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1.
AJR Am J Roentgenol ; : 1-8, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32069079

RESUMO

OBJECTIVE. Adrenal incidentalomas occur in 5% of adults and can produce autonomous cortisol secretion that increases the risk of metabolic syndrome and cardiovascular disease. The objective of our study was to evaluate the relationship between adrenal nodule size measured on CT and autonomous cortisol secretion. SUBJECTS AND METHODS. In a prospective study of 73 patients 22-87 years old with incidentalomas, unilateral in 52 patients and bilateral in 21 patients, we measured maximum nodule diameter on CT and serum cortisol levels at 8:00 am, 60 minutes after the adrenocorticotropic hormone stimulation test, and after the dexamethasone suppression test. We also studied 34 age-, sex-, and body mass index-matched control subjects. Statistics used were Spearman correlation coefficients, t tests, ANOVA test, and multivariate analysis. RESULTS. The mean maximum diameter of unilateral nodules measured on CT was larger on the right (2.47 ± 0.98 [SD] cm) than on the left (2.04 ± 0.86 cm) (p = 0.01). In the bilateral cases, the mean diameter of the right nodules was 2.69 ± 0.93 cm compared with 2.13 ± 0.89 cm on the left (p = 0.06). Mean baseline serum cortisol level was significantly higher in the patients with incidentalomas (bilateral, 13.1 ± 4.5 mcg/dL [p < 0.001]; unilateral, 9.7 ± 3.2 mcg/dL [p = 0.019]) than in the control subjects (7.5 ± 3.6 mcg/dL). After dexamethasone suppression test, serum cortisol levels were suppressed to less than 1.8 mcg/dL in 100% of control subjects, 33% of patients with bilateral incidentalomas, and 62% of patients with unilateral incidentalomas (p < 0.001). There were significant correlations between maximum nodule diameter on CT and serum cortisol levels after the dexamethasone suppression test (ρ = 0.500; p < 0.001) and at baseline (ρ = 0.373; p = 0.003). CONCLUSION. Increasing size of adrenal nodules is associated with more severe hyper-cortisolism and less dexamethasone suppression; these cases need further evaluation and possibly surgery because of increased risks of metabolic syndrome and cardiovascular mortality.

2.
Support Care Cancer ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900619

RESUMO

PURPOSE: Little is known about how breast cancer may impact survivors' financial well-being. This study aims to investigate the financial status, burden, and opinions of breast cancer survivors who received short-term financial assistance, emotional support, and resource navigation from a community organization during treatment. METHODS: Clients previously served by the community organization were mailed a 16-question survey (n = 751) to elicit their perspective on financial status and burden before, during, and after diagnosis and treatment along with general demographic and opinion items. RESULTS: 136 surveys (18.1%) were returned yielding 118 (15.7%) suitable for analyses. Clients' average age was 54.3 years. Most were female (99.2%), Caucasian (66.1%), and diagnosed with Stage 1 or 2 breast cancer (58.5%). Clients reported significantly worse (p < 0.001) financial status after being diagnosed compared to before diagnosis. Financial distress was highest during cancer treatment (mean = 3.92, SD = 0.85), lowest prior to treatment (mean = 2.48, SD = 1.05), and remained high after treatment (mean = 3.59, SD = 1.05). Those with higher distress after treatment were significantly (p = 0.01) more likely to report lower social support during treatment. CONCLUSIONS: Breast cancer survivors reported worsening financial status and distress after being diagnosed and during treatment despite receiving short-term financial assistance, emotional support, and resource navigation. Survivors' financial distress after treatment remained higher than before treatment. However, most felt receiving financial assistance improved their quality of life and made them feel more in control of financial decision-making. Breast cancer survivors who feel they have low social support during treatment may feel higher financial distress posttreatment.

