RESUMEN
Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1-3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.
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Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/química , Histonas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Nucleares/metabolismo , Animales , Biocatálisis , Carcinogénesis/genética , Carcinoma de Células Escamosas/genética , Femenino , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Metilación , Ratones , Modelos Moleculares , Mutación , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/deficiencia , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To investigate overall survival and length of stay (LOS) associated with differing management for high output (>1 L over 24 hours) leaks (HOCL) after cancer-related esophagectomy. BACKGROUND: Although infrequent, chyle leak after esophagectomy is an event that can lead to significant perioperative sequelae. Low-volume leaks appear to respond to nonoperative measures, whereas HOCLs often require invasive therapeutic interventions. METHODS: From a prospective single-institution database, we retrospectively reviewed patients treated from 2001 to 2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital LOS and survival data. RESULTS: A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received nonoperative management, 15 patients received prompt (<72 hours from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer LOSs compared with early intervention (slope = 9.849, 95% CI: 3.431-16.267). Late intervention (hazard ratio: 4.772, CI: 1.384-16.460) and nonoperative management (hazard ratio: 4.731, CI: 1.294-17.305) were associated with increased mortality compared with early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis. CONCLUSIONS: Patients with HOCL should receive early intervention to possibly reverse the prognostic implications of this potentially detrimental complication.
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Fuga Anastomótica , Neoplasias Esofágicas , Esofagectomía , Humanos , Masculino , Esofagectomía/efectos adversos , Femenino , Persona de Mediana Edad , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/mortalidad , Estudios Retrospectivos , Anciano , Fuga Anastomótica/etiología , Fuga Anastomótica/cirugía , Quilo , Tiempo de Internación , Tasa de Supervivencia , Resultado del Tratamiento , Complicaciones Posoperatorias/mortalidadRESUMEN
BACKGROUND AND OBJECTIVES: For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. METHODS: We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. RESULTS: Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. CONCLUSIONS: We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.
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Neoplasias Colorrectales , Neoplasias Pulmonares , Humanos , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Proteínas Proto-Oncogénicas p21(ras) , Terapia Combinada , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugíaRESUMEN
The use of octreotide in managing intrathoracic chyle leak following esophagectomy has gained popularity in the adult population. While the benefits of octreotide have been confirmed in the pediatric population, there remains limited evidence to support its use in the adults post-esophagectomy. Thus, we performed a single-institution cohort study to characterize its efficacy. The study was performed using a prospective, single-center database, from which clinicopathologic characteristics were extracted of patients who had post-esophagectomy chyle leaks. Kaplan-Meier and multivariable Cox regression analyses were performed to investigate the effect of octreotide use on chest tube duration (CTD), hospital length of stay (LOS), and overall survival (OS). In our cohort, 74 patients met inclusion criteria, among whom 27 (36.5%) received octreotide. Kaplan-Meier revealed no significant effect of octreotide on CTD (P = 0.890), LOS (P = 0.740), or OS (P = 0.570). Multivariable Cox regression analyses further corroborated that octreotide had no effect on CTD (HR = 0.62, 95% confidence interval [CI]: 0.32-1.20, P = 0.155), LOS (HR = 0.64, CI: 0.34-1.21, P = 0.168), or OS (1.08, CI: 0.53-2.19, P = 0.833). Octreotide use in adult patients with chyle leak following esophagectomy lacks evidence of association with meaningful clinical outcomes. Level 1 evidence is needed prior to further consideration in this population.
