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Objective: There is limited clinical evidence to support any specific parenchymal air leak resolution criteria when using digital pleural drainage devices following lung resection. The aim of this study is to determine an optimal air leak resolution criteria, where duration of chest tube drainage is minimized while avoiding complications from premature chest tube removal. Methods: Airflow data averaged at 10-minute intervals was collected prospectively using a digital pleural drainage device (Thopaz; Medela) in 400 patients from 2015 to 2019. All permutations of air leak resolution criteria from <10 to 100 mL/minute for 4 to 12 hours were applied retrospectively to the pleural drainage data to determine air leak duration, and air leak recurrence frequency and volume. Air leak recurrence indicates potential for rather than occurrence of adverse events. Descriptive statistics were used to identify the optimal criteria based on patient safety (low frequency and volume of air leak recurrences), and efficiency (shortest initial air leak duration). Results: The majority of the 400 patients underwent lobectomy (57% [227 out of 400]), wedge resections (29% [115 out of 400]), or segmentectomies (8% [32 out of 400]) for lung cancer (90% [360 out of 400]). An airflow threshold <50 mL/minute resulted in longer air leak duration before meeting the criteria for air leak resolution (P < .0001). Air leak recurrence frequency and volume were greater in patients with a monitoring period <8 consecutive hours (P < .0001). Conclusions: When using a digital pleural drainage device, a postoperative air leak resolution criteria <50 mL/minute for 8 consecutive hours was associated with the best safety and efficiency profile.
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Background: This study provides an update to a landmark 2004 report describing demographics, training, and trends in adherence to thoracic surgery practice standards in Canada. Methods: An updated questionnaire was administered to all members of the Canadian Association of Thoracic Surgeons via email (n=142, compared to n=68 in 2004). Our report incorporates internal data from Ontario Health and the Canadian Partnership Against Cancer. Results: Forty-eight surgeons completed the survey (male, 70.8%; mean±standard deviation age, 50.3±9.3 years). This represents a 33.8% response rate, compared to 64.7% in 2004. Most surgeons (69%) served a patient population of over 1 million per center; 32%-34% reported an on-call ratio of 1:4-1:5 days, and the average weekly hours worked was 56.4±11.9. Greater access to dedicated geographic units per center (73% in 2021 vs. 53% in 2004) has improved thoracic-associated services and house staff, notably endoscopy units (100% vs. 91%), with 73% of respondents having access to both endobronchial and endoscopic ultrasound. Access to thoracic radiology has also improved, particularly regarding positron emission tomography scanners per center (76.9% vs. 13%). Annual case volumes for lung (255 vs. 128), esophageal (41 vs. 19), and mediastinal resections (30 vs. 13), along with hiatal hernia repair (45 vs. 20), have increased substantially despite reports of operating room availability and radiology as rate-limiting steps. Conclusion: This survey characterizes compliance with current practice standards, addressing the needs of thoracic surgeons across Canada. Over 85% of respondents were aware of the 2004 compliance paper, and 35% had applied for resources and equipment in response.
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OBJECTIVES: The prominence of "enhanced recovery after surgery" (ERAS) protocols being adopted in thoracic surgery requires a re-evaluation of mechanical venous thromboembolism (VTE) prophylaxis guidelines. The goal of this study was to assess the role of sequential compression devices (SCD) in the prevention of VTEs such as deep vein thrombosis and pulmonary embolism (PE) in thoracic surgical patients. METHODS: We identified 200 patients who underwent elective oncological thoracic surgery between December 2018 and December 2020 in 2 cohorts-1 with SCDs and 1 without (i.e. non-SCD). All patients followed a standardized enhanced recovery after surgery (ERAS) protocol. The quality of care provided by SCDs was evaluated by the incidence and severity of postoperative and follow-up VTEs. Cohorts were compared by the Caprini score (CS) and the Charlson Comorbidity Index (CCI) with a two one-sided t-test analysis. Secondary outcomes include perioperative characteristics and follow-up data. RESULTS: Only 2 patients within the SCD group developed a PE with average CS and CCI metrics, both after hospital discharge and treated with anticoagulants, raising concern over the prophylactic nature of SCDs. The CS (6.9 ± 1.3 and 6.9 ± 1.5; P = 0.96) and the CCI (3.8 ± 2.0 and 4.1 ± 2.6; P = 0.33) for non-SCD and SCD, respectively, did not differ. The two one-sided t-test analysis for CS (P < 0.001) and CCI (P < 0.001) demonstrated equivalence. CONCLUSIONS: Although larger studies are required to confirm these results, routine SCD use may not be required when implementing ERAS protocols because clinically significant VTE rates were minimal.
