RESUMO
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N-glucuronidated NNAL (NNAL-N-gluc), O-glucuronidated NNAL (NNAL-O-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT2B10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.
RESUMO
BACKGROUND: We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). METHODS: We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis. RESULTS: Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67 years, median BMI was 25.9 kg/m2, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (p < 0.01). Mortality risk decreased as the BMI increased from 20 to 30 kg/m2 (HR 0.49, 95% CI 0.28-0.84); however, it was reversed as the BMI surpassed ~ 30 kg/m2. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0-1 had a longer OS (HR 0.42, 95% CI 0.28-0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker. CONCLUSION: We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30 kg/m2.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Índice de Massa Corporal , Estudos RetrospectivosRESUMO
Cancer markers are measurable molecules in the blood or tissue that are produced by tumor cells or immune cells in response to cancer progression. They play an important role in clinical diagnosis, prognosis, and anti-drug monitoring. Although DNA, RNA, and even physical images have been used, proteins continue to be the most common marker. There are currently no specific markers for lung cancer. Metastatic lung cancer, particularly non-small-cell lung cancer (NSCLC), is one of the most common causes of death. SFPQ, YY1, RTN4, RICTOR, LARP6, and HELLS are expressed at higher levels in cells from NSCLC than in control or cells from inflammatory diseases. SFPQ shows the most difference between the three cell types. Furthermore, the cytoplasmic isoform of SFPQ is only found in advanced cancers. We have developed ELISAs to detect SFPQ and the long and short isoforms. Evidence has shown that the short isoform exists primarily in cancers. Furthermore, immunocytometry studies and IHC analysis have revealed that SFPQ levels are consistent with ELISA results. In addition, enhanced DNA methylation in the SFPQ gene may facilitate the SFPQ expression differences between control and cancer cells. Considering this, elevated SFPQ level and the isoform location could serve as a cancer diagnostic and prognostic marker.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Metilação de DNA , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Our earlier work demonstrated varying potency of dihydromethysticin (DHM) as the active kava phytochemical for prophylaxis of tobacco carcinogen nicotine-derived nitrosamine ketone (NNK)-induced mouse lung carcinogenesis. Efficacy was dependent on timing of DHM gavage ahead of NNK insult. In addition to DNA adducts in the lung tissues mitigated by DHM in a time-dependent manner, our in vivo data strongly implicated the existence of DNA damage-independent mechanism(s) in NNK-induced lung carcinogenesis targeted by DHM to fully exert its anti-initiation efficacy. In the present work, RNA seq transcriptomic profiling of NNK-exposed (2 h) lung tissues with/without a DHM (8 h) pretreatment revealed a snap shot of canonical acute phase tissue damage and stress response signaling pathways as well as an activation of protein kinase A (PKA) pathway induced by NNK and the restraining effects of DHM. The activation of the PKA pathway by NNK active metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) at a concentration incapable of promoting DNA adduct was confirmed in a lung cancer cell culture model, potentially through NNAL binding to and activation of the ß-adrenergic receptor. Our in vitro and in vivo data overall support the hypothesis that DHM suppresses PKA activation as a key DNA damage-independent mechanistic lead, contributing to its effective prophylaxis of NNK-induced lung carcinogenesis. Systems biology approaches with a detailed temporal dissection of timing of DHM intake versus NNK exposure are warranted to fill the knowledge gaps concerning the DNA damage-driven mechanisms and DNA damage-independent mechanisms to optimize the implementation strategy for DHM to achieve maximal lung cancer chemoprevention.
