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1.
Clin Cancer Res ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420360

RESUMO

PURPOSE: Previous studies indicate the benefit of therapy depends on patients' risk for cancer recurrence relative to non-cancer mortality (ω ratio). We sought to test the hypothesis that head and neck cancer (HNC) patients with a higher ω ratio selectively benefit from intensive therapy. EXPERIMENTAL DESIGN: We analyzed 2688 patients with stage III-IVB HNC undergoing primary radiation therapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio, and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation (AFX) and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score based on tumor, demographic, and health factors. Analysis was by intention-to-treat. RESULTS: Decreasing age, improved performance status, higher body mass index, node positive status, P16 negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥ 0.80 were more likely to benefit from intensive treatment (5-year OS, 70.0% vs. 56.6%; HR 0.73, 95% CI 0.57-0.94; P=0.016) than those with a ω score < 0.80 (5-year OS, 46.7% vs. 45.3%; HR 1.02, 95% CI 0.92-1.14; P=0.69;P=0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression. CONCLUSION: HNC patients with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

2.
Inhal Toxicol ; 31(5): 192-202, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31345048

RESUMO

Background: Increasing evidence from rodent studies indicates that inhaled multi-walled carbon nanotubes (MWCNTs) have harmful effects on the lungs. In this study, we examined the effects of inhalation exposure to MWCNTs on allergen-induced airway inflammation and fibrosis. We hypothesized that inhalation pre-exposure to MWCNTs would render mice susceptible to developing allergic lung disease induced by house dust mite (HDM) allergen. Methods: Male B6C3F1/N mice were exposed by whole-body inhalation for 6 h a day, 5 d a week, for 30 d to air control or 0.06, 0.2, and 0.6 mg/m3 of MWCNTs. The exposure atmospheres were agglomerates (1.4-1.8 µm) composed of MWCNTs (average diameter 16 nm; average length 2.4 µm; 0.52% Ni). Mice then received 25 µg of HDM extract by intranasal instillation 6 times over 3 weeks. Necropsy was performed at 3 and 30 d after the final HDM dose to collect serum, bronchoalveolar lavage fluid (BALF), and lung tissue for histopathology. Results: MWCNT exposure at the highest dose inhibited HDM-induced serum IgE levels, IL-13 protein levels in BALF, and airway mucus production. However, perivascular and peribronchiolar inflammatory lesions were observed in the lungs of mice at 3 d with MWCNT and HDM, but not MWCNT or HDM alone. Moreover, combined HDM and MWCNT exposure increased airway fibrosis in the lungs of mice. Conclusions: Inhalation pre-exposure to MWCNTs inhibited HDM-induced TH2 immune responses, yet this combined exposure resulted in vascular inflammation and airway fibrosis, indicating that MWCNT pre-exposure alters the immune response to allergens.

3.
Biochem Biophys Res Commun ; 517(1): 36-42, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31311651

RESUMO

Acquired cetuximab resistance is a challenge for oncologists treating advanced head and neck carcinoma (HNC). While intrinsic cetuximab resistance mechanism in colorectal cancer is known, resistance in HNC is unclear. We established two different cetuximab resistant HNC cell lines by culturing epidermal growth factor (EGFR) expressing UM-SCC-1 and UM-SCC-6 cell lines in the presence of 5 µg/ml cetuximab. We then explored potential mechanisms of resistance. We found that the 2 cell lines developed resistance by different mechanisms. Specifically, we found that UM-SCC-1 resistant cells (UM-SCC-1R) showed enhanced EGF-induced downstream signals while UM-SCC-6 resistant cells (UM-SCC-6R) demonstrated EGF-independent signaling. Global kinase activity (kinomic) profiling revealed unique signaling differences in the two resistant cell lines. However, both of the resistant lines demonstrated increased phospho-serine 727 and total STAT3 expression compared to the parental lines. STAT3 knockdown promoted increased cytotoxicity both in the presence and absence of cetuximab in the resistant lines suggesting that STAT3 may be a common target in cetuximab resistance.

