.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Conducto Nasolagrimal , Neoplasias Primarias Desconocidas , Infecciones por Papillomavirus , Humanos , Masculino , Persona de Mediana Edad , Conducto Nasolagrimal/diagnóstico por imagen , Neoplasias Primarias Desconocidas/terapia , Papillomaviridae , Infecciones por Papillomavirus/diagnóstico
4.
J Appl Clin Med Phys ; 20(3): 14-21, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30756466

RESUMEN

This study determines the impact of change in aeration in sinonasal cavities on the robustness of passive-scattering proton therapy plans in patients with sinonasal and nasopharyngeal malignancies. Fourteen patients, each with one planning CT and one CT acquired during radiotherapy were studied. Repeat and planning CTs were rigidly aligned and contours were transferred using deformable registration. The amount of air, tumor, and fluid within the cavity containing the tumor were measured on both CTs. The original plans were recalculated on the repeat CT. Dosimetric changes were measured for the targets and critical structures. Median decrease in gross tumor volume (GTV) was 19.8% and correlated with the time of rescan. The median change in air content was 7.1% and correlated with the tumor shrinkage. The median of the mean dose Dmean change was +0.4% for GTV and +0.3% for clinical target volume. Median change in the maximum dose Dmax of the critical structures were as follows: optic chiasm +0.66%, left optic nerve +0.12%, right optic nerve +0.38%, brainstem +0.6%. The dose to the GTV decreased by more than 5% in 1 case, and the dose to critical structure(s) increased by more than 5% in three cases. These four patients had sinonasal cancers and were treated with anterior proton fields that directly transversed through the involved sinus cavities. The change in dose in the replanning was strongly correlated with the change in aeration (P = 0.02). We found that the change in aeration in the vicinity of the target and the arrangement of proton beams affected the robustness of proton plan.


Asunto(s)
Quimioradioterapia , Linfoma Extranodal de Células NK-T/terapia , Carcinoma Nasofaríngeo/terapia , Terapia de Protones/instrumentación , Planificación de la Radioterapia Asistida por Computador/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Terapia de Protones/métodos
5.
J Neurosci ; 35(4): 1468-80, 2015 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-25632124

RESUMEN

Observing touch has been reported to elicit activation in human primary and secondary somatosensory cortices and is suggested to underlie our ability to interpret other's behavior and potentially empathy. However, despite these reports, there are a large number of inconsistencies in terms of the precise topography of activation, the extent of hemispheric lateralization, and what aspects of the stimulus are necessary to drive responses. To address these issues, we investigated the localization and functional properties of regions responsive to observed touch in a large group of participants (n = 40). Surprisingly, even with a lenient contrast of hand brushing versus brushing alone, we did not find any selective activation for observed touch in the hand regions of somatosensory cortex but rather in superior and inferior portions of neighboring posterior parietal cortex, predominantly in the left hemisphere. These regions in the posterior parietal cortex required the presence of both brush and hand to elicit strong responses and showed some selectivity for the form of the object or agent of touch. Furthermore, the inferior parietal region showed nonspecific tactile and motor responses, suggesting some similarity to area PFG in the monkey. Collectively, our findings challenge the automatic engagement of somatosensory cortex when observing touch, suggest mislocalization in previous studies, and instead highlight the role of posterior parietal cortex.


Asunto(s)
Mapeo Encefálico , Lóbulo Parietal/fisiología , Corteza Somatosensorial/fisiología , Tacto , Percepción Visual/fisiología , Adulto , Femenino , Dedos/inervación , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangre , Lóbulo Parietal/irrigación sanguínea , Estimulación Física , Corteza Somatosensorial/irrigación sanguínea , Visión Ocular , Adulto Joven
6.
Head Neck ; 45(6): E25-E30, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37080924