Assuntos
Neoplasias Pulmonares , Nitrosaminas , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Proteínas Quinases Dependentes de AMP Cíclico/efeitos adversos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Adutos de DNA/metabolismo , Dano ao DNA , Pulmão/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Camundongos , Nitrosaminas/metabolismo , Nitrosaminas/toxicidade , PironasRESUMO
INTRODUCTION: The optimal treatment paradigm for brain metastasis that recurs locally after initial radiosurgery remains an area of active investigation. Here, we report outcomes for patients with BMRS treated with stereotactic laser ablation (SLA, also known as laser interstitial thermal therapy, LITT) followed by consolidation radiosurgery. METHODS: Clinical outcomes of 20 patients with 21 histologically confirmed BMRS treated with SLA followed by consolidation SRS and > 6 months follow-up were collected retrospectively across three participating institutions. RESULTS: Consolidation SRS (5 Gy × 5 or 6 Gy × 5) was carried out 16-73 days (median of 26 days) post-SLA in patients with BMRS. There were no new neurological deficits after SLA/cSRS. While 3/21 (14.3%) patients suffered temporary Karnofsky Performance Score (KPS) decline after SLA, no KPS decline was observed after cSRS. There were no 30-day mortalities or wound complications. Two patients required re-admission within 30 days of cSRS (severe headache that resolved with steroid therapy (n = 1) and new onset seizure (n = 1)). With a median follow-up of 228 days (range: 178-1367 days), the local control rate at 6 and 12 months (LC6, LC12) was 100%. All showed diminished FLAIR volume surrounding the SLA/cSRS treated BMRS at the six-month follow-up; none of the patients required steroid for symptoms attributable to these BMRS. These results compare favorably to the available literature for repeat SRS or SLA-only treatment of BMRS. CONCLUSIONS: This multi-institutional experience supports further investigations of SLA/cSRS as a treatment strategy for BMRS.
Assuntos
Neoplasias Encefálicas , Terapia a Laser , Recidiva Local de Neoplasia , Radiocirurgia , Técnicas de Ablação , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Terapia Combinada , Humanos , Terapia a Laser/métodos , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgia , Radiocirurgia/métodos , Estudos Retrospectivos , Técnicas Estereotáxicas , Resultado do TratamentoRESUMO
Although it is well established that human cytochrome P450 1 family enzymes are induced by cigarette smoking through activation of the Ah receptor, it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N = 170, 1 or 10 µg doses) and non-smokers (N = 57, 1 µg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-h urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (P < 0.01), consistent with increased cancer risk in smokers. The Phe bioactivation ratios ([D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (P < 0.01) to 4.8 (P < 0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of Phe, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.
Assuntos
Carcinogênese/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Neoplasias/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Inativação Metabólica/genética , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/patologia , Fenantrenos/toxicidade , Fenóis/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Nicotiana/efeitos adversosRESUMO
Human urinary DNA adducts may be useful surrogate biomarkers to estimate carcinogen exposure and activation, particularly if such adducts are of high selectivity from a specific carcinogen source. In this report, we provided evidence supporting tobacco use and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being the dominant source for 3-methyladenine (3-mA), while nontobacco factors contribute significantly to 7-methylguanine and 1-methyladenine in the urine. Upon confirmation in human urine samples from larger populations in the future, urinary 3-mA may be used to estimate NNK bioactivation in smokers and to facilitate the development of a chemopreventive agent against NNK-induced carcinogenesis.
Assuntos
Adutos de DNA/urina , DNA/química , Nitrosaminas/análise , Uso de Tabaco , Animais , Carcinógenos/toxicidade , Humanos , Camundongos , Nitrosaminas/químicaRESUMO
Introduction: Recently, an entity known as salivary duct carcinoma with rhabdoid features (SDC-RF) has been associated with somatic CDH1 mutations. Here we present the first known case report of conventional SDC occurring in the setting of a germline CDH1 pathogenic variant accompanied by a somatic loss of heterozygosity at the CDH1 locus. Case discussion: A 67-year-old man presented with chest and back pain and was found to have osteolytic lesions in the sternum and lumbar spine. Vertebral bone biopsies were positive for metastatic carcinoma of unknown primary. A molecular profiling assay consisting of both whole-exome next-generation sequencing (NGS) as well as immunohistochemistry (IHC) for select clinically-relevant proteins performed on the bone biopsy suggested a triple-negative (ER/PR/ERBB2 negative, by IHC), androgen receptor (AR IHC) positive tumor profile. Additionally, the assay uncovered a coding mutation in the CDH1 gene (c.1792C>T, p.R598*) with genomic loss of the second CDH1 allele. Germline testing returned positive for a heterozygous CDH1 pathogenic variant. PET-CT revealed a tumor in the neck suggestive of the primary malignancy consistent with that of salivary gland origin. The patient was initially treated with carboplatin and paclitaxel, then pembrolizumab, and finally with AR-directed therapy using leuprolide and enzalutamide. These treatments were not successful, and the patient eventually succumbed to his disease. Conclusion: Molecular testing revealed that our patient had bi-allelic inactivation of the CDH1 gene. We believe our patient developed a somatic mutation in addition to his preexisting germline CDH1 mutation that ultimately predisposed him to SDC. While previous studies have found somatic CDH1 pathogenic variants in SDC-RF, our patient was found to have a germline CDH1 pathogenic variant in the setting of conventional SDC, without rhabdoid features. This case provokes questions regarding tumor genetics and molecular profiling of SDC in patients with germline CDH1 pathogenic variants. Moreover, this case supports the notion that SDC may be the salivary counterpart of other malignancies associated with germline CDH1 pathogenic variants and may possibly expand the spectrum of tumors that arise in this familial cancer-predisposition syndrome.