4.
Int J Oncol ; 54(6): 2039-2053, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942445

RESUMO

Glioblastoma harbors frequent alterations in receptor tyrosine kinases, phosphatidylinositol­3 kinase (PI3K) and phosphatase and tensin homolog (PTEN) that dysregulate phospholipid signaling driven tumor proliferation and therapeutic resistance. Myristoylated alanine­rich C­kinase substrate (MARCKS) is a 32 kDa intrinsically unstructured protein containing a polybasic (+13) effector domain (ED), which regulates its electrostatic sequestration of phospholipid phosphatidylinositol (4,5)­bisphosphate (PIP2), and its binding to phosphatidylserine, calcium/calmodulin, filamentous actin, while also serving as a nuclear localization sequence. MARCKS ED is phosphorylated by protein kinase C (PKC) and Rho­associated protein kinase (ROCK) kinases; however, the impact of MARCKS on glioblastoma growth and radiation sensitivity remains undetermined. In the present study, using a tetracycline­inducible system in PTEN­null U87 cells, we demonstrate that MARCKS overexpression suppresses growth and enhances radiation sensitivity in vivo. A new image cytometer, Xcyto10, was utilized to quantify differences in MARCKS ED phosphorylation on localization and its association with filamentous actin. The overexpression of the non­phosphorylatable ED mutant exerted growth­suppressive and radiation­sensitizing effects, while the pseudo­phosphorylated ED mutant exhibited an enhanced colony formation and clonogenic survival ability. The identification of MARCKS protein­protein interactions using co­immunoprecipitation coupled with tandem mass spectrometry revealed novel MARCKS­associated proteins, including importin­ß and ku70. On the whole, the findings of this study suggest that the determination of the MARCKS ED phosphorylation status is essential to understanding the impact of MARCKS on cancer progression.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Substrato Quinase C Rico em Alanina Miristoilada/metabolismo , Domínios Proteicos , Tolerância a Radiação , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Humanos , Autoantígeno Ku/metabolismo , Camundongos , Camundongos Nus , Fosforilação , Mapeamento de Interação de Proteínas , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , beta Carioferinas/metabolismo
5.
Oral Oncol ; 90: 80-86, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30846182

RESUMO

PURPOSE: Severe late toxicity is common after re-irradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck. However, many patients experience complications from tumor progression before manifesting late effects. We constructed a nomogram to examine this relationship between late toxicity and competing risks. METHODS AND MATERIALS: Patients with RSP squamous carcinoma originating in a field previously irradiated to ≥40 Gy and treated with IMRT-based re-irradiation to ≥40 Gy were collected. Grade ≥3 late toxicity developing ≥90 days after re-irradiation was collected. A multivariable competing-risk model was fit to the actuarial risk of late toxicity with progression or death as the competing risk. The final bootstrap optimized model was converted into a nomogram. RESULTS: From 9 institutions, 505 patients were included. The 2-year incidence of grade ≥3 late toxicity was 16.7% (95% CI 13.2-20.2%) whereas progression or death was 64.2% (95% CI 59.7-68.8%). The median freedom from late toxicity, progression or death was 10.7, 5.5 and 3.2 months for RPA class I-III patients respectively, whereas the median OS was 44.9, 15.9 and 7.9 months, respectively. The final model included six clinical factors. Notably, dose, volume and fractionation did not significantly impact toxicity. CONCLUSIONS: After re-irradiation, the risk of progression or death is approximately four times the risk of radiation-related severe late toxicity. The risk of late toxicity may be more dependent on patient and disease factors than modifiable treatment factors. This model is useful for patient selection, pre-treatment consent and post-treatment survivorship following re-irradiation.