RESUMEN

BACKGROUND: Human papillomavirus-associated head and neck squamous cell carcinoma (HPV + HNSCC) occurs in the oropharynx (HPV + OPSCC), sinonasal cavity (HPV + SNSCC), and nasopharynx (HPV + NPC). Circulating tumor HPV DNA (ctHPVDNA) is an accurate tool for diagnosis, treatment monitoring, and recurrence detection. An emerging challenge with ctHPVDNA is that ~7.4% of HPV + HNSCC patients develop synchronous or metachronous HPV+ primaries, which could confound ctHPVDNA monitoring. METHODS: We describe a 65-year-old patient with T2N1M0 HPV16 + OPSCC and a 55-year-old patient with T2N2M0 HPV16 + OPSCC. Both patients were enrolled in our prospective observational ctHPVDNA study with longitudinal blood collections throughout treatment. Both patients developed multiple HPV+ primaries. RESULTS: Detailed discussion of the patients' treatment courses, the subsequent diagnoses of their second HPV+ primaries, and their ctHPVDNA monitoring is presented. CONCLUSIONS: As ctHPVDNA use becomes more prevalent, it is important to recognize that an increase in ctHPVDNA can come not only from the primary tumor or metastatic clones, but also from synchronous or metachronous second primaries.


Asunto(s)
Carcinoma de Células Escamosas , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Anciano , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias Orofaríngeas/patología , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Infecciones por Papillomavirus/patología , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/terapia
7.
Clin Transl Radiat Oncol ; 40: 100625, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37090849

RESUMEN

Purpose: This work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes. Methods: IMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT. Results: Daily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D98 degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands. Conclusion: Daily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

8.
PLoS One ; 18(8): e0279235, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37540647

RESUMEN

IMPORTANCE: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood. OBJECTIVE: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center (Massachusetts General Hospital, Boston). PARTICIPANTS: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. MEASUREMENTS: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV). RESULTS: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001). CONCLUSIONS AND RELEVANCE: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.


Asunto(s)
Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Fluorodesoxiglucosa F18/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/metabolismo , Estudios Retrospectivos , Tomografía de Emisión de Positrones/métodos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/metabolismo , Estadificación de Neoplasias , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/metabolismo , Pronóstico
9.
J Surg Oncol ; 105(3): 261-5, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22375288

RESUMEN

BACKGROUND AND OBJECTIVES: To determine the rate and the risk factors for sinonasal-cutaneous fistula formation after treatment for sinonasal malignancy. METHODS: Between 1991 and 2002, 99 patients with advanced sinonasal malignancy received radiation therapy +/- surgery. Primary site was maxillary sinus in 30, ethmoid sinus in 19, nasal cavity in 32, nasopharynx in 3, and sphenoid sinus in 15 patients. Eighty-two percent of patients had T4 disease. Sixty-eight percent of patients had undergone surgical resection. Median follow-up was 70.6 months. RESULTS: Eight patients developed ≥ grade 3 sinonasal-cutaneous fistulas at a median time of 3.8 months after radiation. The overall rates of developing ≥ grade 3 fistulas in the entire group at 2 and 5 years were 6% and 10%, respectively. The fistulas were in the medial canthus in seven patients and in the infraorbital region in one patient. Fistulas developed exclusively along the transfacial incision scar and in patients whose tumors extended to the subcutaneous tissues. In univariate analysis, squamous cell carcinoma histology (P » 0.008), ≤ T4a primary tumor category (P » 0.02), and transfacial incision (P » 0.02) were associated with increased risk of fistula formation. CONCLUSIONS: Histologic subtype, T category, and quality of the skin and the underlying supporting tissues after transfacial incision are risk factors for sinonasal-cutaneous fistula formation.


Asunto(s)
Fístula Cutánea/etiología , Fístula/etiología , Enfermedades de los Senos Paranasales/etiología , Neoplasias de los Senos Paranasales/terapia , Complicaciones Posoperatorias , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/patología , Carcinoma/terapia , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Cavidad Nasal/cirugía , Tumores Neuroectodérmicos/patología , Tumores Neuroectodérmicos/terapia , Neoplasias de los Senos Paranasales/patología , Senos Paranasales/cirugía , Radioterapia/efectos adversos , Radioterapia Adyuvante , Estudios Retrospectivos , Factores de Riesgo , Sarcoma/patología , Sarcoma/terapia , Adulto Joven
10.
Cancers (Basel) ; 14(15)2022 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-35954315