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Quilotórax , Esofagectomía , Fármacos Gastrointestinales , Tiempo de Internación , Octreótido , Complicaciones Posoperatorias , Humanos , Octreótido/uso terapéutico , Esofagectomía/efectos adversos , Quilotórax/etiología , Quilotórax/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Tiempo de Internación/estadística & datos numéricos , Anciano , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Estimación de Kaplan-Meier , Estudios Prospectivos , Resultado del Tratamiento , Tubos Torácicos , Modelos de Riesgos Proporcionales , Adulto , Estudios RetrospectivosRESUMEN
OBJECTIVES: To describe financial toxicity (FT) in patients with resected lung cancer and identify risk factors in this population. BACKGROUND: FT describes the financial burden associated with cancer care and its impact on the quality of survivorship. Few prior studies have examined FT in patients with lung cancer. METHODS: Patients who underwent lung cancer resection at our institution between January 1, 2016 and December 31, 2021, were surveyed to gather demographic information and evaluate FT using a validated questionnaire. A multivariable model was built to identify risk factors for FT. RESULTS: Of the total, 1477 patients were contacted, of whom 463 responded (31.3%). Most patients were stage I (n = 349, 75.4%) and lobectomy was performed often (n = 290, 62.8%). There were 196 patients (42.3%) who experienced FT. Upon multivariable analyses, divorced marital status [odds ratio (OR) = 3.658, 95% CI: 1.180-11.337], household income <$40,000 (OR = 2.544, 95% CI: 1.003-6.455), credit score below 739 (OR = 2.744, 95% CI: 1.326-5.679), clinical stage >I (OR = 2.053, 95% CI: 1.088-3.877), and change in work hours or work cessation (all P < 0.05) were associated with FT. Coping mechanisms, such as decreased spending on food or clothing and increased use of savings or borrowing money, were more likely to be reported by patients experiencing FT than those who did not ( P < 0.001). CONCLUSIONS: Patients undergoing lung cancer resection often experienced significant financial stress with several identifiable risk factors. FT should be considered early in the care of these patients to alleviate detrimental coping mechanisms and enhance their quality of survivorship.
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Neoplasias Pulmonares , Neoplasias , Humanos , Neoplasias Pulmonares/cirugía , Estrés Financiero , Costo de Enfermedad , Neoplasias/epidemiología , Renta , Encuestas y Cuestionarios , Calidad de VidaRESUMEN
OBJECTIVE: Clinical predictors of pathological complete response have not reliably identified patients for whom an organ-sparing approach following neoadjuvant chemoradiation be undertaken for esophageal cancer patients. We sought to identify high-risk predictors of residual carcinoma that may preclude patients from a selective surgical approach. BACKGROUND: Patients treated with neoadjuvant chemoradiation followed by esophagectomy for esophageal adenocarcinoma were identified. PATIENTS AND METHODS: Correlation between clinical and pathologic complete responses were examined. Regression models and recursive partitioning were utilized to identify features associated with residual carcinoma. External validation of these high-risk factors was performed on a data set from an independent institution. RESULTS: A total of 326 patients were identified, in whom clinical complete response was noted in 104/326 (32%). Pathologic complete response was noted in only 33/104 (32%) of these clinical complete responders. Multivariable analysis identified that the presence of stricture ( P =0.011), positive biopsy ( P =0.010), and signet ring cell histology ( P =0.019) were associated with residual cancer. Recursive partitioning corroborated a 94% probability of residual disease, or greater, for each of these features. The positive predictive value was >90% for these characteristics. A SUV max >5.4 at the esophageal primary in the absence of esophagitis was also a high-risk factor for residual carcinoma. External validation confirmed these high-risk factors to be implicated in the finding of residual carcinoma. CONCLUSIONS: Clinical parameters of response are poor predictors of complete pathologic response leading to challenges in selecting candidates for active surveillance. However, we characterize several high-risk features for residual carcinoma which indicate that esophagectomy should not be delayed.
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Adenocarcinoma , Neoplasias Esofágicas , Humanos , Terapia Neoadyuvante , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Adenocarcinoma/terapia , Adenocarcinoma/patología , Esofagectomía , Estudios Retrospectivos , Estadificación de NeoplasiasRESUMEN
INTRODUCTION: The lung represents a frequent site of spread for metastatic melanoma, which has historically been managed with surgical resection achieving promising outcomes. We hypothesized that the role of surgery in the management of melanoma pulmonary metastases (MPM) is evolving among the development of less invasive diagnostic and novel systemic therapeutic strategies. MATERIALS AND METHODS: A single-center thoracic surgery database was reviewed and patients who underwent surgical resection of MPM between 1998 and 2019 were identified. Demographic, clinicopathologic, and surgical data were collected and analyzed, as were the annual volumes and indications for surgical resection. A Cochran-Armitage test was used to assess the trend in surgical indication. RESULTS: Three hundred and seventy seven surgical procedures for MPM were performed during the years of study in the care of 347 patients. Patients were predominantly male, with a mean age of 59.3 y. The mean number of annual resections was 17 and while this number initially increased from six in 1998 to a peak of 39 cases in 2008, a decline was subsequently observed. Diagnostic resection decreased from 22% in 1998-1999 to 5% at the peak of procedures in 2008-2009 and to 0 in 2018-2019 (P = 0.02). Curative resection increased from 44% in 1998-1999 to 73% in 2008-2009 (P < 0.001) and remained the dominant reason for surgery in later years. CONCLUSIONS: Surgical indications in the management of MPM have transformed in conjunction with systemic modalities, and the volume of resections has decreased in the modern era. Despite innovations in systemic management and shifting goals of operative interventions, surgeons continue to play a vital role in caring for these patients with an advanced disease.