6.
Int J Radiat Oncol Biol Phys ; 104(5): 979-986, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30684662

RESUMO

PURPOSE: Understanding the pathways and gateways to leadership and challenges faced by individuals in such roles can inform efforts to promote diversity and equity. We sought to describe the professional experiences and personal characteristics of academic radiation oncology (RO) chairs and to evaluate whether differences exist by gender. METHODS AND MATERIALS: Anonymous surveys were distributed to 95 chairs of RO departments during the 2016 annual meeting of the Society of Chairs of Academic Radiation Oncology Programs. The surveys included 28 closed-ended questions and the Leadership Practices Inventory. Results were analyzed by gender using χ2 tests, rank-sum, and t tests (significance P < .05). RESULTS: A total of 72 chairs responded (61 male, 10 female, 1 declined to identify gender) for a response rate of 76%. There were no significant gender differences in age, academic rank, publications, or prior leadership positions held at the time of the first chair appointment, but female respondents held significantly greater total direct funding from extramural grants than their male counterparts (median, $1.89 million [interquartile range, $0.5-$5 million] vs $0.25 million [interquartile range, $0-$1.0 million]; P = .006). Women were more likely to have spouses employed outside the home at time of their first chair appointment than men were, with a trend toward women experiencing greater difficulty relocating. Men and women identified budgeting and resource allocation as their greatest professional challenges. There were no gender differences in the Leadership Practices Inventory-identified leadership domains or professional goals. CONCLUSIONS: Female RO chairs are as equally qualified as men in terms of productivity or leadership skills, but they face distinct challenges in the context of a gender-structured society. The observation of higher grant funding among women at the time of chair appointment suggests a possible need for interventions such as unconscious bias training to ensure that selection processes do not unnecessarily hold women to a higher standard.

7.
Nanotoxicology ; : 1-17, 2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30317900

RESUMO

The fiber-like shape of multi-walled carbon nanotubes (MWCNTs) is reminiscent of asbestos, suggesting they pose similar health hazards when inhaled, including pulmonary fibrosis and mesothelioma. Mice deficient in the tumor suppressor p53 are susceptible to carcinogenesis. However, the chronic pathologic effect of MWCNTs delivered to the lungs of p53 heterozygous (p53+/-) mice has not been investigated. We hypothesized that p53+/- mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs. Wild-type (p53+/+) or p53+/- mice were exposed to MWCNTs (1 mg/kg) via oropharyngeal aspiration weekly over four consecutive weeks and evaluated for cellular and pathologic outcomes 11-months post-initial exposure. No lung or pleural tumors were observed in p53+/+ or p53+/- mice exposed to either t- or rMWCNTs. In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53+/- and p53+/+ mice. A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in p53+/- mice compared to p53+/+ mice. Importantly, p53+/- mice had larger granulomas induced by rMWCNTs as compared to p53+/+ mice. These findings indicate that a combination of p53 deficiency and physicochemical characteristics including nanotube geometry are factors in susceptibility to MWCNT-induced lymphoid infiltration and granuloma formation.

9.
Analyst ; 143(21): 5176-5184, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30264084

RESUMO

Disulfide heterogeneity and other non-native crosslinks introduced during therapeutic antibody production and storage could have considerable negative effects on clinical efficacy, but tracking these modifications remains challenging. Analysis must also be carried out cautiously to avoid introduction of disulfide scrambling or reduction, necessitating the use of low pH digestion with less specific proteases. Herein we demonstrate that 213 nm ultraviolet photodissociation streamlines disulfide elucidation through bond-selective dissociation of sulfur-sulfur and carbon-sulfur bonds in combination with less specific backbone dissociation. Importantly, both types of fragmentation can be initiated in a single MS/MS activation stage. In addition to disulfide mapping, it is also shown that thioethers and trisulfides can be identified by characteristic fragmentation patterns. The photochemistry resulting from 213 nm excitation facilitates a simplified, two-tiered data processing approach that allows observation of all native disulfide bonds, scrambled disulfide bonds, and non-native sulfur-based linkages in a pepsin digest of Rituximab. Native disulfides represented the majority of bonds according to ion count, but the highly solvent-exposed heavy/light interchain disulfides were found to be most prone to modification. Production and storage methods that facilitate non-native links are discussed. Due to the importance of heavy and light chain connectivity for antibody structure and function, this region likely requires particular attention in terms of its influence on maintaining structural fidelity.