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Embolia Pulmonar , Cirugía Torácica , Procedimientos Quirúrgicos Torácicos , Tromboembolia Venosa , Anticoagulantes/uso terapéutico , Humanos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Embolia Pulmonar/complicaciones , Embolia Pulmonar/prevención & control , Procedimientos Quirúrgicos Torácicos/efectos adversos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & controlRESUMEN
BACKGROUND: A time course analysis was undertaken to evaluate how perioperative process-of-care and outcome measures evolved after implementation of an enhanced recovery after thoracic surgery (ERATS) program. METHODS: Outcome and process-of-care measures were compared between patients undergoing major elective thoracic surgery during a 9-month pre-ERATS implementation period to those at 1-3, 4-6, and 7-9 months post-ERATS implementation. Outcome measures included length of stay, the 30-day readmission rate, 30-day emergency department visits, and minor and major adverse events. Process measures included first time to activity, out-of-bed, ambulation, fluid diet, diet as tolerated, as well as removal of the first and last chest tube, epidural, patient-controlled analgesia, and Foley and intravenous catheters. RESULTS: In total, 704 patients (352 pre-ERATS, 352 post-ERATS) were included. Mobilization-related process measures, including time to first activity (16.5 vs. 6.8 hours, p<0.001), out-of-bed (17.6 vs. 8.9 hours, p<0.001), and ambulation (32.4 vs. 25.4 hours, p=0.04) saw statistically significant improvements by 1-3 months post-ERATS implementation compared to pre-ERATS. Time to Foley removal improved by 4-6 months post-ERATS (19.5 vs. 18.2 hours, p=0.003). Outcome measures, including the 30-day readmission rate and emergency department visits, steadily decreased post-ERATS. By 7-9 months post-ERATS, both minor (18.2% vs. 7.9%, p=0.009) and major (13.6% vs. 4.4%, p=0.007) adverse events demonstrated statistically significant improvements. Length of stay trended towards improvement from 6.2 days pre-ERATS to 4.8 days by 7-9 months post-ERATS (p=0.06). CONCLUSION: The adoption of ERATS led to improvements in multiple process-of-care measures, which may collectively and gradually achieve optimization of clinical outcomes.
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Primary biphasic tumors of the lung are rare. Lung lesions with a biphasic pattern are far more commonly primary or metastatic soft tissue tumors with entrapped native respiratory epithelium, giving the false impression of a biphasic tumor. We report a case of bilateral benign metastasizing leiomyomas in a 69-year-old female where the tumor cells diffusely entrapped native respiratory glands in a phyllodes-like pattern. The radiographic characteristics and histologic appearance were not immediately diagnostic and covered a wide differential. Reaching the final diagnosis required the use of immunohistochemical studies as well as correlation with the patient's history and radiographic findings. To the best of our knowledge, this is the first report of pulmonary benign metastasizing leiomyoma presenting in a phyllodes-like pattern. This case illustrates the importance of considering entrapment of native lung epithelium in the differential diagnosis of biphasic-appearing lung tumors.
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Leiomioma , Neoplasias Pulmonares , Neoplasias Uterinas , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Leiomioma/diagnóstico , Leiomioma/patología , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologíaRESUMEN
Improving evidence-based chest tube removal may reduce the length of stay following surgery. Presently, most chest tube removal protocols include a fluid output threshold based on a 24-hour observation period. The purpose of this study was to evaluate if, within a 24-hour time period, fluid output measurements at 6, 8, and 12 hours could predict if the total 24-hour fluid output would comply with a predetermined volume threshold considered acceptable for safe chest tube removal. Following lung resection, pleural fluid output data were prospectively recorded by a digital drainage system and analyzed retrospectively. Twenty-four-hour fluid output was calculated from every available 6-, 8-, and 12-hour measurement and compared to set 24-hour output criteria for chest tube removal (ie, 400 mL, 250 mL, and 20% of whole-body lymphatic flow). Performance of interim fluid outputs in predicting whether 24-hour fluid output criteria were satisfied was measured. From 2015 to 2018, 150 patients had digital pleural fluid drainage data suitable for analysis. Performance of interim fluid output data in identifying which patients would satisfy 24-hour output criteria ranged from 85% (95% confidence interval [CI]â¯=â¯83-86) to 94% (95% CIâ¯=â¯93-94) for specificity, 75% (95% CIâ¯=â¯73-76) to 92% (95% CIâ¯=â¯90-93) for positive predictive value, and 6% (95% CIâ¯=â¯6-7) to 15% (95% CIâ¯=â¯14-17) for false-positive rate. Potential time saved in duration of drainage using interim fluid output data ranged from 10 to 16 hours. Pleural fluid output measured for 6-, 8-, and 12-hour durations can accurately identify patients who will meet 24-hour fluid output threshold for safe chest tube removal.