RESUMEN

This study aims to evaluate the efficacy of the Pooled Cohort Equation (PCE), U.S. Preventative Services Task Force (USPSTF), and Framingham Risk Score (FRS) models in predicting ASCVD events among patients receiving radiation therapy (RT) for head and neck cancer (HNCA). From a large cohort of HNCA patients treated with RT, ASCVD events were adjudicated. Observed vs. predicted ASCVD events were compared. We compared rates by statin eligibility status. Regression models and survival analysis were used to identify the relationship between predicted risk and post-RT outcomes. Among the 723 identified patients, 274 (38%) were statin-eligible based on USPSTF criteria, 359 (49%) based on PCE, and 234 (32%) based on FRS. During follow-up, 17% developed an ASCVD, with an event rate of 27 per 1000 person-years, 68% higher than predicted (RR 1.68 (95% CI: 1.02, 2.12), p < 0.001). In multivariable regression, there was no difference in event rates by statin eligibility status (p > 0.05). Post-RT, the observed event rate was higher than the predicted ASCVD risk across all grades of predicted risk (p < 0.05) and the observed risk of an ASCVD event was high even among patients predicted to have a low risk of ASCVD. In conclusion, current ASCVD risk calculators significantly underestimate the risk for ASCVD among patients receiving RT for HNCA.

11.
Clin Cancer Res ; 28(4): 719-727, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-34857594

RESUMEN

PURPOSE: HPV-associated head and neck squamous cell carcinoma (HPV+HNSCC) is the most common HPV-associated malignancy in the United States and continues to increase in incidence. Current diagnostic approaches for HPV+HNSCC rely on tissue biopsy followed by histomorphologic assessment and detection of HPV indirectly by p16 IHC. Such approaches are invasive and have variable sensitivity. EXPERIMENTAL DESIGN: We conducted a prospective observational study in 140 subjects (70 cases and 70 controls) to test the hypothesis that a noninvasive diagnostic approach for HPV+HNSCC would have improved diagnostic accuracy, lower cost, and shorter diagnostic interval compared with standard approaches. Blood was collected, processed for circulating tumor HPV DNA (ctHPVDNA), and analyzed with custom ddPCR assays for HPV genotypes 16, 18, 33, 35, and 45. Diagnostic performance, cost, and diagnostic interval were calculated for standard clinical workup and compared with a noninvasive approach using ctHPVDNA combined with cross-sectional imaging and physical examination findings. RESULTS: Sensitivity and specificity of ctHPVDNA for detecting HPV+HNSCC were 98.4% and 98.6%, respectively. Sensitivity and specificity of a composite noninvasive diagnostic using ctHPVDNA and imaging/physical examination were 95.1% and 98.6%, respectively. Diagnostic accuracy of this noninvasive approach was significantly higher than standard of care (Youden index 0.937 vs. 0.707, P = 0.0006). Costs of noninvasive diagnostic were 36% to 38% less than standard clinical workup and the median diagnostic interval was 26 days less. CONCLUSIONS: A noninvasive diagnostic approach for HPV+HNSCC demonstrated improved accuracy, reduced cost, and a shorter time to diagnosis compared with standard clinical workup and could be a viable alternative in the future.


Asunto(s)
Ácidos Nucleicos Libres de Células , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , ADN Viral/genética , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/virología , Humanos , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico
12.
Curr Biol ; 18(1): 56-62, 2008 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-18164202

RESUMEN

Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.


Asunto(s)
Genes de Neurofibromatosis 1 , Neoplasias/genética , Factores de Transcripción/fisiología , Animales , Línea Celular , Ciclina D , Ciclinas/genética , Ciclinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR , Factores de Transcripción/metabolismo
13.
Sci Rep ; 11(1): 10442, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-34001935

RESUMEN

Combatting the current global epidemic of obesity requires that people have a realistic understanding of what a healthy body size looks like. This is a particular issue in different population sub-groups, where there may be increased susceptibility to obesity-related diseases. Prior research has been unable to systematically assess body size judgement due to a lack of attention to gender and race; our study aimed to identify the contribution of these factors. Using a data-driven multi-variate decision tree approach, we varied the gender and race of image stimuli used, and included the same diversity among participants. We adopted a condition-rich categorization visual task and presented participants with 120 unique body images. We show that gender and weight categories of the stimuli affect accuracy of body size perception. The decision pattern reveals biases for male bodies, in which participants showed an increasing number of errors from leaner to bigger bodies, particularly under-estimation errors. Participants consistently mis-categorized overweight male bodies as normal weight, while accurately categorizing normal weight. Overweight male bodies are now perceived as part of an expanded normal: the perceptual boundary of normal weight has become wider than the recognized BMI category. For female bodies, another intriguing pattern emerged, in which participants consistently mis-categorized underweight bodies as normal, whilst still accurately categorizing normal female bodies. Underweight female bodies are now in an expanded normal, in opposite direction to that of males. Furthermore, an impact of race type and gender of participants was also observed. Our results demonstrate that perceptual weight categorization is multi-dimensional, such that categorization decisions can be driven by ultiple factors.