3.
Ann Surg ; 271(2): 296-302, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30188400

RESUMO

OBJECTIVE: Comparative analyses of survival and funding statistics in cancers with high mortality were performed to quantify discrepancies and identify areas for intervention. BACKGROUND: Discrepancies in research funding may contribute to stagnant survival rates in pancreatic ductal adenocarcinoma (PDAC). METHODS: The Surveillance, Epidemiology, and End Results database was queried for survival statistics. Funding data were obtained from the National Cancer Institute (NCI). Clinical trial data were obtained from www.clinicaltrials.gov. Cancers with high mortality were included for analyses. RESULTS: Since 1997, PDAC has received lesser funding ($1.41 billion) than other cancers such as breast ($10.52 billion), prostate ($4.93 billion), lung ($4.80 billion), and colorectal ($4.50 billion). Similarly, fewer clinical trials have been completed in PDAC (n = 608) compared with breast (n = 1904), lung (n = 1629), colorectal (n = 1080), and prostate (n = 1055) cancer. Despite this, since 1997, dollars invested in PDAC research produced a greater return on investment with regards to 5-year overall survival (5Y-OS) compared with breast, prostate, uterine, and ovarian cancer. Incremental cost-effectiveness analysis demonstrates that millions (liver, non-Hodgkin lymphoma, and melanoma) and billions (colorectal and lung) of dollars were required for each additional 1% increase in 5Y-OS compared with PDAC. Funding of research towards early diagnosis of PDAC has decreased by 19% since 2007. For nearly all cancers, treatment-related research receives the highest percentage of NCI funding. CONCLUSIONS: Funding of PDAC research is significantly less than other cancers, despite its higher mortality and greater potential to improve 5Y-OS. Increased awareness and lobbying are required to increase funding, promote research, and improve survival.

4.
Cancer Treat Res Commun ; 22: 100162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31675535

RESUMO

BACKGROUND: Relapsed/refractory small cell lung cancer (SCLC) has a poor prognosis, with no good options. We evaluated a novel combination of topotecan and doxorubicin, providing sequential topoisomerase I and II inhibition, in this setting. MATERIALS AND METHODS: Adult patients (>19 years) with relapsed/refractory SCLC, who had received at least one prior chemotherapy regimen were eligible. Patients received escalating doses of oral topotecan on days 1-5 of each three week cycle (maximum - 5 cycles). The dosing cohorts were: 0.85 mg/m2, 1.05 mg/m2, 1.35 mg/m2, 1.65 mg/m2 and 2.30 mg/m2. All patients received weekly doxorubicin 20 mg/m2 intravenously starting day 6 of the first cycle and continued weekly for a maximum of 15 weeks. In the absence of pre-specified dose limiting toxicities (DLT), patients were enrolled serially to escalated dose level cohorts. RESULTS: Twenty-two patients were enrolled, of which 20 were evaluable. Median age was 61 years; 74% were male and 95% were Caucasian. Hematologic side effects were the most common adverse events. There were no therapy-related Grade 5 toxicities. Incidence of DLT based on cohorts were: DL2: 1/6 (Grade 4 thrombocytopenia), DL3: 1/6 (AST elevation) and DL4: 2/4 (Grade 4 thrombocytopenia). Response rate was 20% (4/20) and disease control rate (SD + PR) was 36%. The median progression free and overall survival were 3.6 months and 6 months, respectively. CONCLUSIONS: The combination of topotecan and doxorubicin was safe and effective in relapsed/refractory SCLC. The maximum tolerated dose of oral topotecan was 1.35 mg/m2 when given concurrently with weekly doxorubicin.