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Neoplasias Pulmonares , Melanoma , Metastasectomía , Procedimientos Quirúrgicos Torácicos , Femenino , Humanos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Masculino , Melanoma/patología , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND). METHODS: This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992. FINDINGS: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis. INTERPRETATION: Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended. FUNDING: Varian Medical Systems and US National Cancer Institute (National Institutes of Health).
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Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Neumonectomía , Radiocirugia , Cirugía Torácica Asistida por Video , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neumonectomía/efectos adversos , Neumonectomía/mortalidad , Supervivencia sin Progresión , Estudios Prospectivos , Radiocirugia/efectos adversos , Radiocirugia/mortalidad , Texas , Cirugía Torácica Asistida por Video/efectos adversos , Cirugía Torácica Asistida por Video/mortalidad , Factores de TiempoRESUMEN
OBJECTIVE: The aim of this study was to assess the effect of an enhanced recovery after surgery (ERAS) pathway on pain and opioid use following lung resection. SUMMARY BACKGROUND DATA: A major component ERAS pathways is opioid-sparing analgesia; however, the effect on postoperative pain and opioid use in patients undergoing lung resection is unknown. METHODS: Following implementation of an ERAS pathway for lung resection, 123 consecutive patients were identified. Patients were propensity-matched 1:1 with a group of consecutive patients (n = 907) undergoing lung resection before ERAS. Differences regarding in-hospital opioid consumption, discharge prescribing of opioids, and postoperative pain scores were examined. Morphine milligram equivalents were separately calculated including and excluding tramadol as an opioid medication. RESULTS: There were no significant differences between matched patients regarding age, sex, performance status, receipt of preoperative treatment, extent of lung resection, or operative approach. Epidural analgesia was used in 66% of controls and in none of the ERAS group (P < 0.001). The number of adjunct analgesics used postoperatively was greater in the ERAS group (median 3 vs 2, P < 0.001). There was a major reduction in morphine milligram equivalents in the ERAS group whether tramadol was included (median 14.2 vs 57.8, P < 0.001) or excluded (median 2.7 vs 57.8, P < 0.001) and regardless of surgical approach. Average daily pain scores were lower in the ERAS group (median 1.3 vs 1.8, P = 0.004); however, this difference was present only among patients undergoing thoracotomy. The proportion of patients who were prescribed discharge opioids varied whether tramadol was included (96% each group, P = 1.00) or excluded (39% vs 80%, P < 0.001) in the analysis. CONCLUSIONS: Implementation of an ERAS pathway was associated with effective post-operative analgesia, major reductions in in-hospital consumption of opioids, and reduced pain, compared to conventional management.
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Analgésicos Opioides/uso terapéutico , Recuperación Mejorada Después de la Cirugía , Enfermedades Pulmonares/cirugía , Manejo del Dolor/métodos , Dolor Postoperatorio/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
A compact frequency-doubled diode-pumped Nd:YAG master-oscillator power-amplifier laser system with programmable microsecond pulse length has been developed. Analog pulse shaping of the output from a single-frequency continuous-wave Nd:YAG oscillator, and subsequent amplification, allowed the generation of rectangular pulses with pulse lengths on the order of the Nd:YAG fluorescence lifetime. Temporally flat-top pulses of 1064 nm light with 520 mJ pulse energy, 2.6 kW peak power, and 200 µs duration, with linewidth below 10 kHz, were obtained at a repetition rate of 2 Hz. Second harmonic generation in a LBO crystal yielded pulses of 262 mJ and 1.3 kW peak power at 532 nm. The peak power can be maintained within 2.9% over the duration of the laser pulse, and long-term intensity stability of 1.1% was observed. The spatially flat-top beam at 1064 nm used in the amplifier is converted to a Gaussian beam at 532 nm with beam quality factor M2 = 1.41(14) during the second harmonic generation. This system has potential as a pump source for Ti:sapphire, dye, or optical parametric amplifiers to generate tunable high-power single-frequency radiation for applications in precision measurements and laser slowing.
