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1.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33597293

RESUMO

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Citocinas/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Interferon Tipo I/metabolismo , NAD/deficiência , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Citocinas/genética , Citocinas/metabolismo , Humanos , Interferon Tipo I/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Proc Natl Acad Sci U S A ; 116(14): 6842-6847, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894490

RESUMO

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.


Assuntos
Ácido Aspártico/deficiência , Carcinoma Ductal Pancreático , Cloroquina/farmacologia , Lisossomos/metabolismo , Mitocôndrias , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Lisossomos/patologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estresse Fisiológico , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Surg Res ; 233: 20-25, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502249

RESUMO

BACKGROUND: Loss of intestinal barrier integrity plays a fundamental role in the pathogenesis of various gastrointestinal diseases and is implicated in the onset of sepsis and multiple organ failure. An array of methods to assess different aspects of intestinal barrier function suffers from lack of sensitivity, prolonged periods of specimen collection, or high expense. We have developed a technique to measure the concentration of the food dye FD&C Blue #1 from blood and sought to assess its utility in measuring intestinal barrier function in humans. MATERIALS AND METHODS: Four healthy volunteers and 10 critically ill subjects in the intensive care unit were recruited in accordance with an institutional review board approved protocol. Subjects were given 0.5 mg/kg Blue #1 enterally as an aqueous solution of diluted food coloring. Five blood specimens were drawn per subject: 0 h (before dose), 1, 2, 4, and 8 h. After plasma isolation, organic extracts were analyzed by high-performance liquid chromatography/mass spectrometry detecting the presence of unmodified dye. RESULTS: We found no baseline detectable absorption in healthy volunteers. After including the subjects in the intensive care unit, we compared dye absorption in the six subjects who met criteria for septic shock with the eight who did not. Septic patients demonstrated significantly greater absorption of Blue #1 after 2 h. CONCLUSIONS: We have developed a novel, easy-to-use method to measure intestinal barrier integrity using a food grade dye detectable by mass spectrometry analysis of patient blood following oral administration.


Assuntos
Corantes de Alimentos/farmacocinética , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Choque Séptico/diagnóstico , Administração Oral , Adulto , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/sangue , Benzenossulfonatos/farmacocinética , Estado Terminal , Estudos de Viabilidade , Feminino , Corantes de Alimentos/administração & dosagem , Corantes de Alimentos/análise , Voluntários Saudáveis , Humanos , Unidades de Terapia Intensiva , Masculino , Permeabilidade , Estudos Prospectivos , Choque Séptico/sangue , Choque Séptico/fisiopatologia
4.
J Cell Biochem ; 119(8): 6598-6603, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29737543

RESUMO

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm3 ; DOX (G2): 308 ± 31 mm3 , P = 0.272; TEM (G3): 85 ± 21 mm3 , P < 0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs.


Assuntos
Doxorrubicina/farmacologia , Medicina de Precisão , Sarcoma/tratamento farmacológico , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Sarcoma/metabolismo , Sarcoma/patologia
5.
J Cell Biochem ; 119(4): 3537-3544, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29143983

RESUMO

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.


Assuntos
Liases de Carbono-Enxofre/uso terapêutico , Doxorrubicina/uso terapêutico , Melanoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Modelos Animais de Doenças , Docetaxel , Feminino , Indazóis , Camundongos , Camundongos Nus , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Taxoides/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
6.
BMC Cancer ; 18(1): 840, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30126369

RESUMO

BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.


Assuntos
Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Lipossarcoma/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Tetra-Hidroisoquinolinas/administração & dosagem , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Lipossarcoma/genética , Lipossarcoma/patologia , Masculino , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Trabectedina , Ensaios Antitumorais Modelo de Xenoenxerto
7.
HPB (Oxford) ; 20(5): 418-422, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29398424

RESUMO

BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 µg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.