5.
J Surg Oncol ; 121(3): 547-560, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31867736

RESUMO

BACKGROUND: Na+ /H+ exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC). METHODS: NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and in the orthotopically implanted tumors in mice. NHERF1 expression was manipulated in CRC cells using inducible short hairpin RNAs to determine its biological functions. RESULTS: High expression of NHERF1 correlated with CRC progression and metastasis, as well as significantly worse overall survival, recurrence-free survival, and disease-specific survival. Orthotopic implantation studies demonstrated increased NHERF1 expression in liver metastases. Treatment of CRC xenografts with insulin-like growth factor 1 receptor (IGF1R) inhibitors downregulated NHERF1 expression, indicating NHERF1 is downstream of IGF1R signaling. Knockdown of NHERF1 increased apoptosis and reduced X-linked inhibitor of apoptosis protein (XIAP) and survivin expression, indicating NHERF1 is critical for CRC cell survival. CONCLUSION: NHERF1 expression levels correlated with worse prognosis in patients with CRC and plays a critical role in CRC cell survival. Together, our findings establish NHERF1 as a novel potential marker for increased risk of CRC-specific mortality and identify NHERF1 as an attractive therapeutic target for mCRC treatment.


Assuntos
Neoplasias Colorretais/metabolismo , Fosfoproteínas/biossíntese , Trocadores de Sódio-Hidrogênio/biossíntese , Idoso , Animais , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Células HCT116 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Taxa de Sobrevida
6.
Violence Against Women ; : 1077801219890420, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31802693

RESUMO

This study examined health profession students' comfort levels, perceived knowledge, attitudes, and preferences for domestic and sexual violence education at an academic medical center. Students indicated their perceived knowledge of community resources was poor, whereas comfort, attitudes, and perceived knowledge of the topic remained fair. A majority of students (83.2%) reported receiving less than 3 hr of training in their coursework, which remained consistent for students with more years of education. Students preferred content be incorporated into existing curricula or presented in lunch seminars. Study results reveal opportunities for improvement in domestic and sexual violence education.

7.
Blood ; 134(24): 2159-2170, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31562134

RESUMO

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.

8.
Cancers (Basel) ; 11(9)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500290

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.

9.
J Pharmacol Exp Ther ; 371(2): 327-338, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420526

RESUMO

The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl pyrophosphate, which is used in geranylgeranylation reactions. We have demonstrated that GGDPS inhibitors in multiple myeloma (MM) cells disrupt Rab geranylgeranylation, leading to inhibition of monoclonal protein trafficking, induction of the unfolded protein response pathway (UPR), and apoptosis. We have previously reported preclinical studies with the GGDPS inhibitor VSW1198, which is a mixture of homogeranyl/homoneryl triazole bisphosphonates. Additional structure-function efforts have led to development of the α-methylated derivatives RAM2093 (homogeranyl) and RAM2061 (homoneryl). As little is known regarding the impact of olefin stereochemistry on drug properties in vivo, we pursued additional preclinical evaluation of RAM2093 and RAM2061. In MM cell lines, both isomers induce activation of UPR/apoptotic markers in a concentration-dependent manner and with similar potency. Single-dose testing in CD-1 mice identified a maximum tolerated i.v. dose of 0.5 mg/kg for RAM2061 and 0.3 mg/kg for RAM2093. Liver toxicity was the primary barrier to dose escalation for both compounds. Disruption of geranylgeranylation in vivo was confirmed after multidose administration of either compound. Pharmacokinetic studies revealed plasma terminal half-lives of 29.2 ± 6 (RAM2061) and 22.1 ± 4 hours (RAM2093). Relative to RAM2061, RAM2093 levels were significantly higher in liver tissue but not in other tissues. Using MM.1S flank xenografts, we observed a significant reduction in tumor growth in mice treated with RAM2061 relative to controls. Collectively, these studies reveal olefin stereochemistry-dependent effects on GGDPS inhibitor biodistribution and confirm the in vivo efficacy of this novel therapeutic approach. SIGNIFICANCE STATEMENT: These studies reveal olefin stereochemistry-dependent effects on the in vivo properties of two novel triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase and demonstrate the therapeutic potential of this class of inhibitors for the treatment of multiple myeloma.