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Tubos Torácicos , Remoción de Dispositivos , Drenaje/instrumentación , Derrame Pleural/terapia , Neumonectomía , Anciano , Diagnóstico Precoz , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Derrame Pleural/diagnóstico , Derrame Pleural/etiología , Neumonectomía/efectos adversos , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Anthracyclines, such as doxorubicin, are used as first-line chemotherapeutics, usually in combination therapies, for the treatment of advanced breast cancer. While these drugs have been successful therapeutic options, their use is limited due to serious drug related toxicities and acquired tumor resistance. Uncovering the molecular mechanisms that mediate doxorubicin's cytotoxic effect will lead to the identification of novel more efficacious combination therapies and allow for reduced doses of doxorubicin to be administered while maintaining efficacy. In our study, we demonstrate that activating transcription factor (ATF) 3 expression was upregulated by doxorubicin treatment in a representative panel of human breast cancer cell lines MCF7 and MDA-MB-231. We have also shown that doxorubicin treatment can induce ATF3 expression in ex vivo human breast and ovarian tumor samples. The upregulation of ATF3 in the cell lines was regulated by multiple cellular mechanisms including the activation of JNK and ATM signaling pathways. Importantly, loss of ATF3 expression resulted in reduced sensitivity to doxorubicin treatment in mouse embryonic fibroblasts. Through a 1200 FDA-approved compound library screen, we identified a number of agents whose cytotoxicity is dependent on ATF3 expression that also enhanced doxorubicin induced cytotoxicity. For example, the combination of the HDAC inhibitor vorinostat or the nucleoside analogue trifluridine could synergistically enhance doxorubicin cytotoxicity in the MCF7 cell line. Synergy in cell lines with the combination of ATF3 inducers and patients with elevated basal levels of ATF3 shows enhanced response to chemotherapy. Taken together, our results demonstrate a role for ATF3 in mediating doxorubicin cytotoxicity and provide rationale for the combination of ATF3-inducing agents with doxorubicin as a novel therapeutic approach.
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OBJECTIVE: To determine whether all grades of severity of postoperative adverse events are associated with prolonged length of stay in patients undergoing pulmonary cancer resection. METHODS: This was a retrospective cohort study of all patients who underwent pulmonary resection with curative intent for malignancy at The Ottawa Hospital, Division of Thoracic Surgery (January 2008 to July 2015). Postoperative adverse events were collected prospectively with the Thoracic Morbidity & Mortality System, based on the Clavien-Dindo severity classification. Patient demographics, comorbidities, preoperative investigations, cardiopulmonary assessment, pathologic staging, operative characteristics, and length of stay were retrospectively reviewed. Prolonged hospital stay was defined as >75th percentile for each procedure performed (wedge resection 6 days, segmentectomy 6 days, lobectomy 7 days, extended lobectomy 8 days, pneumonectomy 10 days). Univariable and multivariable logistic regression analyses were conducted to identify factors associated with prolonged hospital stay. RESULTS: Of 1041 patients, 579 (55.6%) were female, 610 (58.1%) were >65 years old, 232 (22.3%) experienced prolonged hospital stay, and 416 (40.0%) patients had ≥1 postoperative adverse event. Multivariable analyses identified significant (P < .05) factors associated with prolonged hospital stay to be (odds ratio; 95% confidence interval): lower diffusion capacity of the lung for carbon monoxide (0.99; 0.98-0.99), surgical approach: open thoracotomy (1.8; 1.3-2.5), and presence of any postoperative adverse event: Grade I (5.8; 3.3-10.2), Grade II (6.0; 4.0-8.9), Grade III (11.4; 7.0-18.7), and Grade IV (19.40; 7.1-55.18). CONCLUSIONS: Lower diffusion capacity of the lung for carbon monoxide, open thoracotomy approach, and the development of any postoperative adverse event, including minor events that required no additional therapy, were factors associated with prolonged hospital stay.