10.
Ann Am Thorac Soc ; 15(Supplement_2): S129-S130, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29676624

RESUMO

RATIONALE: Multiwalled carbon nanotubes (MWCNTs) are a potential risk for pulmonary fibrosis because of their fiber-like shape; other physicochemical features, such as rigidity, could also confer fibrogenicity. The signal transducer and activator of transcription 1 (STAT1) is an important antifibrogenic transcription factor that promotes fibroblast growth arrest. STAT1-deficient (Stat1-/-) mice are susceptible to pulmonary fibrosis. OBJECTIVES: In this study, we hypothesized that Stat1-/- mice exhibit a differential fibrogenic response to tangled MWCNTs versus rigid MWCNTs above that seen with wild-type (Stat1+/+) mice. METHODS: Stat1+/+ and Stat1-/- mice were exposed to tangled MWCNTs or rigid MWCNTs (4 mg/kg) via oropharyngeal aspiration, and lung tissues were collected after 1 and 21 days to measure messenger RNA and protein levels of fibrogenic mediators. RESULTS: Compared with tangled MWCNTs, rigid MWCNTs caused mucous cell metaplasia, epithelial cell proliferation, increased fibrosis, and larger granulomas in the lungs of mice. Both MWCNT types induced acute neutrophilia; however, only rigid MWCNTs induced chronic neutrophilia. Stat1-/- mice exhibited higher serum levels of immunoglobin E and even higher levels when treated with rigid MWCNTs. Twenty-one days after treatment with rigid MWCNTs, compared with Stat1+/+ mice, Stat1-/- mice had higher levels of transforming growth factor-ß1 (TGF-ß1) protein in bronchoalveolar lavage fluid, increased transforming growth factor-ß1 signaling activation, and higher airway collagen deposition. Some of the results of this study were previously reported in the form of an abstract and a paper ( 1 , 2 ). CONCLUSIONS: Our data emphasize that rigid MWCNTs produce much stronger immune and fibrogenic responses than tangled MWCNTs and that these effects are exaggerated by STAT1 deficiency, highlighting the importance of tube rigidity and genetic susceptibility. The mechanism of STAT1 susceptibility to MWCNTs-induced fibrosis appears to be through dysregulated transforming growth factor-ß1 production and signaling.

11.
Curr Environ Health Rep ; 5(1): 100-109, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29441464

RESUMO

PURPOSE OF REVIEW: The explosive growth of the nanotechnology industry has necessitated the examination of engineered nanomaterials (ENMs) for their toxicity. The unique properties that make ENMs useful also make them a health risk, and individuals with pre-existing diseases such as asthma are likely more susceptible. This review summarizes the current literature on the ability of ENMs to both exacerbate and directly cause asthma. RECENT FINDINGS: Recent studies highlight the ability of metal nanoparticles (NPs) and carbon nanotubes (CNTs) to not only exacerbate pre-existing asthma in animal models but also initiate allergic airway disease directly. CNTs alone are shown to cause airway mucus production, elevated serum IgE levels, and increased TH2 cytokine levels, all key indicators of asthma. The ability of ENMs to modulate the immune response in asthma varies depending on their physicochemical properties and exposure timing. CNTs consistently exacerbate asthma, as do Ni and TiO2 NPs, whereas some NPs like Au attenuate asthma. Evidence is strong that ENMs can contribute to allergic airway disease; however, more work is required to determine their mechanisms, and more epidemiological studies are needed to validate results from animal models.