10.
J Nutr Biochem ; 70: 56-64, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153019

RESUMO

Organic dust exposure particularly within hog confinement facilities is a significant cause of airway inflammation and lung disease. In a cohort of Midwestern veterans with COPD and agricultural work exposure we observed reduced zinc intakes which were associated with decreased lung function. Because insufficient zinc intake is common within the U.S. and a potent modulator of innate immune function, we sought to determine whether deficits in zinc intake would impact the airway inflammatory response to hog confinement facility dust extract (HDE). Adult male C57BL/6 mice were randomized to zinc deficient or matched zinc sufficient diets for 3 weeks and subsequently treated with intranasal HDE inhalation or saline once or daily for 3 weeks while maintained on specific diets. Lavage fluid and lung tissue was collected. Conditions of zinc deficiency were also studied in macrophages exposed to HDE. Single and repetitive HDE inhalation exposure resulted in increased influx of total cells and neutrophils, increased mediator hyper-responsiveness (TNFα, IL-6, CXCL1, and amphiregulin), and enhanced tissue pathology that was more pronounced in zinc deficient mice compared to normal dietary counterparts. Airway inflammation was most pronounced in zinc deficient mice treated with repetitive HDE for 3 weeks. Similarly, macrophages maintained in a zinc deficient environment exhibited increased CXCL1 and IL-23 production as a result of increased NF-κB activation. Conclusion: Given the relatively high incidence of dietary deficiencies in agriculture workers, we anticipate that zinc intake, or a lack thereof, may play an important role in modulating the host response to organic dust exposure.

11.
J Natl Compr Canc Netw ; 17(5): 450-458, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085762

RESUMO

BACKGROUND: Despite the fact that stereotactic body radiation therapy (SBRT) is the only recommended first-line therapy for inoperable early-stage non-small cell lung cancer (NSCLC), several thermal ablative procedures (TAPs; defined herein as laser/cryoablation and electrocautery) are available. Studies showing outcomes of these procedures and how they compare with SBRT are scarce. We sought to evaluate the comparative efficacy of SBRT versus TAPs using the National Cancer Database (NCDB). METHODS: The NCDB was queried for patients with early-stage NSCLC who did not undergo surgical resection. Treatment-specific inclusion criteria were applied to select for patients receiving either TAPs or SBRT. Univariate logistic regression and Cox proportional hazards modeling were performed, and Kaplan-Meier curves were generated. Serial propensity matches were performed using a modified greedy 8→n matching 1:1 algorithm. RESULTS: A total of 27,734 patients were analyzed; 26,725 underwent SBRT and 1,009 underwent TAPs. Patients who received SBRT were older and more likely to have clinical stage IB (vs IA) disease. Despite this, SBRT was associated with longer median overall survival (mOS; 37.7 vs 33.5 months; P=.001) and 1-, 2-, and 5-year OS rates compared with the TAPs cohort (86.7% vs 83.1%, 67.5% vs 62.7%, and 30.6% vs 26.9%, respectively; P=.001). Upon propensity matching, improved OS with SBRT remained, with a mOS of 40.4 versus 33.4 months and 1-, 2-, and 5-year OS rates of 89.0% versus 82.9%, 69.7% versus 62.7%, and 34.4% versus 26.4%, respectively (P=.003). CONCLUSIONS: Despite being associated with more higher-risk factors, SBRT was associated with higher OS compared with TAPs for treatment of nonoperative patients diagnosed with early-stage NSCLC. However, causation cannot be implied owing to the inherent limitations of large heterogeneous datasets such as the NCDB.

12.
Am J Clin Pathol ; 152(2): 132-145, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31140550

RESUMO

OBJECTIVES: To characterize the clinical and pathologic features of mantle cell lymphoma with mantle zone growth pattern (MCL-MZGP). METHODS: The clinicopathologic data from 35 cases of MCL-MZGP obtained in 12 centers were analyzed. RESULTS: The patients with MCL-MZGP typically sought treatment at high clinical stages (81%). Intriguingly, 40% (14/35) of cases were incidentally noted. The lymph nodes with MCL-MZGP showed preserved architecture and expanded mantles containing lymphoma cells with classic or small cell cytology. MCL-MZGP was positive for BCL2 (96%, bright), CD5 (82%, moderate), cyclin D1 (100%), and SOX11 (89%). Clinically, our study revealed no significant difference in the overall survival between patients managed with observation alone and those who received chemotherapy. CONCLUSIONS: MCL-MZGP was often incidentally identified and resembled reactive mantles. Therefore, recognition of this unusual morphology emphasizes the utility of cyclin D1 immunostain in the cases with suspicious morphology. However, the clinical significance of these findings is still unclear.