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Tiempo de Internación , Neoplasias Pulmonares/cirugía , Pulmón/cirugía , Neumonectomía/efectos adversos , Complicaciones Posoperatorias/etiología , Anciano , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Ontario , Neumonectomía/mortalidad , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/fisiopatología , Complicaciones Posoperatorias/terapia , Capacidad de Difusión Pulmonar , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Toracotomía/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The viral-transforming proteins E6 and E7 make human papillomavirus-positive (HPV+) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8+ T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 × 106 E7-specific CD8+ T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV+ murine model TC1 clears large tumors in a CD8+-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV+ cancer, as demonstrated by marked infection of HPV+ patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV+ cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. Cancer Immunol Res; 5(10); 847-59. ©2017 AACR.
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Inmunoterapia , Neoplasias/etiología , Neoplasias/patología , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Adenovirus Humanos/genética , Animales , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Epítopos de Linfocito T/inmunología , Femenino , Vectores Genéticos/genética , Humanos , Inmunoterapia/métodos , Ratones , Mutación , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/inmunología , Viroterapia Oncolítica , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/inmunología , Proteolisis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Transgenes , Carga Tumoral/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Postoperative adverse events (AEs), prolonged length of stay (PLOS), and patient experience are common quality measures after thoracic surgical procedures. Our objective was to investigate the relationship of postoperative AEs on patient experience and hospital length of stay (LOS) after lung cancer resection. METHODS: AEs (using Thoracic Morbidity and Mortality system based on Clavien-Dindo schema) and LOS were prospectively collected for all patients undergoing lung cancer resection. A 21-item questionnaire, retrospectively asking about patient experience, was mailed to patients twice (October 2015 and January 2016). The impact of AEs on experience was investigated and stratified by hospital LOS, with PLOS defined as the 75th percentile. Univariate analysis used parametric (t test) and nonparametric (Mann-Whitney) tests according to test conditions. RESULTS: Of 288 patients who responded to the survey (70% response rate), 175 (61%) had no AEs, 113 (39%) had experienced at least one AE, and 52 (18%) had experienced PLOS. Lung cancer patients who experienced PLOS showed significantly decreased experience on several questionnaire items, including their impression of comprehensiveness of surgeons information provision during inpatient period (p = 0.008), inpatient recovery from operation (p = 0.001), quality of life 30 days after operation (p = 0.032), follow-up care, (p = 0.022), and satisfaction with outcome 1 year after operation during follow-up care (p = 0.022). The presence of postoperative AEs led only to reduced impression about inpatient recovery from the operation (p = 0.01). CONCLUSIONS: In this cohort, postoperative AEs were minimally associated with negative patient experience. However, patients who experienced PLOS demonstrated a marked reduction in experience after thoracic surgical procedures.
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Tiempo de Internación/tendencias , Neoplasias Pulmonares/cirugía , Neumonectomía/efectos adversos , Complicaciones Posoperatorias/epidemiología , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Ontario/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de TiempoRESUMEN
Long non-coding RNAs (lncRNA) are a new class of regulatory molecules with diverse cellular functions. Recent reports have suggested that extracellular lncRNAs are detectable in human plasma and may serve as biomarkers. Here, we sought to investigate circulating lncRNAs as potential biomarkers for pulmonary arterial hypertension (PAH). Eighty-four lncRNAs, representing some of the most abundant and functionally relevant candidates identified in cellular studies, were assessed via RT-qPCR in plasma from PAH and healthy subjects. However, despite preamplification, the majority of lncRNAs were surprisingly undetectable or sporadically detectable, and showed no differential changes. Systematic characterization of plasma/RNA quality and technical performance via internal and external controls revealed no evidence of RNA degradation or RT-qPCR inhibition, and most lncRNAs were robustly detectable in pulmonary tissue. In plasma, lncRNA levels were the lowest among several different RNA species examined, and this was generalizable to other chronic and acute vascular conditions including coronary artery disease, acute coronary syndrome, and septic shock. In addition, two of three previously reported circulating lncRNA biomarker candidates were not detectable in any of the plasma samples. This study reveals new insight on the relative levels of lncRNAs in circulation, which has important implications for their potential development as biomarkers.