12.
Int J Radiat Oncol Biol Phys ; 100(3): 606-617, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29413274

RESUMO

PURPOSE: Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity. METHODS AND MATERIALS: Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints. RESULTS: From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates. CONCLUSIONS: Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity.

13.
Int J Radiat Oncol Biol Phys ; 101(1): 30-45, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29477292

RESUMO

PURPOSE: A lack of diversity has been observed in radiation oncology (RO), with women and certain racial/ethnic groups underrepresented as trainees, faculty, and practicing physicians. We sought to gain a nuanced understanding of how to best promote diversity, equity, and inclusion (DEI) based on the insights of RO department chairs, with particular attention given to the experiences of the few women and underrepresented minorities (URMs) in these influential positions. METHODS AND MATERIALS: From March to June 2016, we conducted telephone interviews with 24 RO department chairs (of 27 invited). Purposive sampling was used to invite all chairs who were women (n = 13) or URMs (n = 3) and 11 male chairs who were not URMs. Multiple analysts coded the verbatim transcripts. RESULTS: Five themes were identified: (1) commitment to DEI promotes quality health care and innovation; (2) gaps remain despite some progress with promoting diversity in RO; (3) women and URM faculty continue to experience challenges in various career domains; (4) solutions to DEI issues would be facilitated by acknowledging realities of gender and race; and (5) expansion of the career pipeline is needed. CONCLUSIONS: The chairs' insights had policy-relevant implications. Bias training should broach tokenism, blindness, and intersectionality. Efforts to recruit and support diverse talent should be deliberate and proactive. Bridge programs could engage students before their application to medical school.

14.
Artigo em Inglês | MEDLINE | ID: mdl-28984415

RESUMO

Carbon nanotubes (CNTs) are engineered nanomaterials (ENMs) with numerous beneficial applications. However, they could pose a risk to human health from occupational or consumer exposures. Rodent models demonstrate that exposure to CNTs via inhalation, instillation, or aspiration results in pulmonary fibrosis. The severity of the fibrogenic response is determined by various physicochemical properties of the nanomaterial such as residual metal catalyst content, rigidity, length, aggregation status, or surface charge. CNTs are also increasingly functionalized post-synthesis with organic or inorganic agents to modify or enhance surface properties. The mechanisms of CNT-induced fibrosis involve oxidative stress, innate immune responses of macrophages, cytokine and growth factor production, epithelial cell injury and death, expansion of the pulmonary myofibroblast population, and consequent extracellular matrix accumulation. A comprehensive understanding of how physicochemical properties affect the fibrogenic potential of various types of CNTs should be considered in combination with genetic variability and gain or loss of function of specific genes encoding secreted cytokines, enzymes, or intracellular cell signaling molecules. Here, we cover the current state of the literature on mechanisms of CNT-exposed pulmonary fibrosis in rodent models with a focus on physicochemical characteristics as principal drivers of the mechanisms leading to pulmonary fibrosis. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.


Assuntos
Nanotubos de Carbono , Fibrose Pulmonar/induzido quimicamente , Animais , Células Cultivadas , Fenômenos Químicos , Modelos Animais de Doenças , Exposição Ambiental , Transição Epitelial-Mesenquimal , Camundongos , Nanotubos de Carbono/química , Nanotubos de Carbono/toxicidade , Nanotubos de Carbono/ultraestrutura , Estresse Oxidativo , Ratos
15.
Int J Radiat Oncol Biol Phys ; 100(3): 595-605, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28899556