Assuntos
Pancreatectomia/efeitos adversos , Fístula Pancreática/prevenção & controle , Pancreaticoduodenectomia/efeitos adversos , Somatostatina/análogos & derivados , Idoso , Estudos de Casos e Controles , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Fístula Pancreática/diagnóstico por imagem , Fístula Pancreática/etiologia , Estudos Prospectivos , Fatores de Risco , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
9.
Ann Thorac Surg ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38490310

RESUMO

BACKGROUND: Lepidic-type adenocarcinomas (LPAs) can be multifocal, and treatment is often deferred until growth is observed. This study investigated the potential downside of that strategy by evaluating the relationship of nodal involvement with tumor size and survival. METHODS: The impact of tumor size on lymph node involvement and survival was evaluated for National Cancer Database patients who underwent surgery without induction therapy as primary treatment for cT1-3 N0 M0 histologically confirmed LPA from 2006 to 2019 by using logistic regression, Kaplan-Meier, and Cox analyses. RESULTS: Positive nodes occurred in 442 of 8286 patients (5.3%). The incidence of having positive nodes approximately doubled with each 1-cm increment increase in size. Patients with positive nodes were more likely to have larger tumors (27 mm vs 20 mm, P < .001) and clinical ≥T2 disease (40.7% vs 26.8%, P < .001) compared with node-negative patients. However, tumor size was the only significant independent predictor of having positive nodal disease in logistic regression analysis, and this association grew stronger with each incremental centimeter increase in size. Patients with positive nodes were more likely to undergo adjuvant radiotherapy (23.5% vs 1.1%, P < .001) and chemotherapy (72.9% vs 7.9%, P < .001), and expectedly, had worse survival compared with the node-negative group in univariate (5-year overall survival, 50.9% vs 81.1%, P < .001) and multivariable (hazard ratio, 2.56; 95% CI, 2.14-3.05; P < .001) analyses. CONCLUSIONS: Nodal involvement is relatively uncommon in early-stage LPAs but steadily increases with tumor size and is associated with dramatically worse survival. These data can be used to inform treatment decisions when evaluating LPA patients.

10.
JTO Clin Res Rep ; 5(3): 100654, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38496376

RESUMO

Introduction: Multiple clinical trials have revealed the benefit of immunotherapy (IO) for NSCLC, including unresectable stage III disease. Our aim was to investigate the impact of IO use on treatment and outcomes of potentially resectable stage IIIA NSCLC in a broader nationwide patient cohort. Methods: We queried the National Cancer Database (2004-2019) for patients with stage IIIA (T1-2N2) NSCLC. Treatment and survival were evaluated with descriptive statistics, logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling. Results: Overall, 5.5% (3777 of 68,335) of patients received IO. IO use was uncommon until 2017, but by 2019, it was given to 40.1% (1544 of 2308) of stage IIIA patients. The increased use of IO after 2017 was associated with increased definitive chemoradiation treatment (54.2% [6800 of 12,535] from years 2017 to 2019 versus 46.9% [26,251 of 55,914] from 2004 to 2016, p < 0.001) and less use of surgery (18.1% [2266 of 12,535] from years 2017 to 2019 versus 22.0% [12,300 of 55,914] from 2004 to 2016, p < 0.001). IO treatment was associated with significantly better 5-year survival in the entire cohort (36.9% versus 23.4%, p < 0.001) and the subsets of patients treated with chemoradiation (37.2% versus 22.7%, p < 0.001) and surgery (48.6% versus 44.3%, p < 0.001). Pneumonectomy use decreased with increased IO treatment (5.1% of surgical patients [116 of 2266] from years 2017 to 2019 versus 9.2% [1127 of 12,300] from 2004 to 2016, p < 0.001). Conclusions: Increased use of IO was associated with a change in treatment patterns and improved survival for patients with stage IIIA(N2) NSCLC.

