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1.
Ann Thorac Surg ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619137

RESUMO

BACKGROUND: Postoperative empyema following pleurectomy decortication (PDC) for malignant pleural mesothelioma (MPM) is a serious complication that necessitates prolonged hospitalization. The aim of this study was to determine the incidence, risk factors and prognosis in patients who develop postoperative empyema following PDC. METHODS: The background, type of PDC, neo-adjuvant treatment, date of empyema, pleural fluid cultures, post empyema treatment and prognosis from a series of consecutive 355 patients treated over 9 years at a single high-volume center were investigated. Fisher's exact test, Kaplan Meier estimators and log rank test were used to identify significant risk factors for postoperative empyema and compare the overall survival. RESULTS: 355 patients underwent PDC for MPM in a 9-year period. There were 263 males and median age at surgery was 69. Neoadjuvant therapy was given to 87 and 282 received intraoperative heated chemotherapy (IOHC). During the study 24 patients (6.8%) developed empyema. The length of stay (LOS) of patients who developed postoperative empyema was significantly longer. Median survival for patients who developed postoperative empyema was 11.7 months and 21.3 months for patients without empyema (HR-1.78, p=0.009). Postoperative empyema was associated with male sex, prolonged air leak and use of prosthetic mesh. CONCLUSIONS: Postoperative empyema following PDC is associated with prolonged length of stay and higher mortality. The rates of this serious postoperative complication might decrease by developing better strategies to avoid prolonged air leak after PDC.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34536000

RESUMO

OBJECTIVES: Prolonged air leak (PAL; >5 days) following lung resection is associated with postoperative morbidity. We investigated factors associated with PAL and PAL requiring intervention. METHODS: Retrospective review of all patients undergoing lobectomy, segmentectomy or wedge resection from 2016 to 2019 at our institution. Bronchoplastic reconstructions and lung-volume reduction surgeries were excluded. Incidence and risk factors for PAL and PAL requiring intervention were evaluated. RESULTS: In total, 2384 patients were included. PAL incidence was 5.4% (129/2384); 22.5% (29/129) required intervention. PAL patients were more commonly male (56.6% vs 39.7%), older (mean age 69 vs 65 years) and underwent lobectomy or thoracotomy (all P < 0.001). Patients with PAL had longer length of stay (9 vs 3 days), more discharge needs and increased odds of complication (all P < 0.050).Twenty-nine patients required intervention (9 chest tubes; 4 percutaneous drains; 16 operations). In 50% of operative interventions, an air leak source was identified; however, the median time from intervention to resolution was 13 days. Patients requiring intervention had increased steroid use, lower diffusion capacity for carbon monoxide and twice the length of stay versus PAL patients (all P < 0.050).On univariable analysis, forced expiratory volume in 1 s (FEV1) <40%, diffusion capacity for carbon monoxide <50%, steroid use and albumin <3 had increased odds of intervention (P < 0.050). CONCLUSIONS: Age, gender and operative technique were related to PAL development. Patients with worse forced expiratory volume in 1 s or diffusion capacity for carbon monoxide, steroid use or poor nutrition were less likely to heal on their own, indicating a population that could benefit from earlier intervention.

4.
Am J Surg Pathol ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469333

RESUMO

While most resection specimens from patients with neoadjuvantly treated esophageal squamous cell carcinoma show therapy-related changes in the form of inflammation and fibrosis, others harbor a florid foreign body-type giant cell response to keratin debris. The purpose of our study was to perform a detailed clinicopathologic analysis of these histologic types of treatment responses and correlate these findings with patient outcome. Clinical and pathologic parameters from 110 esophagogastrectomies were recorded and analyzed. Two main types of histologic responses were observed: inflammatory-predominant response (59%) and florid foreign body-type giant cell response to keratin (41%). Irrespective of cG, cTNM, and amount of residual cancer, florid foreign body-type giant cell reaction was predominantly noted deep within the esophageal wall, while the inflammatory response was restricted to the mucosa, submucosa, and inner half of muscularis propria. Patients with foreign body-type giant cell response showed significantly better overall survival compared with the inflammatory response group (log-rank test P=0.015). Florid foreign body-type giant cell response was the only factor associated with improved survival in a multivariable analysis for overall survival (hazard ratio=0.5; 95% confidence interval=0.3-1.0; P=0.038), but not in the model for disease-specific survival, whereas ypTNM stage II was the only significant risk factor for disease-specific survival in multivariable analysis (hazard ratio=3.4; 95% confidence interval=1.0-11.2; P=0.047). Our results suggest that in addition to the College of American Pathologists Tumor Regression Score and ypTNM stage, subtype of histologic response to therapy may represent another prognostic marker for neoadjuvantly treated esophageal squamous cell carcinoma.