RESUMO

PURPOSE: Two modern methods of reirradiation, intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), are established for patients with recurrent or second primary squamous cell carcinoma of the head and neck (rSCCHN). We performed a retrospective multi-institutional analysis to compare methods. METHODS AND MATERIALS: Data from patients with unresectable rSCCHN previously irradiated to ≥40 Gy who underwent reirradiation with IMRT or SBRT were collected from 8 institutions. First, the prognostic value of our IMRT-based recursive partitioning analysis (RPA) separating those patients with unresectable tumors with an intertreatment interval >2 years or those with ≤2 years and without feeding tube or tracheostomy dependence (class II) from other patients with unresected tumors (class III) was investigated among SBRT patients. Overall survival (OS) and locoregional failure were then compared between IMRT and SBRT by use of 2 methods to control for baseline differences: Cox regression weighted by the inverse probability of treatment and subset analysis by RPA classification. RESULTS: The study included 414 patients with unresectable rSCCHN: 217 with IMRT and 197 with SBRT. The unadjusted 2-year OS rate was 35.4% for IMRT and 16.3% for SBRT (P<.01). Among SBRT patients, RPA classification retained an independent association with OS. On Cox regression weighted by the inverse probability of treatment, no significant differences in OS or locoregional failure between IMRT and SBRT were demonstrated. Analysis by RPA class showed similar OS between IMRT and SBRT for class III patients. In all class II patients, IMRT was associated with improved OS (P<.001). Further subset analysis demonstrated comparable OS when ≥35 Gy was delivered with SBRT to small tumor volumes. Acute grade ≥4 toxicity was greater in the IMRT group than in the SBRT group (5.1% vs 0.5%, P<.01), with no significant difference in late toxicity. CONCLUSIONS: Reirradiation both with SBRT and with IMRT appear relatively safe with favorable toxicity compared with historical studies. Outcomes vary by RPA class, which informs clinical trial design. Survival is poor in class III patients, and alternative strategies are needed.

16.
Int J Radiat Oncol Biol Phys ; 100(3): 586-594, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28865925

RESUMO

PURPOSE: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups. PATIENTS AND METHODS: Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40 Gy) who underwent reirradiation with IMRT (≥40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS. RESULTS: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P<.001): class I included patients >2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation. CONCLUSIONS: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status.

17.
J Biol Chem ; 293(3): 984-994, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29191829

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Gemcitabine, as a single agent or in combination therapy, remains the frontline chemotherapy despite its limited efficacy due to de novo or acquired chemoresistance. There is an acute need to decipher mechanisms underlying chemoresistance and identify new targets to improve patient outcomes. Here, we report a novel role for the ST6Gal-I sialyltransferase in gemcitabine resistance. Utilizing MiaPaCa-2 and BxPC-3 PDAC cells, we found that knockdown (KD) of ST6Gal-I expression, as well as removal of surface α2-6 sialic acids by neuraminidase, enhances gemcitabine-mediated cell death assessed via clonogenic assays and cleaved caspase 3 expression. Additionally, KD of ST6Gal-I potentiates gemcitabine-induced DNA damage as measured by comet assays and quantification of γH2AX foci. ST6Gal-I KD also alters mRNA expression of key gemcitabine metabolic genes, RRM1, RRM2, hENT1, and DCK, leading to an increased gemcitabine sensitivity ratio, an indicator of gemcitabine toxicity. Gemcitabine-resistant MiaPaCa-2 cells display higher ST6Gal-I levels than treatment-naïve cells along with a reduced gemcitabine sensitivity ratio, suggesting that chronic chemotherapy selects for clonal variants with more abundant ST6Gal-I. Finally, we examined Suit2 PDAC cells and Suit2 derivatives with enhanced metastatic potential. Intriguingly, three metastatic and chemoresistant subclones, S2-CP9, S2-LM7AA, and S2-013, exhibit up-regulated ST6Gal-I relative to parental Suit2 cells. ST6Gal-I KD in S2-013 cells increases gemcitabine-mediated DNA damage, indicating that suppressing ST6Gal-I activity sensitizes inherently resistant cells to gemcitabine. Together, these findings place ST6Gal-I as a critical player in imparting gemcitabine resistance and as a potential target to restore PDAC chemoresponse.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/genética , Sialiltransferases/metabolismo , Linhagem Celular Tumoral , Ensaio Cometa , Dano ao DNA/genética , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Transportador Equilibrativo 1 de Nucleosídeo/genética , Humanos , Immunoblotting , Neuraminidase/metabolismo , RNA Mensageiro/genética , Ribonucleosídeo Difosfato Redutase/genética , Sialiltransferases/genética , Proteínas Supressoras de Tumor/genética
18.
J Healthc Manag ; 62(5): 302-313, 2017 Sep/Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28885530