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BACKGROUND AND OBJECTIVES: Adoptive T-cell therapies (ACTs) using expansion of tumor-infiltrating lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. METHODS: Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. RESULTS: 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. CONCLUSIONS: Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.
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Inmunoterapia Adoptiva/métodos , Neoplasias Pulmonares/terapia , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/terapia , Procedimientos Quirúrgicos Pulmonares/métodos , Adulto , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Masculino , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Cuidados Posoperatorios , Pronóstico , Estudios ProspectivosRESUMEN
The intramural the National Cancer Institute (NCI) and more recently the University of Texas Southwestern Medical Center with many different collaborators comprised a complex, multi-disciplinary team that collaborated to generated large, comprehensively annotated, cell-line related research resources which includes associated clinical, and molecular characterization data. This material has been shared in an anonymized fashion to accelerate progress in overcoming lung cancer, the leading cause of cancer death across the world. However, this cell line collection also includes a range of other cancers derived from patient-donated specimens that have been remarkably valuable for other types of cancer and disease research. A comprehensive analysis conducted by the NCI Center for Research Strategy of the 278 cell lines reported in the original Journal of Cellular Biochemistry Supplement, documents that these cell lines and related products have since been used in more than 14 000 grants, and 33 207 published scientific reports. This has resulted in over 1.2 million citations using at least one cell line. Many publications involve the use of more than one cell line, to understand the value of the resource collectively rather than individually; this method has resulted in 2.9 million citations. In addition, these cell lines have been linked to 422 clinical trials and cited by 4700 patents through publications. For lung cancer alone, the cell lines have been used in the research cited in the development of over 70 National Comprehensive Cancer Network clinical guidelines. Finally, it must be underscored again, that patient altruism enabled the availability of this invaluable research resource.
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BACKGROUND: The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS). METHODS: We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS. RESULTS: There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS. CONCLUSION: The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.
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Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nomogramas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores Sexuales , Tasa de Supervivencia/tendencias , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: It is unclear if a specific strategy for simultaneous treatment of primary thymic neoplasms and pleural metastases confers benefit for Masaoka stage IVA disease. We reviewed our experience with thymic neoplasms with concurrent pleural metastases to identify factors influencing outcomes. METHODS: Records of patients who presented with stage IVA thymic neoplasms from 2000 to 2018 were assessed. Multivariate Cox proportional hazards analyses were completed to determine predictors of progression-free and overall survival. RESULTS: Forty-eight patients were identified, including 34 (71%) who underwent surgery. Median overall and progression-free survival were 123 and 21 months, respectively. The extent of resection varied, and was most commonly thymectomy plus partial pleurectomy (22, 65%). Median progression-free survival for patients who underwent surgical resection versus those who had not was 24 versus 12 months (P = .018). Following surgical resection, mediastinal recurrence was uncommon (2, 6%, vs 7, 50% nonoperatively). Five-year survival rates in these groups were suggestive of possible benefit to surgery (87% vs 68%). CONCLUSIONS: Thymic neoplasms with pleural dissemination represents a treatment challenge. As part of a multidisciplinary approach, surgery appears to be associated with more favorable long-term results, although selection bias may account for some of the survival differences observed.