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Hipertensión Pulmonar/sangre , ARN Largo no Codificante/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adulto , Biomarcadores/sangre , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.
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Factor de Transcripción Activador 3/metabolismo , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/farmacología , Neoplasias Pulmonares/metabolismo , Factor de Transcripción Activador 3/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Daño del ADN , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neoplasias Pulmonares/genética , RatonesRESUMEN
BACKGROUND: Predictive models of prolonged air leak have relied on information not always available preoperatively (eg, extent of resection, pleural adhesions). Our objective was to construct a model to identify patients at increased risk of prolonged air leak using preoperative factors exclusively. METHODS: From 2012 to 2014, data on consecutive patients undergoing pulmonary resection were collected prospectively. Prolonged air leak was defined as lasting longer than 7 days and requiring hospitalization. Factors associated with the primary outcome (p < 0.2) were included in a multivariate model. Regression coefficients were used to develop a weighted risk score for prolonged air leak. RESULTS: Of 225 patients, 8% (18/225) experienced a prolonged air leak. Male gender (p = 0.08), smoking history (p = 0.03), body mass index (BMI) 25 or below (p < 0.01), Medical Research Council (MRC) dyspnea score above 1 (p = 0.06), and diffusion capacity for carbon monoxide below 80% (Dlco) (p = 0.01) were selected for inclusion in the final model. Weighted scores were male gender (1 point), BMI 25 or below (0.5 point), smoker (2 points), Dlco% below 80% (2 points), and MRC dyspnea score above 1 (1 point). The area under the receiver operating characteristic curve was 0.8 (95% confidence interval [CI] = 0.7 to 0.9]. An air leak score above 4 points offered the best combination of sensitivity (83% [95% CI = 58 to 96]) and specificity (65% [95% CI = 58 to 71]). CONCLUSIONS: A subgroup of lung resection patients at higher risk for a prolonged air leak can be effectively identified with the use of widely available, preoperative factors. The proposed scoring system is simple, is clinically relevant to the informed consent, and allows preoperative patient selection for interventions to reduce the risk of prolonged air leak.
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Fuga Anastomótica/diagnóstico , Bronquios/cirugía , Neoplasias Pulmonares/cirugía , Enfermedades Pleurales/diagnóstico , Neumonectomía/efectos adversos , Medición de Riesgo , Anciano , Anastomosis Quirúrgica/efectos adversos , Fuga Anastomótica/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Enfermedades Pleurales/epidemiología , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Targeting the EGFR, with inhibitors such as erlotinib, represents a promising therapeutic option in advanced head and neck squamous cell carcinomas (HNSCC). However, they lack significant efficacy as single agents. Recently, we identified the ability of statins to induce synergistic cytotoxicity in HNSCC cells through targeting the activation and trafficking of the EGFR. However, in a phase I trial of rosuvastatin and erlotinib, statin-induced muscle pathology limited the usefulness of this approach. To overcome these toxicity limitations, we sought to uncover other potential combinations using a 1,200 compound screen of FDA-approved drugs. We identified monensin, a coccidial antibiotic, as synergistically enhancing the cytotoxicity of erlotinib in two cell line models of HNSCC, SCC9 and SCC25. Monensin treatment mimicked the inhibitory effects of statins on EGFR activation and downstream signaling. RNA-seq analysis of monensin-treated SCC25 cells demonstrated a wide array of cholesterol and lipid synthesis genes upregulated by this treatment similar to statin treatment. However, this pattern was not recapitulated in SCC9 cells as monensin specifically induced the expression of activation of transcription factor (ATF) 3, a key regulator of statin-induced apoptosis. This differential response was also demonstrated in monensin-treated ex vivo surgical tissues in which HMG-CoA reductase expression and ATF3 were either not induced, induced singly, or both induced together in a cohort of 10 patient samples, including four HNSCC. These results suggest the potential clinical utility of combining monensin with erlotinib in patients with HNSCC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Monensina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Monensina/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