RESUMO
The extent of metabolism of [D10]phenanthrene to [D(10)]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetradeuterophenanthrene ([D10]PheT) could be a biomarker of human metabolic activation of carcinogenic polycyclic aromatic hydrocarbons, leading to identification of smokers particularly susceptible to lung cancer. The longitudinal stability of [D10]PheT was evaluated in 24 cigaret smokers given 7-8 oral doses of [D10]phenanthrene (10 µg) over 5.5 months. [D10]PheT in 6 h urine was quantified after each dose. The overall coefficient of variation for 24 subjects was (mean ± S.D.) 27.4% ± 8.83%. Thus, a single administration of [D10]phenanthrene is likely sufficient to determine a smoker's ability to metabolize it to [D10]PheT.
Assuntos
Carcinógenos/metabolismo , Neoplasias Pulmonares/prevenção & controle , Fenantrenos/urina , Administração Oral , Adulto , Biomarcadores/urina , Biotransformação , Carcinógenos/farmacocinética , Suscetibilidade a Doenças , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Estudos Longitudinais , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Fumar/efeitos adversosRESUMO
New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14- myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE®) to enhance NK cytotoxicity against mesothelin+ targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro. Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Mesotelina , Células Matadoras Naturais/metabolismo , Citotoxicidade Celular Dependente de Anticorpos , Imunossupressores/metabolismoRESUMO
Genetic sequencing has allowed better understanding of non-small-cell lung cancer, leading to improvements in the ability to diagnose and treat the disease through targeted therapy. This article describes some of the past and ongoing studies of targeted therapies for lung cancers, the genetic mutations in lung cancers that develop in people who never smoked, and the role of Minnesota researchers in understanding the pathogenesis of lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular/tendências , Análise de Sequência de DNA/tendências , Biomarcadores Tumorais/genética , Análise Mutacional de DNA/tendências , Previsões , Heterogeneidade Genética , Humanos , Minnesota , Fumar/efeitos adversos , Fumar/genéticaRESUMO
We present a patient with metastatic NSCLC harboring a compound EGFR mutation with co-occurring G719A and T790M mutation. T790M mutation was treatment emergent mutation when patient was on early generation tyrosine kinase inhibitors. Initial Guardant 360 showed that G719A was the dominant clone. Following, osimertinib, the patient had only a radiographic disease stabilization and then developed both clinical and radiographic progression. On progression, T790M was undetectable but G719A continued to be the dominant clone. Subsequent administration of afatinib led to a clinical and radiological response. To our knowledge, this is the first case report describing co-occurrence of EGFR G719A and T790M mutations and the clonal evolution during treatment with anti-EGFR therapies.
RESUMO
Watercress is an excellent source of phenethyl isothiocyanate (PEITC), shown in many studies to enhance carcinogen and toxicant detoxification and to inhibit carcinogenesis. Based on a previous observation that PEITC can enhance the detoxification of common environmental pollutants such as acrolein, crotonaldehyde, benzene, and 1,3-butadiene, we designed a clinical trial testing the hypothesis that daily consumption of a drink containing freeze-dried watercress, an abundant source of PEITC, would have a similar effect, particularly observed in subjects who were null in certain glutathione S-transferase genes. This manuscript describes the preparation of nearly 100 pounds of freeze-dried watercress for this trial, starting with laboratory-scale pilot studies and proceeding to industrial-scale production of the fully validated product in compliance with all food safety requirements. Initial results validating subject compliance in the clinical trial are also presented. PREVENTION RELEVANCE: This study describes the preparation of a beverage containing freeze-dried watercress suitable for consumption in a clinical trial to determine whether a constituent of this beverage-PEITC, which has cancer prevention properties-can enhance detoxification of common environmental carcinogens and toxicants such as benzene, which may have a role in environmentally induced cancer. See related Spotlight, p. 139.