Asunto(s)
Imagen Corporal/psicología , Tamaño Corporal , Juicio , Modelos Psicológicos , Percepción del Tamaño , Adulto , Árboles de Decisión , Femenino , Cuerpo Humano , Humanos , Masculino , Sobrepeso/diagnóstico , Sobrepeso/psicología , Valores de Referencia , Factores Sexuales , Delgadez/diagnóstico , Delgadez/psicología , Adulto Joven
14.
Int J Radiat Oncol Biol Phys ; 110(4): 984-992, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-33600889

RESUMEN

PURPOSE: Uncertainties in relative biological effectiveness (RBE) constitute a major pitfall of the use of protons in clinics. An RBE value of 1.1, which is based on cell culture and animal models, is currently used in clinical proton planning. The purpose of this study was to determine RBE for temporal lobe radiographic changes using long-term follow-up data from patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: Five hundred sixty-six patients with newly diagnosed nasopharyngeal carcinoma received double-scattering proton therapy or intensity modulated radiation therapy at our institutions. The 2 treatment cohorts were well matched. Proton dose distributions were simulated using Monte Carlo and compared with those obtained from the proton clinical treatment planning system. Late treatment effect was defined as development of enhancement of temporal lobe on T1-weighted magnetic resonance imaging, with or without accompanying clinical symptoms. The tolerance dose was calculated with receiving operator characteristic analysis and the Youden index. Tolerance curves, expressed as a cumulative dose-volume histogram, were generated using the cutoff points. RESULTS: With a median follow-up period >5 years for both cohorts, 10% of proton patients and 4% of patients undergoing intensity modulated radiation therapy developed temporal lobe enhancement in unilateral temporal lobe. There was no significant difference in dose distributions between the Monte Carlo method and treatment planning system. The tolerance dose-volume levels were V10 (26.1%), V20 (21.9%), V30 (14.0%), V40 (7.7%), V50 (4.8%), and V60 (3.3%) for proton therapy (P < .03). Comparison of the two tolerance curves revealed that tolerance doses of proton treatments were lower than that of photon treatments at all dose levels. The dose tolerance at D1% was 58.56 Gy for protons and 69.07 Gy for photons. The RBE for temporal lobe enhancement from proton treatments were calculated to be 1.18. CONCLUSIONS: Using long-term clinical outcome of patients with nasopharyngeal carcinoma, our data suggest that the RBE for temporal lobe enhancement is 1.18 at D1%. A prospective study in a large cohort would be necessary to confirm these findings.


Asunto(s)
Encéfalo/efectos de la radiación , Carcinoma Nasofaríngeo/radioterapia , Terapia de Protones , Efectividad Biológica Relativa , Adulto , Femenino , Humanos , Masculino , Método de Montecarlo , Estudios Prospectivos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada , Resultado del Tratamiento
15.
Vision (Basel) ; 3(1)2019 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-31735810

RESUMEN

Facial recognition is widely thought to involve a holistic perceptual process, and optimal recognition performance can be rapidly achieved within two fixations. However, is facial identity encoding likewise holistic and rapid, and how do gaze dynamics during encoding relate to recognition? While having eye movements tracked, participants completed an encoding ("study") phase and subsequent recognition ("test") phase, each divided into blocks of one- or five-second stimulus presentation time conditions to distinguish the influences of experimental phase (encoding/recognition) and stimulus presentation time (short/long). Within the first two fixations, several differences between encoding and recognition were evident in the temporal and spatial dynamics of the eye-movements. Most importantly, in behavior, the long study phase presentation time alone caused improved recognition performance (i.e., longer time at recognition did not improve performance), revealing that encoding is not as rapid as recognition, since longer sequences of eye-movements are functionally required to achieve optimal encoding than to achieve optimal recognition. Together, these results are inconsistent with a scan path replay hypothesis. Rather, feature information seems to have been gradually integrated over many fixations during encoding, enabling recognition that could subsequently occur rapidly and holistically within a small number of fixations.