11.
JTCVS Open ; 18: 234-252, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38690441

RESUMO

Objective: Randomized control trials are considered the highest level of evidence, yet the scalability and practicality of implementing randomized control trials in the thoracic surgical oncology space are not well described. The aim of this study is to understand what types of randomized control trials have been conducted in thoracic surgical oncology and ascertain their success rate in completing them as originally planned. Methods: The ClinicalTrials.gov database was queried in April 2023 to identify registered randomized control trials performed in patients with lung cancer who underwent surgery (by any technique) as part of their treatment. Results: There were 68 eligible randomized control trials; 33 (48.5%) were intended to examine different perioperative patient management strategies (eg, analgesia, ventilation, drainage) or to examine different intraoperative technical aspects (eg, stapling, number of ports, port placement, ligation). The number of randomized control trials was relatively stable over time until a large increase in randomized control trials starting in 2016. Forty-four of the randomized control trials (64.7%) were open-label studies, 43 (63.2%) were conducted in a single facility, 66 (97.1%) had 2 arms, and the mean number of patients enrolled per randomized control trial was 236 (SD, 187). Of 21 completed randomized control trials (31%), the average time to complete accrual was 1605 days (4.4 years) and average time to complete primary/secondary outcomes and adverse events collection was 2125 days (5.82 years). Conclusions: Given the immense investment of resources that randomized control trials require, these findings suggest the need to scrutinize future randomized control trial proposals to assess the likelihood of successful completion. Future study is needed to understand the various contributing factors to randomized control trial success or failure.

12.
Ann Thorac Surg ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38734402

RESUMO

BACKGROUND: Sublobar resection offers noninferior survival vs lobectomy for ≤2 cm non-small cell lung cancer and is commonly used for subsolid tumors. Although data exist for solid tumors, the minimum adequate margin of resection for subsolid adenocarcinomas remains unclear. METHODS: This was a retrospective review of 1101 adenocarcinoma resections at our institution from 2006 to 2022. Inclusion criteria were tumors ≤3 cm with ≥10% radiographic ground glass, excised by sublobar resection. Exclusions were positive nodes or positive or unreported margin. The primary outcome was the rate of local recurrence (LR) at multiple thresholds of margin distance. The relationship between margin distance and solid component size was also explored. RESULTS: Inclusion criteria were met by 194 patients. Median (interquartile range) tumor diameter and margin distance were 12 mm (9-17 mm) and 10 mm (5-17 mm), respectively. Median follow-up was 42.5 months. There was a progressive increase in LR with diminishing margin (0.1-cm decrements) from 1.5 cm to 0.5 cm. The difference in the rate of LR between "over" (n = 143) and "under" (n = 51) was most significant at 0.5 cm (8 of 51 [15.7%] vs 6 of 143 [4.2%]; P = .01) but did not reach α adjusted for multiple comparisons. On Cox regression for LR-free survival, margin ≤0.5 cm (P = .19) and solid component percentage (P = .14) trended to significance. Combining these using a ratio of margin distance-to-solid component size, a ratio of ≤1 showed a significantly higher rate of LR (7 [14.3%] vs 2 [2.0%], P = .009). Treatment of LRs provided at least intermediate-term survival in 87% of recurrences (median postrecurrence follow-up was 44 months). CONCLUSIONS: During sublobar resection of subsolid lung adenocarcinomas, a margin distance-to-solid component size ratio of >1.0 appears to be a more reliable factor than margin distance alone to minimize local recurrence. Local recurrence, however, may not impact survival in patients with subsolid adenocarcinomas if timely treatment is administered.