5.
PLoS One ; 16(8): e0254136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34383785

RESUMO

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.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34331065

RESUMO

OBJECTIVES: Recent trials have begun to explore immune checkpoint inhibitors for non-small cell lung cancer in the neoadjuvant setting, but data on tumour response and surgical outcome remain limited. METHODS: Retrospective evaluation of clinical data from patients with non-small cell lung cancer treated with immune checkpoint inhibitors followed by lung resection was performed at 2 large volume institutions (1 North American, 1 European). Data were analysed using Chi-squared, Fisher's and Wilcoxon rank-sum tests where appropriate. RESULTS: Thirty-seven patients were identified from 2017 to 2019. Forty-nine per cent were Stage IIIB and IV. Forty-six per cent received immunotherapy alone and 54% in combination with chemo- and/or radiotherapy. Sixteen per cent of cases were successfully performed minimally invasively. Twenty patients were operated with lobectomy (6 of these with wedges or segments of a neighbouring lobe, 2 with sleeve resections and 1 with a chest wall resection), 4 with bilobectomies, 11 with pneumonectomy (including 5 extrapleural pneumonectomies and 1 atrial resection) and 1 with a wedge resection. Overall, 10 patients (27%) developed postoperative complications and the 90-day mortality was zero. One-year recurrence-free survival was 73% for stage II/IIIA and 55% for stage IIIB/stage IV. The major pathologic response rate was 34%. CONCLUSION: In this retrospective study, lung resection after immunotherapy (alone or in combination) is safe, although often requires complex surgery. Due to increasing number of clinical trials adopting immunotherapy in the neoadjuvant setting, it is likely that this therapy will become part of standard of care. Immunotherapy may also allow surgery to have a role for selected patients with advanced disease.

7.
J Thorac Oncol ; 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34242791

RESUMO

INTRODUCTION: Prognostic models for malignant pleural mesothelioma have been limited to demographics, symptoms, and laboratory values. We hypothesize higher accuracy using both tumor and patient characteristics. The mesothelioma prognostic test (MPT) and molecular subtype based on claudin-15-to-vimentin expression ratio are molecular signatures associated with survival. Tumor volume (TV) has improved performance compared with clinical staging, whereas neutrophil-to-lymphocyte ratio (NLR) is prognostic for malignant pleural mesothelioma. METHODS: Tumor specimens and clinical data were collected prospectively from patients who underwent extrapleural pneumonectomy (EPP) or pleurectomy and decortication (PD) during 2007 to 2014. MPT and claudin-15-to-vimentin ratio were determined by real-time quantitative polymerase chain reaction, whereas TV was assessed from preoperative scans. Risk groups were derived from combinations of adverse factors on the basis of the Cox model. Predictive accuracy was assessed using Harrell's c-index. RESULTS: MPT, molecular subtype, TV, and NLR were independently prognostic in patients with EPP (N = 191), suggesting equal weighting in a final three-group model (c = 0.644). In the PD cohort (N = 193), MPT poor risk combined with TV greater than 200 cm3 was associated with triple the risk compared with other subgroups (hazard ratio = 2.94, 95% confidence interval: 1.70-5.09, p < 0.001) persisting when adjusted for molecular subtype, NLR, performance status, and serum albumin to yield a final three-group model (c = 0.641). The EPP and PD models achieved higher accuracy than published models (c ≤ 0.584, c ≤ 0.575) and pathologic staging (c = 0.554, c = 0.571). CONCLUSIONS: The novel models use pretreatment parameters obtained from minimally invasive biopsy, imaging, and blood tests to evaluate the expected outcome of each type of surgery in newly diagnosed patients and improve stratification on clinical trials.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34217786

RESUMO

Delay in time to esophagectomy for esophageal cancer has been shown to have worse peri-operative and long-term outcomes. We hypothesized that COVID-19 would cause a delay to surgery, with worse perioperative outcomes, compared to standard operations. All esophagectomies for esophageal cancer at a single institution from March-June 2020, COVID-19 group, and from 2019 were reviewed and peri-operative details were compared between groups. Ninety-six esophagectomies were performed in 2019 vs 37 during March-June 2020 (COVID-19 group). No differences between groups were found for preoperative comorbidities. Wait-time to surgery from final neoadjuvant treatment was similar, median 50 days in 2019 vs 53 days during COVID-19 p = 0.601. There was no increased upstaging, from clinical stage to pathologic stage, 9.4% in 2019 vs 7.5% in COVID-19 p = 0.841. Fewer overall complications occurred during COVID-19 vs 2019, 43.2% vs 64.6% p = 0.031, but complications were similar by specific grades. Readmission rates were not statistically different during COVID-19 than 2019, 16.2% vs 10.4% p = 0.38. No peri-operative mortalities or COVID-19 infections were seen in the COVID-19 group. Esophagectomy for esophageal cancer was not associated with worse outcomes during the COVID-19 pandemic with minimal risk of infection when careful COVID-19 guidelines are followed. Prioritization is recommended to ensure no delays to surgery.