13.
EBioMedicine ; 42: 375-385, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30956167

RESUMO

BACKGROUND: Trefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC. METHODS: Trefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent to tumor (NAT), precursor lesions (PanIN), and various pathological grades of PC by immunohistochemistry (IHC). Serum TFFs and CA19.9 levels were evaluated via ELISA in comprehensive sample set (n = 362) comprised of independent training and validation sets each containing benign controls (BC), chronic pancreatitis (CP), and various stages of PC. Univariate and multivariate logistic regression and receiver operating characteristic curves (ROC) were used to examine their diagnostic potential both alone and in combination with CA19.9. FINDINGS: The publicly available datasets and expression analysis revealed significant increased expression of TFF1, TFF2, and TFF3 in human PanINs and PC tissues. Assessment of KC mouse model also suggested upregulated expression of TFFs in PanIN lesions and early stage of PC. In serum analyses studies, TFF1 and TFF2 were significantly elevated in early stages of PC in comparison to benign and CP control group while significant elevation in TFF3 levels were observed in CP group with no further elevation in its level in early stage PC group. In receiver operating curve (ROC) analyses, combination of TFFs with CA19.9 emerged as promising panel for discriminating early stage of PC (EPC) from BC (AUCTFF1+TFF2+TFF3+CA19.9 = 0.93) as well as CP (AUCTFF1+TFF2+TFF3+CA19.9 = 0.93). Notably, at 90% specificity (desired for blood-based biomarker panel), TFFs combination improved CA19.9 sensitivity by 10% and 25% to differentiate EPC from BC and CP respectively. In an independent blinded validation set, the combination of TFFs and CA19.9 (AUCTFF1+TFF2+TFF3+CA19.9 = 0.82) also improved the overall efficacy of CA19.9 (AUCCA19.9 = 0.66) to differentiate EPC from CP proving unique biomarker capabilities of TFFs to distinguish early stage of this deadly lethal disease. INTERPRETATION: In silico, tissue and serum analyses validated significantly increased level of all TFFs in precursor lesions and early stages of PC. The combination of TFFs enhanced sensitivity and specificity of CA19.9 to discriminate early stage of PC from benign control and chronic pancreatitis groups.


Assuntos
Antígeno CA-19-9/sangue , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Fatores Trefoil/sangue , Animais , Área Sob a Curva , Biomarcadores Tumorais , Bases de Dados Genéticas , Modelos Animais de Doenças , Detecção Precoce de Câncer , Imunofluorescência , Humanos , Imuno-Histoquímica , Camundongos , Neoplasias Pancreáticas/genética , Curva ROC , Reprodutibilidade dos Testes
14.
Anticancer Res ; 39(4): 1907-1914, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952732

RESUMO

BACKGROUND/AIM: HPV-mediated oropharyngeal squamous cell carcinoma is associated with an increased survival. The prognostic value of HPV status for other primary sites is unclear. We aimed to assess the effect of HPV status on overall survival in patients with non-oropharyngeal head and neck squamous cell carcinoma (non-OPSCC) using the National Cancer Database (NCDB). PATIENTS AND METHODS: Adults with non-OPSCC [gum, lip, floor of mouth, tongue (excluding base), hypopharynx, nasopharynx, other pharynx] and known HPV status were included in our study. Associations between HPV status, primary site, patient characteristics and overall survival (OS) were assessed. RESULTS: HPV positivity was associated with a better OS compared to HPV-negative patients (HR=0.83, 95%CI=0.74-0.93, p<0.001). Female gender, gum, lip, nasopharynx primaries, and private insurance predicted for improved OS. CONCLUSION: HPV positivity and female gender are good prognostic factors in non-OPSCC. Routine HPV testing should be considered for HPV positive non-OPSCC, as well as studies evaluating de-escalation of treatment if this association is confirmed.