13.
Ann Thorac Surg ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38866199

RESUMO

BACKGROUND: Sublobar resection of early-stage non-small cell lung cancer (NSCLC) is increasingly considered appropriate but may compromise margins compared with lobectomy. This study evaluated resection extent, margin status, and survival in patients with clinical stage I NSCLC. METHODS: Patients with clinical T1-2 N0 M0 NSCLC in the National Cancer Database (2006-2020) who were treated with primary surgery were compared stratified by margin status. The potential benefit of radiation was explored in subgroup analysis of patients who underwent sublobar resection with positive margins. RESULTS: Positive margins occurred in 5089 (2.8%) of 181,824 patients and were more common in sublobar resections compared with lobectomy (4.3% vs 2.4%; P < .001). Sublobar resection had the strongest association with positive margins in multivariable analysis (odds ratio, 2.06; 95% CI, 1.91-2.23; P < .001). Patients with positive margins were more likely to undergo both adjuvant chemotherapy (16% vs 13%; P < .001) and radiation (17% vs 1%; P < .001) but had worse survival in univariate analysis (44.0% 5-year overall survival vs 69.2%; P < .001) and multivariable Cox analysis (hazard ratio, 1.71; 95% CI, 1.63-1.78; P < .001) in the entire cohort, as well as in a univariate subset analysis of lobectomy (46.9% vs 70.4%; P < .001) and sublobar resection (37.5% vs 64.1%; P < .001). Postoperative radiation for patients who underwent sublobar resection with positive margins did not improve 5-year overall survival (36.3% for irradiated patients vs 38.3% for nonirradiated patients; P = .57), and patients who underwent sublobar resection with positive margins who were treated with radiation had survival inferior to that of patients who underwent lobectomy with negative margins. CONCLUSIONS: Positive margins occur more frequently after sublobar resection of clinical stage I NSCLC compared with lobectomy. Patients with positive margins have worse survival than patients who undergo complete resection and are not rescued by postoperative radiation.

14.
Clin Lung Cancer ; 25(5): 424-430, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38749902

RESUMO

INTRODUCTION: Annual low-dose computed tomography (LDCT) screening has been shown to reduce lung cancer mortality in high-risk individuals by detecting the disease at an earlier stage. This study aims to assess the barriers to completing LDCT in a cohort of patients who were determined eligible for lung cancer screening (LCS). METHODS: We performed a single institution, mixed methods, cross-sectional study of patients who had a LDCT ordered from July to December 2022. We then completed phone surveys with patients who did not complete LDCT to assess knowledge, attitude, and perceptions toward LCS. RESULTS: We identified 380 patients who met inclusion criteria, including 331 (87%) who completed LDCT and 49 (13%) who did not. Patients who completed a LDCT and those who did not were similar regarding age, sex, race, primary language, household income, body mass index, median pack years, and quit time. Positive predictors of LDCT completion were: meeting USPSTF guidelines (97.9% vs 81.6%), being married (58.3% vs 44.9%), former versus current smokers (55% vs 41.7%), personal history of emphysema (60.4% vs 42.9%), and family history of lung cancer (13.9% vs 4.1%) (all P < .05). Of the patients who participated in the phone survey, only 7% of respondents thought they were high risk for developing lung cancer despite attending a shared decision-making visit and only 10% wanted to re-schedule their LDCT. CONCLUSION: There exist barriers to completing LDCT even after patients are identified as eligible and complete a shared decision-making visit secondary to knowledge barriers, misperceptions, and patient disinterest.


Assuntos
Detecção Precoce de Câncer , Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Feminino , Masculino , Estudos Transversais , Detecção Precoce de Câncer/métodos , Tomografia Computadorizada por Raios X/métodos , Pessoa de Meia-Idade , Idoso , Doses de Radiação , Conhecimentos, Atitudes e Prática em Saúde , Inquéritos e Questionários
15.
J Thorac Dis ; 15(11): 6140-6150, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38090290

RESUMO

Background: Pleural mesothelioma (PM) is rare but portends a poor prognosis. Multimodal treatment, including aggressive surgical resection, may offer the best chance of treatment response and improved survival. Single-center studies suggest that hyperthermic intrathoracic chemotherapy (HITHOC) during surgical resection improves outcomes, but the impact of HITHOC on postoperative morbidity and survival has not been examined on a larger scale. Methods: The National Cancer Database was queried for patients undergoing resection for PM from 2006-2017. Patients were excluded if staging or survival data was incomplete. After propensity-score matching, patients who underwent HITHOC were compared to patients who did not (case-control study). Perioperative outcomes and survival were analyzed. Results: The final cohort consisted of 3,232 patients; of these, 365 patients underwent HITHOC. After propensity-score matching, receipt of HITHOC was associated with increased length of stay (12 vs. 7 days, P<0.001) and increased 30-day readmissions (9.9% vs. 4.9%, P=0.007), but decreased 30-day mortality (3.2% vs. 6.0%, P=0.017) and 90-day mortality (7.5% vs. 10.9%). Kaplan-Meier modeling demonstrated that HITHOC was associated with improved survival in the overall cohort (median 20.5 vs. 16.8 months, P=0.001). In multivariable analysis, HITHOC remained associated with improved overall survival [hazard ratio (HR) =0.80; 95% confidence interval (CI): 0.69-0.92; P=0.002], and this persisted in the propensity-matched analysis (HR =0.73; 95% CI: 0.61-0.88; P=0.001). Conclusions: Using a large national database, we describe the impact of HITHOC on survival in patients with PM. Despite observed increased short-term morbidity, in multivariable analysis HITHOC was associated with an overall survival advantage for patients undergoing surgical resection of PM.