16.
Neuroimage Clin ; 23: 101882, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31226622

RESUMEN

Phantom limb pain (PLP) following amputation, which is experienced by the vast majority of amputees, has been reported to be relieved with daily sessions of mirror therapy. During each session, a mirror is used to view the reflected image of the intact limb moving, providing visual feedback consistent with the movement of the missing/phantom limb. To investigate potential neural correlates of the treatment effect, we measured brain responses in volunteers with unilateral leg amputation using functional magnetic resonance imaging (fMRI) during a four-week course of mirror therapy. Mirror therapy commenced immediately following baseline scans, which were repeated after approximately two and four week intervals. We focused on responses in the region of sensorimotor cortex corresponding to primary somatosensory and motor representations of the missing leg. At baseline, prior to starting therapy, we found a strong and unexpected response in sensorimotor cortex of amputees to visually presented images of limbs. This response was stronger for images of feet compared to hands and there was no such response in matched controls. Further, this response to visually presented limbs was no longer present at the end of the four week mirror therapy treatment, when perceived phantom limb pain was also reduced. A similar pattern of results was also observed in extrastriate and parietal regions typically responsive to viewing hand actions, but not in regions corresponding to secondary somatosensory cortex. Finally, there was a significant correlation between initial visual responsiveness in sensorimotor cortex and reduction in PLP suggesting a potential marker for predicting efficacy of mirror therapy. Thus, enhanced visual responsiveness in sensorimotor cortex is associated with PLP and modulated over the course of mirror therapy.


Asunto(s)
Amputación Quirúrgica/efectos adversos , Retroalimentación Sensorial/fisiología , Extremidad Inferior/fisiopatología , Rehabilitación Neurológica/métodos , Evaluación de Resultado en la Atención de Salud/métodos , Miembro Fantasma/fisiopatología , Miembro Fantasma/rehabilitación , Corteza Sensoriomotora/fisiopatología , Extremidad Superior/fisiopatología , Percepción Visual/fisiología , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miembro Fantasma/etiología , Corteza Sensoriomotora/diagnóstico por imagen
17.
Int J Radiat Oncol Biol Phys ; 103(3): 654-668, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30712708

RESUMEN

PURPOSE: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era. METHODS AND MATERIALS: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. RESULTS: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95% confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity. CONCLUSIONS: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV.


Asunto(s)
Neoplasias de Cabeza y Cuello/radioterapia , Carcinoma Nasofaríngeo/radioterapia , Radioterapia/métodos , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Neoplasias Nasofaríngeas/radioterapia , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Terapia de Protones , Traumatismos por Radiación , Radiometría , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
18.
J Natl Cancer Inst ; 111(9): 933-942, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30715409

RESUMEN

BACKGROUND: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. METHODS: To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. RESULTS: Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. CONCLUSION: In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.


Asunto(s)
Biomarcadores de Tumor , Receptor alfa de Estrógeno/genética , Expresión Génica , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/mortalidad , Adulto , Anciano , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Transducción de Señal
19.
Skull Base ; 18(5): 327-37, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19240832

RESUMEN

OBJECTIVES: To determine the efficacy of craniofacial resection and proton radiation for the management of esthesioneuroblastoma (ENB). DESIGN: A retrospective chart review was performed of all patients presenting with ENB and completely managed at the Massachusetts General Hospital (MGH) and the Massachusetts Eye and Ear Infirmary (MEEI) from 1997 to 2006. SETTING: A tertiary referral center. MAIN OUTCOME MEASURES: Disease-free and overall survival. PARTICIPANTS: All patients presenting with ENB and completely managed at the MGH and the MEEI from 1997 to 2006. RESULTS: Ten patients were identified with a median follow-up time of 52.8 months. Average age at presentation was 45 years. Nasal obstruction was the most common presenting symptom. Three patients presented with Kadish stage B disease and seven with stage C. No patient had evidence of cervical or metastatic disease at presentation. Seven patients were treated with craniofacial resections (CFR) followed by proton beam radiation with or without chemotherapy. Three patients were treated with initial chemotherapy with no response. They subsequently underwent CFR followed by proton beam radiation. The 5-year disease-free and overall survival rates were 90% and 85.7%, respectively, by Kaplan-Meier analysis. No patient suffered any severe radiation toxicity. CONCLUSION: ENB can be safely and effectively treated with CFR followed by proton beam irradiation. Proton irradiation may be associated with less toxicity than photon irradiation. The role of chemotherapy remains unclear.

20.
Cancer Commun (Lond) ; 43(5): 613-614, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37069789
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