Assuntos
Neoplasias Orofaríngeas/epidemiologia , Infecções por Papillomavirus/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Fatores de Tempo , Estados Unidos/epidemiologia
15.
Med Oncol ; 36(4): 34, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840157

RESUMO

Clinical trial accrual is vital to advancing care. A single study elucidated demographic data correlating with glioma patients' clinical trial enrollment. However, it did not investigate the underlying decision-making process for non-participation. In this study, we seek to understand this key aspect of patient accrual. All notes for glioma patients seen by a single neuro-oncologist from July 2010 to May 2017 were examined for mention of clinical trial offerings. When a trial was declined, the patient's reasoning was recorded along with the following: diagnosis, KPS, extent of resection, age, gender, race, marital status, income group, religion, trial offered at initial visit versus subsequent, and distance from trial site. Of 279 consecutive glioma patients, 88 were eligible for and offered a clinical trial. Fifty-seven accepted (65%), and 31 (35%) declined participation (Fig. 1). Of those offered a clinical trial, patients with glioblastoma (GBM) were significantly more likely to accept (44 out of 57 (77%) vs. 13 out of 57 (23%), p =0.03). After we adjusted for gender and travel distance, GBM was the only significant predictor of clinical trial acceptance, with an odds ratio of 3.18 (95% CI 1.17, 8.61, p =0.02). Reasons cited for non-participation included: travel distance (39%), lack of interest (39%), visit frequency (16%), and fear of randomization (6%). This study clarified for the first time individual glioma patient rationale for non-participation and potential areas for improving enrollment. Allowing off-site treatment centers or telemedicine visits may entice rural patients to participate. Visit frequency should be carefully considered and minimized whenever possible. Further prospective study of rationale for non-participation may improve enrollment over time.


Assuntos
Neoplasias Encefálicas/psicologia , Ensaios Clínicos como Assunto/psicologia , Tomada de Decisões , Glioma/psicologia , Participação do Paciente/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto/psicologia , Adulto , Neoplasias Encefálicas/terapia , Feminino , Glioma/terapia , Acesso aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Oncogene ; 38(26): 5308-5320, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30918331

RESUMO

Rab proteins play an essential role in regulating intracellular membrane trafficking processes. Rab activity is dependent upon geranylgeranylation, a post-translational modification that involves the addition of 20-carbon isoprenoid chains via the enzyme geranylgeranyl transferase (GGTase) II. We have focused on the development of inhibitors against geranylgeranyl diphosphate synthase (GGDPS), which generates the isoprenoid donor (GGPP), as anti-Rab agents. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abnormal mucin production and these mucins play important roles in tumor development, metastasis and chemo-resistance. We hypothesized that GGDPS inhibitor (GGDPSi) treatment would induce PDAC cell death by disrupting mucin trafficking, thereby inducing the unfolded protein response pathway (UPR) and apoptosis. To this end, we evaluated the effects of RAM2061, a potent GGDPSi, against PDAC. Our studies revealed that GGDPSi treatment activates the UPR and triggers apoptosis in a variety of human and mouse PDAC cell lines. Furthermore, GGDPSi treatment was found to disrupt the intracellular trafficking of key mucins such as MUC1. These effects could be recapitulated by incubation with a specific GGTase II inhibitor, but not a GGTase I inhibitor, consistent with the effect being dependent on disruption of Rab-mediated activities. In addition, siRNA-mediated knockdown of GGDPS induces upregulation of UPR markers and disrupts MUC1 trafficking in PDAC cells. Experiments in two mouse models of PDAC demonstrated that GGDPSi treatment significantly slows tumor growth. Collectively, these data support further development of GGDPSi therapy as a novel strategy for the treatment of PDAC.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Farnesiltranstransferase/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/fisiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncogene ; 38(26): 5265-5280, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30914801