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Neoplasias Pleurales/secundario , Neoplasias Pleurales/cirugía , Neoplasias del Timo/patología , Neoplasias del Timo/cirugía , Adulto , Anciano , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Procedimientos Quirúrgicos Torácicos , TimectomíaRESUMEN
BACKGROUND AND OBJECTIVES: Precision medicine has altered the management of colorectal cancer (CRC). However, the concordance of mutational findings between primary CRC tumors and associated pulmonary metastases (PM) is not well-described. This study aims to determine the concordance of genomic profiles between primary CRC and PM. METHODS: Patients treated for colorectal PM at a single institution from 2000 to 2017 were identified. Mutational concordance was defined as either both wild-type or both mutant alleles in lung and colorectal lesion; genes with opposing mutational profiles were reported as discordant. RESULTS: Thirty-eight patients met inclusion criteria, among whom KRAS, BRAF, NRAS, MET, RET, and PIK3CA were examined for concordance. High concordance was demonstrated among all evaluated genes, ranging from 86% (KRAS) to 100% concordance (NRAS, RET, and MET). De novo KRAS mutations were detected in the PM of 4 from 35 (11%) patients, 3 of whom had previously received anti-epidermal growth factor receptor (EGFR) therapy. Evaluation of Cohen's κ statistic demonstrated moderate to perfect correlation among evaluated genes. CONCLUSIONS: Because high intertumoral genomic homogeneity exists, it may be reasonable to use primary CRC mutational profiles to guide prognostication and targeted therapy for PM. However, the possibility of de novo KRAS-mutant PM should be considered, particularly among patients previously treated with anti-EGFR therapy.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Análisis Mutacional de ADN , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Medicina de Precisión , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Circulating microRNAs (miRNAs) are potential biomarkers for cancer diagnosis, screening and prognosis. This study aimed to identify serum miRNAs as predictors of survival in patients with advanced non-small cell lung cancer (NSCLC). We profiled serum miRNAs in a pilot set of four patients with good survival (>24 months) and four patients with poor survival (<6 months). We selected 140 stably detectable miRNAs and 42 miRNAs reported in literature for further analysis. Expression of these 182 miRNAs was measured using high-throughput polymerase chain reaction assay, and their association with 3-year survival in the discovery (n = 345) and validation (n = 177) cohorts was assessed. Five serum miRNAs (miR-191, miR-28-3p, miR-145, miR-328 and miR-18a) were significantly associated with 3-year overall survival in both cohorts. A combined 5-miRNA risk score was created to assess the cumulative impact of these miRNAs on risk of death. Quartile analysis of the risk score showed significant association with 3-year death risk, with a 4.6-, 6.8- and 9.3-month reduction in median survival time for the second, third and fourth quartiles, respectively. Survival tree analysis also identified distinct risk groups with different 3-year survival durations. Data from The Cancer Genome Atlas revealed all five miRNAs were differentially expressed (P < 0.0001) in paired tumor and normal tissues. Pathway analysis indicated that target genes of these five miRNAs were mainly enriched in inflammatory/immune response pathways and pathways implicated in resistance to chemoradiotherapy and/or targeted therapy. Our results suggested that the 5-miRNA signature could serve as a prognostic predictor in patients with advanced NSCLC.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , MicroARN Circulante/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/mortalidad , MicroARNs/genética , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , MicroARN Circulante/sangre , Estudios de Cohortes , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/sangre , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Patient-derived xenograft (PDX) models increasingly are used in translational research. However, the engraftment rates of patient tumor samples in immunodeficient mice to PDX models vary greatly. METHODS: Tumor tissue samples from 308 patients with non-small cell lung cancer were implanted in immunodeficient mice. The patients were followed for 1.5 to approximately 6 years. The authors performed histological analysis of PDXs and some residual tumor tissues in mice with failed PDX growth at 1 year after implantation. Quantitative polymerase chain reaction and enzyme-linked immunoadsorbent assay were performed to measure the levels of Epstein-Barr virus genes and human immunoglobulin G in PDX samples. Patient characteristics were compared for PDX growth and overall survival as outcomes using Cox regression analyses. Disease staging was based on the 7th TNM staging system. RESULTS: The overall engraftment rate for PDXs from patients with non-small cell lung cancer was 34%. Squamous cell carcinomas had a higher engraftment rate (53%) compared with adenocarcinomas. Tumor samples from patients with stage II and stage III disease and from larger tumors were found to have relatively high engraftment rates. Patients whose tumors successfully engrafted had worse overall survival, particularly those individuals with adenocarcinoma, stage III or stage IV disease, and moderately differentiated tumors. Lymphoma formation was one of the factors associated with engraftment failure. Human CD8-positive and CD20-positive cells were detected in residual samples of tumor tissue that failed to generate a PDX at 1 year after implantation. Human immunoglobulin G was detected in the plasma of mice that did not have PDX growth at 14 months after implantation. CONCLUSIONS: The results of the current study indicate that the characteristics of cancer cells and the tumor immune microenvironment in primary tumors both can affect engraftment of a primary tumor sample.