9.
Cell Death Dis ; 12(8): 741, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315868

RESUMO

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.

10.
Br J Cancer ; 125(4): 582-592, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34088988

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM. METHODS: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways. RESULTS: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth. CONCLUSIONS: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34098122

RESUMO

To determine if wedge resection is equivalent to lobectomy for Stage I Non-Small Cell Lung Cancer (NSCLC) and to evaluate the impact of radiologic and pathologic variables not available in large national databases. Records were reviewed from 2010-2016 for patients with pathologic Stage I NSCLC who underwent wedge resection or lobectomy. Propensity score matching was performed on pre-operative variables and patients with ≥1 lymph node removed. Clinical variables were compared. Kaplan-Meier curves and multivariable Cox proportional hazard models for 5-year overall survival (OS), disease-free (DFS), and locoregional-recurrence-free survival (LRFS) were created. A total of 1086 patients met inclusion criteria; 391 lobectomies and 695 wedge resections. Propensity score matching yielded 167 pairs of lobectomy and wedge resection patients. Complications were fewer for wedge resections than lobectomies, 19.2% for wedge resection patients vs 34.1% for lobectomy patients, p < 0.01. OS was equivalent between groups, 86.2% for lobectomy patients vs 83.4% for wedge resection patients p = 0.47. DFS was similar, 79.0% for lobectomy patients vs 72.5% for wedge resection patients p = 0.10. Overall LRFS was worse in wedge resection patients vs lobectomy patients, 82.0% vs 93.4% p < 0.01. However, in the matched wedge resection patients with a margin >10 mm the LRFS was equal to that of lobectomy patients, 86.4% for wedge resection patients vs 91.8% for lobectomy patients p = 0.140. Patients with Stage I NSCLC can experience similar OS, DFS, and LRFS with wedge resection as compared to lobectomy, when wedge resection margins are >10 mm and appropriate lymph node dissection is performed.

12.
Commun Biol ; 4(1): 370, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854168

RESUMO

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.


Assuntos
Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazinas/farmacologia , Células A549 , Animais , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Terapia de Alvo Molecular , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA-Seq , Análise de Célula Única , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Surg Oncol ; 47(9): 2313-2322, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33714649

RESUMO

INTRODUCTION: The prognostic significance of radial margin (RM) involvement in esophagectomy cancer specimens is unclear. Our study investigated survival and recurrence rates between different depths of RM involvement. MATERIALS AND METHODS: We retrospectively analyzed 1103 esophagectomies at our institution from 2005 to 2019. Patients were grouped by three-tier stratification: negative RM > 1 mm away, direct RM involvement at 0 mm, and close RM between 0 mm and 1 mm. Survival, loco-regional and distant recurrences were analyzed. RESULTS: 1103 esophageal cancer patients were analyzed. 389 patients had recurrence (35.3%). Median survival (13.2 months) and recurrence rates (71%) were worst with direct RM (p < 0.001) as compared to negative RM (median survival not achieved within 5-years from surgery and 30%). Without nodal involvement, RM involvement of <1 mm was associated with decreased overall survival, and overall, loco-regional and distant recurrence-free survival compared to negative RM (log rank p-value <0.05). In those with persistent nodal disease, only direct RM was associated with decreased overall and loco-regional recurrence-free survival as compared to negative margins (p < 0.05). Direct RM tended to do worse compared to close RM in terms of median survival and trended worse for recurrence. Direct RM (baseline negative RM), but not close RM, was an independent RF in a multivariable Cox model for worse overall survival (HR 2.74; p < 0.001), recurrence-free survival (HR 1.96; p = 0.019), and loco-regional recurrence-free survival (HR 3.19; p = 0.011). CONCLUSION: RM involvement affects survival and recurrence. Tumor at 0 mm remained an independent RF for worse survival and overall and loco-regional recurrence.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33600992