OBJECTIVE: To clarify the biologic behavior of esophageal signet ring cell (SRC) carcinomas of the esophagus and gastroesophageal junction (GEJ). To evaluate the accuracy of pretreatment biopsies in diagnosing true SRC carcinoma. BACKGROUND: In contrast with gastric cancer, little is known about the biologic behavior and prognosis of SRC. METHODS: All adenocarcinomas (ADC) of the esophagus and GEJ-patients undergoing primary resection between 1990 and 2009 were included (n = 920). Specimens containing SRCs (n = 114) were classified according to World Health Organization criteria (>50% SRC or <50% SRC). RESULTS: Thirty-two patients showed more than 50% SRC and 71 patients showed less than 50% SRC. Overall cancer-specific 5-year survival was worse for SRC (22.4%, P < 0.0001) and for SRC > 50% (13.6%, P = 0.0001) compared with ADC. Complete resection was achieved in 86.5% of patients (n = 697) in ADC, 69.5% (n = 57) in SRC < 50%, and 78.1% (n = 25) in SRC > 50% (vs ADC, respectively, P < 0.0001 and P = 0.1801). In 379 pN + R0 patients, the median number of positive lymph nodes was comparable between ADC and SRC < 50% (4 vs 5, P = 0.207) or SRC > 50% (4 vs 8, P = 0.077). Compared with ADC, SRC > 50% showed more pN3's (30% vs 61%, P = 0.006), higher recurrence (56% vs 42% for ADC, P = 0.003), and local-regional recurrences (29% vs 16%, P = 0.002). Pretreatment biopsies were unreliable to define the presence of SRC > 50% (sensitivity = 56.3%, positive predictive value = 43.9%). CONCLUSIONS: SRCs are aggressive neoplasms associated with poorer prognosis than other ADCs after primary esophagectomy. Because our data suggest that pretreatment biopsies failed to reliably define presence of SRC > 50%, presence of SRCs in pretreatment biopsies seems to be of no use to define treatment strategy or prognosis.
Asunto(s)
Carcinoma de Células en Anillo de Sello/secundario , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Estadificación de Neoplasias , Bélgica/epidemiología , Biopsia , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/cirugía , Progresión de la Enfermedad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Esofagectomía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de TiempoRESUMEN
BACKGROUND: Surgical resection for tissue diagnosis of lung nodules exposes patients to unnecessary risks and consumes health care resources for questionable benefit. We describe the impact of routine percutaneous lung biopsy on the management of suspicious lung nodules. METHODS: A retrospective review of consecutive patients referred to a regional cancer assessment center for evaluation of suspected primary or metastatic lung cancer was performed. RESULTS: From 2008 to 2010, 901 patients (male to female ratio, 0.97:1 [443 to 458]; mean age, 69.4 ± 0.3 years) underwent 1,016 percutaneous lung biopsy (fluoroscopy, 77%; computed tomography-guided, 20%). Diagnoses were non-small cell lung cancer (602 of 901; 66.8%), other malignancy (159 of 901; 17.6%), indeterminate (61 of 901; 6.8%), benign (47 of 901; 5.2%), or nondiagnostic (32 of 901; 3.6%). Of these, 393 (43.6%) were surgical candidates. Operation was avoided in 16.0% (63 of 393; benign, 36; indeterminate, 13; nondiagnostic, 14). Computed tomography follow-up in 82.5% (52 of 63) showed no change or resolution at 14.0 ± 1 months. Only 2.7% (9 of 330) underwent resection of a pathologically benign nodule. Diagnostic yield of percutaneous lung biopsy was 82.7%. Sensitivity, specificity, and positive and negative predictive values, respectively, were 100% (95% confidence interval, 98 to 100), 75% (95% confidence interval, 22 to 99), 99.7% (95% confidence interval, 98 to 100), and 100% (95% confidence interval, 31 to 100). The mean operating room time saved with this strategy was 165 ± 13.2 hours. The total cost of performing routine percutaneous biopsy ($395,500) was 44.5% of the cost of upfront wedge resection for tissue diagnosis ($888,300). CONCLUSIONS: In surgical candidates, routine needle biopsy of suspicious lung nodules may lead to decreased costs, more efficient use of limited operating room resources, and a low probability of resecting pathologically benign lesions.