RESUMO

Farnesyl diphosphate synthase (FDPS), a mevalonate pathway enzyme, is highly expressed in several cancers, including prostate cancer (PCa). To date, the mechanistic, functional, and clinical significance of FDPS in cancer remains unexplored. We evaluated the FDPS expression and its cancer-associated phenotypes using in vitro and in vivo methods in PTEN-deficient and sufficient human and mouse PCa cells and tumors. Interestingly, FDPS overexpression synergizes with PTEN deficiency in PTEN conditionally knockout mice (P < 0.05) and expressed significantly higher in human (P < 0.001) PCa tissues, cell lines, and murine tumoroids compared to respective controls. In silico analysis revealed that FDPS is associated with increasing Gleason score, PTEN functionally deficient status, and poor survival of PCa. Ectopic overexpression of FDPS promotes oncogenic phenotypes such as colony formation (P < 0.01) and proliferation (P < 0.01) through activation of AKT and ERK signaling by prenylating Rho A, Rho G, and CDC42 small GTPases. Of interest, knockdown of FDPS in PCa cells exhibits decreased colony growth and proliferation (P < 0.001) by modulating AKT and ERK pathways. Further, genetic and pharmacological inhibition of PI3K but not AKT reduced FDPS expression. Pharmacological targeting of FDPS by zoledronic acid (ZOL), which is already in clinics, exhibit reduced growth and clonogenicity of human and murine PCa cells (P < 0.01) and 3D tumoroids (P < 0.02) by disrupting AKT and ERK signaling through direct interference of small GTPases protein prenylation. Thus, FDPS plays an oncogenic role in PTEN-deficient PCa through GTPase/AKT axis. Identifying mevalonate pathway proteins could serve as a therapeutic target in PTEN dysregulated tumors.


Assuntos
Adenocarcinoma/patologia , Geraniltranstransferase/fisiologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adenocarcinoma/genética , Animais , Linhagem Celular Tumoral , Progressão da Doença , Deleção de Genes , Geraniltranstransferase/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Neoplasias da Próstata/genética , Transdução de Sinais/fisiologia
18.
Clin Cancer Res ; 25(13): 4168-4178, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824586

RESUMO

PURPOSE: One third of patients with diffuse large B-cell lymphoma (DLBCL) succumb to the disease partly due to rituximab resistance. Rituximab-induced calcium flux is an important inducer of apoptotic cell death, and we investigated the potential role of calcium channels in rituximab resistance. EXPERIMENTAL DESIGN: The distinctive expression of calcium channel members was compared between patients sensitive and resistant to rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone (RCHOP) regimen. The observation was further validated through mechanistic in vitro and in vivo studies using cell lines and patient-derived xenograft mouse models. RESULTS: A significant inverse correlation was observed between CACNA1C expression and RCHOP resistance in two independent DLBCL cohorts, and CACNA1C expression was an independent prognostic factor for RCHOP resistance after adjusting for International Prognostic Index, cell-of-origin classification, and MYC/BCL2 double expression. Loss of CACNA1C expression reduced rituximab-induced apoptosis and tumor shrinkage. We further demonstrated direct interaction of CACNA1C with CD20 and its role in CD20 stabilization. Functional modulators of L-type calcium channel showed expected alteration in rituximab-induced apoptosis and tumor suppression. Furthermore, we demonstrated that CACNA1C expression was directly regulated by miR-363 whose high expression is associated with worse prognosis in DLBCL. CONCLUSIONS: We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.