16.
JTCVS Open ; 16: 987-995, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38204633

RESUMO

Objective: Patients with esophageal cancer may be reluctant to proceed with surgery due to high complication rates. This study aims to compare outcomes between eligible surgical candidates who proceeded with surgery versus those who refused surgery. Methods: Characteristics and survival of patients with locally advanced (cT3N0M0, cT1-3N+M0) mid-/distal esophageal adenocarcinoma in the National Cancer Database (2006-2019) who either proceeded with or refused surgery after chemoradiotherapy were evaluated with logistic regression, Kaplan-Meier curves, and Cox proportional hazards methods. Results: Of the 13,594 patients included in the analysis, 595 (4.4%) patients refused esophagectomy. Patients who refused surgery were older, had less distance to travel to their treatment facility, were more likely to have cN0 disease, and were more likely to be treated at a community rather than academic or integrated network program, but did not have significantly different comorbid disease distributions. On multivariable analysis, refusing surgery was independently associated with older age, uninsured, lower income, less distance to a hospital, and treatment in a community program versus an academic/research or integrated network program. Esophagectomy was associated with better survival (5-year survival 40.1% [39.2-41] vs 23.6% [19.9-27.9], P < .001) and was also independently associated with better survival in the Cox model (hazard rate, 0.78 [95% confidence interval, 0.7-0.87], P < .001). Conclusions: The results of this study can inform selected patients with resectable esophageal adenocarcinoma that their survival will be significantly diminished if surgery is not pursued. Many factors associated with refusing surgery are non-clinical and suggest that access to or support for care could influence patient decisions.

17.
Ann Thorac Surg ; 115(3): 719-724, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35618049

RESUMO

BACKGROUND: The sensitivity of fluoroscopic esophagography with oral administration of contrast material to exclude anastomotic leak after esophagectomy is not well documented, and the consequences of missing a leak in this setting have not been previously described. METHODS: We performed a retrospective cohort study of a prospectively maintained institutional database of patients undergoing esophagectomy with esophagogastric anastomosis from 2008 to 2020. Relevant details of leaks, management, and outcomes were obtained from the database and formal chart review. Statistical analysis was performed to compare patients with and without leaks and those with false-negative vs positive esophagrams. RESULTS: There were 384 patients who underwent esophagectomy with gastric reconstruction; the majority were Ivor-Lewis (82%), and 51% were wholly or partially minimally invasive. By use of a broad definition of leak, 55 patients (16.7%) developed an anastomotic leak. Of the 55 patients, 27 (49%) who ultimately were found to have a leak initially had a normal esophagram result (performed on average on postoperative day 6). Those with a normal initial esophagram result were more likely to have an uncontained leak (81% vs 29%; P < .01), to require unplanned readmission (70% vs 39%; P = .02), and to undergo reoperation (44% vs 11%; P < .01). CONCLUSIONS: Early postoperative esophagrams intended to evaluate anastomotic integrity have a low sensitivity of 51%, and leaks missed on the initial esophagram have greater clinical consequences than those identified on the initial esophagram. These findings suggest that a high index of suspicion must be maintained even after a normal esophagram result and call into question the common practice of using this test to triage patients for diet advancement.