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Adenocarcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Modelos Animales de Enfermedad , Neoplasias Pulmonares/patología , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Animales , Antígenos CD20/inmunología , Antígenos CD20/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Estadificación de Neoplasias , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND AND OBJECTIVES: While knowledge has grown extensively regarding the impact of mutations on colorectal cancer prognosis, their role in outcomes after pulmonary metastasectomy (PM) remains minimally understood. We sought to determine the prognostic role of mutant disease on survival and recurrence after metastasectomy. METHODS: Patients with available tumor sequencing profiles who underwent PM for colorectal cancer at a single institution from 2011 to 2017 were reviewed. Various demographic and clinicopathologic factors, as well as mutational status, were tested in the Cox regression analyses to identify predictors of survival and disease-free survival (DFS). RESULTS: A total of 130 patients met inclusion criteria, among whom 78 (60%) were male and the mean age was 57 years. The median survival time and 5-year survival rate were 58.2 months and 47%, respectively. A single pulmonary nodule was present in 54%. Disease recurrence occurred for 87 (67%) patients, including 75 (58%) who had at least one lung recurrence after metastasectomy at a median time to recurrence of 19.4 months. Upon multivariable analysis, RAS and TP53 mutations were associated with shorter survival DFS, while APC is associated with prolonged survival. CONCLUSIONS: After metastasectomy for colorectal cancer, mutations in RAS, TP53, and APC play an important role in survival and recurrence.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Pulmonares/mortalidad , Metastasectomía/mortalidad , Mutación , Recurrencia Local de Neoplasia/mortalidad , Neumonectomía/mortalidad , Adulto , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Endoscopic mucosal resection (EMR) can be an effective therapy for superficial esophageal cancer. Many patients with cT2 invasion by endoscopic ultrasound (EUS) receive surgery but are subsequently found to have superficial disease. The purpose of this study was to investigate the safety profile and the added value of attempting EMR for EUS-staged cT2N0 esophageal cancer. A retrospective review was performed at a single institution from 2008 to 2017. Patients who were staged cT2N0 by EUS were identified from a prospectively maintained surgical database. Among 75 patients identified for analysis, 30 underwent an attempt at EMR. No perforations or other immediate complications occurred. EMR was more likely to be attempted among older patients (P = 0.001) with smaller tumor size (P < 0.001) and diminished SUVmax (P = 0.001). At the time of treatment, EMR was successful in clearing all known disease among 17/30 patients, with 12 representing pT1a or less and 5 representing pT1b with negative margins. Among the 17 patients for whom EMR was able to clear all known disease, there were no recurrences or cancer-related deaths. Although all the patients were staged as cT2N0 by EUS, many patients were identified by EMR to have superficial disease. There were no perforations or other adverse events related to EMR. Furthermore, EMR cleared all known disease among 17 patients with no known recurrences or cancer-related deaths. The results indicate that EMR for cT2N0 esophageal cancer is a safe diagnostic option that is therapeutic for some.
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Resección Endoscópica de la Mucosa/estadística & datos numéricos , Neoplasias Esofágicas/cirugía , Esofagectomía/estadística & datos numéricos , Selección de Paciente , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Resección Endoscópica de la Mucosa/métodos , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Esofagectomía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Estudios Retrospectivos , Resultado del Tratamiento , UltrasonografíaRESUMEN
BACKGROUND: Next-generation sequencing of cell-free DNA (cfDNA) has been shown to be a useful noninvasive test for detecting mutations in solid tumors. METHODS: Targeted gene sequencing was performed with a panel of 263 cancer-related genes for cfDNA and genomic DNA of peripheral blood mononuclear cells (PBMCs) obtained from presurgical specimens of 6 lung cancer patients, and mutation calls in these samples were compared with those of primary tumors and corresponding patient-derived xenografts (PDXs). RESULTS: Approximately 67% of the mutations detected in the tumor samples (primary tumors and/or PDXs) were also detected in genomic DNA from PBMCs as background mutations. These background mutations consisted of germline polymorphisms and a group of mutations with low allele frequencies, mostly <10%. These variants with a low allele frequency were repeatedly detected in all types of samples from the same patients and at similarly low allele frequency levels in PBMCs from different patients; this indicated that their detection might be derived from common causes, such as homologous sequences in the human genome. Allele frequencies of mutations detected in both primary tumors and cfDNA showed 2 patterns: 1) low allele frequencies (approximately 1%-10%) in cfDNA but high allele frequencies (usually >10% or >3-fold increase) in primary tumors and further enrichment in PDXs and 2) similar allele frequencies across samples. CONCLUSIONS: Because only a small fraction of total cfDNA might be derived from tumor cells, only mutations with the first allele frequency pattern may be regarded as tumor-specific mutations in cfDNA. Effective filtering of background mutations will be required to improve the accuracy of mutation calls in cfDNA. Cancer 2018;124:1061-9. © 2017 American Cancer Society.