19.
PLoS One ; 14(1): e0210405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30703126

RESUMO

INTRODUCTION: In this paper we perform a replication analysis of "Effect of a cash transfer programme for schooling on prevalence of HIV and herpes simplex type 2 in Malawi: a cluster randomised trial" by Sarah Baird and others published in "The Lancet" in 2012. The original study was a two-year cluster randomized intervention trial of never married girls aged 13-22 in Malawi. Enumeration areas were randomized to either an intervention involving cash transfer (conditional or unconditional of school enrollment) or control. The study included 1708 Malawian girls, who were enrolled at baseline and had biological testing for HIV and herpes simplex virus type 2 (HSV-2) at 18 months. The original findings showed that in the cohort of girls enrolled in school at baseline, the intervention had an effect on school enrollment, sexual outcomes, and HIV and HSV-2 prevalence. However, in the baseline school dropout cohort, the original study showed no intervention effect on HIV and HSV-2 prevalence. METHODS: We performed a replication of the study to investigate the consistency and robustness of key results reported. A pre-specified replication plan was approved and published online. Cleaned data was obtained from the original authors. A pure replication was conducted by reading the methods section and reproducing the results and tables found in the original paper. Robustness of the results were examined with alternative analysis methods in a measurement and estimation analysis (MEA) approach. A theory of change analysis was performed testing a causal pathway, the effect of intervention on HIV awareness, and whether the intervention effect depended on the wealth of the individual. RESULTS: The pure replication found that other than a few minor discrepancies, the original study was well replicated. However, the randomization and sampling weights could not be verified due to the lack of access to raw data and a detailed sample selection plan. Therefore, we are unable to determine how sampling influenced the results, which could be highly dependent on the sample. In MEA it was found that the intervention effect on HIV prevalence in the baseline schoolgirls cohort was somewhat sensitive to model choice, with a non-significant intervention effect for HIV depending on the statistical model used. The intervention effect on HSV-2 prevalence was more robust in terms of statistical significance, however, the odds ratios and confidence intervals differed from the original result by more than 10%. A theory of change analysis showed no effect of intervention on HIV awareness. In a causal pathway analysis, several variables were partial mediators, or potential mediators, indicating that the intervention could be working through its effect on school enrollment or selected sexual behaviors. CONCLUSIONS: The effect of intervention on HIV prevalence in the baseline schoolgirls was sensitive to the model choice; however, HSV-2 prevalence results were confirmed. We recommend that the results from the original published analysis indicating the impact of cash transfers on HIV prevalence be treated with caution.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Promoção da Saúde/economia , Herpes Genital/epidemiologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2 , Adolescente , Estudos de Coortes , Feminino , Infecções por HIV/economia , Herpes Genital/economia , Humanos , Malaui/epidemiologia , Modelos Econômicos , Prevalência , Comportamento Sexual , Fatores Socioeconômicos , Estudantes , Adulto Jovem
20.
Nutrients ; 11(1)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650613

RESUMO

Despite the importance of n-3 fatty acids for health, intakes remain below recommended levels. The objective of this study was to provide an updated assessment of fish and n-3 fatty acid intake (i.e., eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and EPA+DHA) in the United States using the 2003⁻2014 National Health and Nutrition Examination Survey (NHANES) data (n = 45,347)). Over this survey period, toddlers, children, and adolescents (aged 1⁻19) had significantly lower n-3 fatty acid intake (p < 0.001) compared to adults and seniors, which remained significant after adjusting for caloric intake. Females demonstrated lower n-3 fatty acid intake than males (p < 0.001), with adult and senior women having significantly lower intakes compared to men in the same age categories (p < 0.001) after adjustment for energy intake. Women also consumed less fish than men (5.8 versus 6.1 servings/month, p < 0.001). The estimated intakes of n-3 fatty acids in pregnant women did not differ from non-pregnant women (p = 0.6 for EPA+DHA), although pregnant women reported consuming less high n-3 fatty acid-containing fish than non-pregnant women (1.8 versus 2.6 servings/month, p < 0.001). Our findings indicate that subgroups of the population may be at higher risk of n-3 fatty acid intakes below recommended levels.


Assuntos
Dieta , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/análogos & derivados , Avaliação Nutricional , Gravidez , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Necessidades Nutricionais , Alimentos Marinhos , Estados Unidos , Adulto Jovem
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