RESUMO

EXECUTIVE SUMMARY: The importance of emotional intelligence (EI) in physicians has attracted attention as researchers begin to focus on the relationship of EI to retention, promotion, and productivity among academic physicians. However, to date, no formal evaluation of EI has been conducted among current department chairs. The objectives of this study were to assess the EI of current chairs of academic radiation oncology departments and to correlate EI with a self-reported assessment of burnout.The authors invited 95 chairs of academic radiation oncology departments to participate in a survey, approved by an institutional review board, consisting of the Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF) and the abbreviated Maslach Burnout Inventory (a-MBI). TEIQue-SF scores were evaluated for correlation with respondents' demographics and self-reported burnout scores on the a-MBI. Sixty chairs responded to the survey, for a response rate of 63.2%. The median (interquartile range) TEIQue-SF for the responding cohort was 172 (155-182) out of a maximum possible score of 210. The a-MBI emotional exhaustion and depersonalization subscores were low, with median (interquartile range) scores of 4 (2.25-6.75) and 1 (0-2.75) out of maximum possible scores of 18 and 30, respectively. Higher TEIQue-SF global scores were weakly correlated with decreased burnout. The study results show that academic radiation oncology chairs had a high EI and low rates of self-reported burnout. EI may be of increasing importance with respect to recruitment and retention of academic medical leaders.


Assuntos
Esgotamento Profissional , Radioterapia (Especialidade) , Inteligência Emocional , Humanos , Médicos , Inquéritos e Questionários
19.
J Clin Oncol ; 35(36): 4057-4065, 2017 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-28777690

RESUMO

Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Neoplasias de Cabeça e Pescoço/mortalidade , Nomogramas , Neoplasias Orofaríngeas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/radioterapia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida
20.
J Am Chem Soc ; 139(30): 10286-10293, 2017 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-28678494

RESUMO

Structural characterization of proteins in the gas phase is becoming increasingly popular, highlighting the need for a greater understanding of how proteins behave in the absence of solvent. It is clear that charged residues exert significant influence over structures in the gas phase due to strong Coulombic and hydrogen-bonding interactions. The net charge for a gaseous ion is easily identified by mass spectrometry, but the presence of zwitterionic pairs or salt bridges has previously been more difficult to detect. We show that these sites can be revealed by photoinduced electron transfer dissociation, which produces characteristic c and z ions only if zwitterionic species are present. Although previous work on small molecules has shown that zwitterionic pairs are rarely stable in the gas phase, we now demonstrate that charge-separated states are favored in larger molecules. Indeed, we have detected zwitterionic pairs in peptides and proteins where the net charge equals the number of basic sites, requiring additional protonation at nonbasic residues. For example, the small protein ubiquitin can sustain a zwitterionic conformer for all charge states up to 14+, despite having only 13 basic sites. Virtually all of the peptides/proteins examined herein contain zwitterionic sites if both acidic and basic residues are present and the overall charge density is low. This bias in favor of charge-separated states has important consequences for efforts to model gaseous proteins via computational analysis, which should consider not only charge state isomers that include salt bridges but also protonation at nonbasic residues.


Assuntos
Peptídeos/química , Proteínas/química , Transporte de Elétrons , Gases/química , Simulação de Dinâmica Molecular , Processos Fotoquímicos , Teoria Quântica
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