Assuntos
Anticarcinógenos , Neoplasias , Anticarcinógenos/farmacologia , Benzeno , Bebidas , Carcinógenos/toxicidade , Humanos , Isotiocianatos/farmacologia , Neoplasias/tratamento farmacológicoRESUMO
Up to 60% of patients with small cell lung cancer (SCLC) continue to smoke, which is associated with worse clinical outcomes. Platinum-based chemotherapies, in combination with topoisomerase inhibitors, are first-line therapies for SCLC, with rapid chemoresistance as a major barrier. We provided evidence in this study that nicotine and its major metabolite, cotinine, at physiologically relevant concentrations, reduced the efficacy of platinum-based chemotherapies and facilitated chemoresistance in SCLC cells. Mechanistically, nicotine or cotinine reduced chemotherapy-induced DNA damage by modulating cellular redox processes, with nAChRs as the upstream targets. Surprisingly, cisplatin treatment alone also increased the levels of nAChRs in SCLC cells, which served as a self-defense mechanism against platinum-based therapies. These discoveries were confirmed in long-term in vitro and in vivo studies. Collectively, our results depicted a novel and clinically important mechanism of chemoresistance in SCLC treatment: nicotine exposure significantly compromises the efficacy of platinum-based chemotherapies in SCLC treatment by reducing therapy-induced DNA damage and accelerating chemoresistance acquisition. The results also emphasized the urgent need for tobacco cessation and the control of NRT use for SCLC management.
RESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR) is coactivated by the µ-opioid receptor (MOR), expressed on non-small cell lung cancer (NSCLC) cells and human lung cancer. We hypothesized that clinically used opioid analgesics that are MOR agonists coactivate EGFR, resulting in growth- and survival-promoting signaling. METHODS: We used H2009, a human adenocarcinoma NSCLC cell line, with constitutive EGFR phosphorylation, which showed increased expression of MOR and the δ-opioid receptor by reverse transcriptase polymerase chain reaction. We used Western immunoblotting, magnetic bead-based Bio-Plex cytokine assay, immunofluorescent staining, BrdU incorporation enzyme-linked immunosorbent assay, and BioCoat™ Matrigel™ invasion assay to examine cell signaling, cytokine expression, colocalization of MOR and EGFR in human lung cancer, and cell proliferation and invasion, respectively. RESULTS: Similar to epidermal growth factor (EGF), morphine stimulated phosphorylation of EGFR, Akt/protein kinase B (Akt), and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling in H2009 cells. Opioid receptor (OR) antagonist, naloxone, EGFR tyrosine kinase inhibitor, erlotinib, and silencing of MOR and δ-opioid receptor abrogated morphine- and EGF-induced phosphorylation of signaling, suggestive of OR-mediated coactivation of EGFR. H2009 cells secreted significantly higher levels of cytokines compared with control Beas2B epithelial cells. H2009-conditioned medium stimulated MOR expression in Beas2B cells, suggesting that cytokines secreted by H2009 may be associated with increased OR expression in H2009. We observed colocalization of EGFR and MOR, in human NSCLC tissue. Functionally, morphine- and EGF-induced proliferation and invasion of H2009 cells was ameliorated by naloxone as well as erlotinib. CONCLUSION: Morphine-induced phosphorylation of EGFR occurs via ORs, leading to downstream MAPK/ERK, Akt phosphorylation, cell proliferation, and increased invasion. Notably, ORs are also associated with EGF-induced phosphorylation of EGFR. Increased coexpression of MOR and EGFR in human lung cancer suggests that morphine may have a growth-promoting effect in lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Morfina/farmacologia , Linhagem Celular Transformada , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/fisiologia , Receptores ErbB/fisiologia , Cloridrato de Erlotinib , Humanos , Neoplasias Pulmonares/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinazolinas/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/fisiologiaRESUMO
Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease is rare but may occur in high-risk settings, often manifesting as a pulmonary infection. To date HCMV has not been investigated in malignant pleural mesothelioma (MPM). In a consecutive case series of 144 MPM patients we evaluated two biomarkers of HCMV: IgG serostatus (defined as positive and negative) and DNAemia (>100 copies/mL of cell free HCMV DNA in serum). Approximately half of the MPM patient population was HCMV IgG seropositive (51%). HCMV DNAemia was highly prevalent (79%) in MPM and independent of IgG serostatus. DNAemia levels consistent with high level current infection (>1000 copies/mL serum) were present in 41% of patients. Neither IgG serostatus nor DNAemia were associated with patient survival. In tissues, we observed that HCMV DNA was present in 48% of tumors (n = 40) and only 29% of normal pleural tissue obtained from individuals without malignancy (n = 21). Our results suggest nearly half of MPM patients have a high level current HCMV infection at the time of treatment and that pleural tissue may be a reservoir for latent HCMV infection. These findings warrant further investigation to determine the full spectrum of pulmonary infections in MPM patients, and whether treatment for high level current HCMV infection may improve patient outcomes.