RESUMO

N1-positive (T1-3, N1, M0) non-small cell lung cancer (NSCLC) represents a minority distribution (∼8%) of the approximately 234,000 diagnosed cases per year. As such, there is a paucity of modern high-quality data regarding outcomes following surgically-resected, stage N1-positive NSCLC. Randomized controlled trials from more than a decade ago have demonstrated a modest 5.4% survival benefit with adjuvant chemotherapy but have included heterogenous patient populations and stage distributions. Large database analyses have questioned the role of perioperative chemotherapy in resected patients with N1 disease, but without much granular detail regarding staging, quality of surgery, and chemotherapy. This single-institution study sought to evaluate the role of perioperative chemotherapy, specifically in N1-positive NSCLC patients. Data for all patients with surgically resected N1-positive NSCLC (T1-3, N1, M0) between 2006 and 2016 were collected for this study. Patients who underwent pneumonectomy were excluded from analysis. A retrospective chart review was conducted, and comprehensive clinicopathologic data were collected relative to staging, surgery, pathologic review, and perioperative oncology treatment. After exclusion criteria were applied, 148 patients with surgically resected, N1-positive disease (T1-3, N1, M0) remained for analysis. The majority of patients underwent lobectomy (75.0%), of which 55.4% underwent minimally invasive resection. There were no differences in postoperative complications, length of stay, number of lymph nodes sampled, or mortality associated with the surgery only and surgery with adjuvant therapy subgroups. 107 patients (72.3%) received adjuvant therapy, and this was associated with higher 5-year overall survival (62.8%) and disease-free survival (45.1%) than patients who underwent surgery only (33.9% overall survival at 5 years, P = 0.01; 22.4% disease-free survival at 5 years, P = 0.04). The presence of multistation N1 nodal metastases in patients was associated with lower 5-year overall survival (22.7%) and disease-free survival (5.6%) than patients with single-station N1 nodal metastasis (60.4% overall survival at 5 years, P = 0.003; 46.0% disease-free survival at 5 years, P < 0.001). On multivariable analysis, receiving any adjuvant chemotherapy was associated with improved overall survival and disease-free survival (Overall Survival HR 0.47, P < 0.01 | Disease-Free Survival HR 0.46, P <0.01). Multistation N1 disease was associated with significantly worse disease-free survival (HR 2.11, P = 0.04). Perioperative chemotherapy was associated with improved survival in N1-positive NSCLC, and the potential magnitude of benefit exceeded 25% in this study. Patients with single-station N1 lymph node metastasis were observed to have better disease-free survival.

15.
Comput Med Imaging Graph ; 88: 101814, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33486368

RESUMO

Classifying ground-glass lung nodules (GGNs) into atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) on diagnostic CT images is important to evaluate the therapy options for lung cancer patients. In this paper, we propose a joint deep learning model where the segmentation can better facilitate the classification of pulmonary GGNs. Based on our observation that masking the nodule to train the model results in better lesion classification, we propose to build a cascade architecture with both segmentation and classification networks. The segmentation model works as a trainable preprocessing module to provide the classification-guided 'attention' weight map to the raw CT data to achieve better diagnosis performance. We evaluate our proposed model and compare with other baseline models for 4 clinically significant nodule classification tasks, defined by a combination of pathology types, using 4 classification metrics: Accuracy, Average F1 Score, Matthews Correlation Coefficient (MCC), and Area Under the Receiver Operating Characteristic Curve (AUC). Experimental results show that the proposed method outperforms other baseline models on all the diagnostic classification tasks.

19.
J Thorac Cardiovasc Surg ; 161(4): 1510-1518, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32631662

RESUMO

OBJECTIVES: Cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury. METHODS: We conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 µmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days. RESULTS: Acute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P < .001), intraoperative cisplatin administration (odds ratio, 3.12; P < .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models. CONCLUSIONS: Acute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.


Assuntos
Injúria Renal Aguda/epidemiologia , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Mesotelioma Maligno/terapia , Neoplasias Pleurais/terapia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Idoso , Terapia Combinada , Feminino , Humanos , Hipertermia Induzida/efeitos adversos , Tempo de Internação , Masculino , Mesotelioma Maligno/mortalidade , Pessoa de Meia-Idade , Razão de Chances , Duração da Cirurgia , Neoplasias Pleurais/mortalidade , Pneumonectomia/efeitos adversos , Estudos Retrospectivos
20.
J Thorac Oncol ; 16(1): 89-103, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32927122

RESUMO

INTRODUCTION: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. METHODS: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. RESULTS: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. CONCLUSIONS: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Proliferação de Células , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Camundongos , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/genética , Ubiquitina-Proteína Ligases
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