Assuntos
Fístula Anastomótica , Neoplasias Esofágicas , Humanos , Fístula Anastomótica/cirurgia , Esofagectomia , Estudos Retrospectivos , Neoplasias Esofágicas/cirurgia , Anastomose Cirúrgica , Complicações Pós-Operatórias/cirurgia
18.
JTCVS Open ; 16: 855-872, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38204720

RESUMO

Objective: Failure to rescue (FTR), defined as in-hospital death following a major complication, has been increasingly studied in patients who undergo cardiothoracic surgery. This study tested the hypothesis that elderly patients undergoing lung cancer resection have greater rates of FTR compared with younger patients. Methods: Patients who underwent surgery for primary lung cancer between 2011 and 2020 and had at least 1 major postoperative complication were identified using the National Surgical Quality Improvement Program database. Patients who died following complications (FTR) were compared with those who survived in an elderly (80+ years) and younger (<80 years) cohort. Results: Of the 2823 study patients, the younger cohort comprised 2497 patients (FTR: n = 139 [5.6%]), whereas the elderly cohort comprised 326 patients (FTR: n = 39 [12.0%]). Pneumonia was the most common complication in younger (877/2497, 35.1%) and elderly patients (118/326, 36.2%) but was not associated with FTR on adjusted analysis. Increasing age was associated with FTR (adjusted odds ratio [AOR], 1.55 per decade, P < .001), whereas unplanned reoperation was associated with reduced risk (AOR, 0.55, P = .01). Within the elderly cohort, surgery conducted by a thoracic surgeon was associated with lower FTR risk (AOR, 0.29, P = .028). Conclusions: FTR following lung cancer resection was more frequent with increasing age. Pneumonia was the most common complication but not a predictor of FTR. Unplanned reoperation was associated with reduced FTR, as was treatment by a thoracic surgeon for elderly patients. Surgical therapy for complications after lung cancer resection and elderly patients managed by a thoracic specialist may mitigate the risk of death following an adverse postoperative event.

19.
JTCVS Open ; 16: 919-928, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38204675

RESUMO

Background: Radiotherapy (RT) is integral to breast cancer treatment, especially in the current era that emphasizes breast conservation. The aim of our study was to determine the incidence of subsequent primary lung cancer after RT exposure for breast cancer over a time span of 3 decades to quantify this risk over time as modern oncologic treatment continues to evolve. Methods: The SEER (Surveillance, Epidemiology, and End Results) database was queried from 1988 to 2014 for patients diagnosed with nonmetastatic breast cancer. Patients who subsequently developed primary lung cancer were identified. Multivariable regression modeling was performed to identify independent factors associated with the development of lung cancer stratified by follow up intervals of 5 to 9 years, 10 to 15 years, and >15 years after breast cancer diagnosis. Results: Of the 612,746 patients who met our inclusion criteria, 319,014 (52%) were irradiated. primary lung cancer developed in 5556 patients (1.74%) in the RT group versus 4935 patients (1.68%) in the non-RT group. In a multivariable model stratified by follow-up duration, the overall HR of developing subsequent ipsilateral lung cancer in the RT group was 1.14 (P = .036) after 5 to 9 years of follow-up, 1.28 (P = .002) after 10 to 15 years of follow-up, and 1.30 (P = .014) after >15 years of follow-up. The HR of contralateral lung cancer was not increased at any time interval. Conclusions: The increased risk of developing a primary lung cancer secondary to RT exposure for breast cancer is much lower than previously published. Modern RT techniques may have contributed to the improved risk profile, and this updated study is important for counseling and surveillance of breast cancer patients.

20.
Thorac Surg Clin ; 32(1): 33-42, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34801193

RESUMO

Social disparities in lung cancer diagnosis, treatment, and survival have been studied using national databases, statewide registries, and institution-level data. Some disparities emerge consistently, such as lower adherence to treatment guidelines and worse survival by race and socioeconomic status, whereas other disparities are less well studied. A critical appraisal of current data is essential to increasing equity in lung cancer care.


Assuntos
Disparidades em Assistência à Saúde , Neoplasias Pulmonares , Fidelidade a Diretrizes , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Sistema de Registros , Classe Social
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