Assuntos
Anticorpos Antivirais/sangue , Citomegalovirus/metabolismo , DNA Viral/sangue , Imunoglobulina G/sangue , Mesotelioma Maligno , Neoplasias Pleurais , Pneumonia Viral , Idoso , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Mesotelioma Maligno/sangue , Mesotelioma Maligno/mortalidade , Mesotelioma Maligno/virologia , Pessoa de Meia-Idade , Neoplasias Pleurais/sangue , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/virologia , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
INTRODUCTION: The impact of dysphagia in persons with lung cancer is unknown. The objective of this study is to measure the prevalence and survival differences associated with dysphagia in older adults with lung cancer. MATERIALS AND METHODS: Linked SEER cancer registries - Medicare data, 1991-2009 was utilized to identify 201,674 persons with lung cancer. Most were male (53%), had regional or distant disease (74%), and were aged <80 years (82%). The pre-existing prevalence of dysphagia was identified using claims codes before the lung cancer diagnosis. Survival was analyzed using Kaplan Meier curves and Cox proportional hazard models. RESULTS: 8517 (4%) had dysphagia prior to their lung cancer diagnoses. Younger age, worse disease stage, more comorbidities, and hospital rurality were associated with higher likelihood of dysphagia. Patients with dysphagia had worse survival (median survival 8 months [95%CI 7,9]) than those without dysphagia (median survival 12 months [95%CI 11,13]). After adjusting for sociodemographic, clinical, and disease characteristics, dysphagia was still associated with worse survival (Hazard ratio of death 1.34, [95%CI 1.28-1.35], p ≤ .0001). DISCUSSION AND CONCLUSIONS: This is the first Medicare claims-based study of older adults with lung cancer and dysphagia. Pre-existing dysphagia occurred in approximately 1 in 25 patients with lung cancer and was associated with worse survival. Determining the best methods to evaluate and treat dysphagia in patients with lung cancer is an important avenue for future studies.
Assuntos
Transtornos de Deglutição , Neoplasias Pulmonares , Idoso , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Medicare , Estadiamento de Neoplasias , Prevalência , Modelos de Riscos Proporcionais , Programa de SEER , Estados Unidos/epidemiologiaRESUMO
This pilot study evaluated nutrition status and health-related quality of life (HRQOL) outcomes among outpatients with head and neck cancer (HNC). Data were collected from 19 patients (18 males, 1 female) during 3 time points: once before chemoradiotherapy (CRT) initiation and 1 and 3 months after CRT. Nutrition status was evaluated using the Scored Patient-Generated Subjective Global Assessment (PG-SGA). Malnutrition was defined as PG-SGA stage B (moderate/suspected malnutrition) or stage C (severely malnourished). HRQOL was assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its HNC-specific module (QLQ-H&N35). We found that well-nourished patients reported having fewer issues with pain, fatigue, appetite loss, chewing, sticky saliva, coughing, and social eating than those categorized as malnourished (P < .05). The association between the global quality-of-life score and PG-SGA score was statistically significant but weak in strength (r = -0.37, P = .012). Although PG-SGA identified 70% as either moderately or severely malnourished before treatment initiation, the mean body mass index was in the overweight category (29 ± 5 kg/m2 ). Compared with pretreatment, patients reported more severe problems with chewing, swallowing, sticky saliva, dry mouth, speech, social eating, and taste and smell sensations at 1-month follow-up, although issues with dry mouth persisted 3 months post treatment (P = .003). In conclusion, malnourished patients reported having worse HRQOL symptoms compared with well-nourished patients. Routine nutrition and psychosocial assessment through PG-SGA and EORTC tools might help identify patients in need of nutrition and psychosocial care.
Assuntos
Neoplasias de Cabeça e Pescoço , Estado Nutricional , Qualidade de Vida , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Pacientes Ambulatoriais , Projetos PilotoRESUMO
Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.