The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).
We ...identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic LEP, acinar or papillary ACI/PAP, and micropapillary or solid MIP/SOL). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.
MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).
These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
AKI associated with cardiac surgery Thiele, Robert H; Isbell, James M; Rosner, Mitchell H
Clinical journal of the American Society of Nephrology,
2015-Mar-06, Letnik:
10, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Approximately 18% of patients undergoing cardiac surgery experience AKI (on the basis of modern standardized definitions of AKI), and approximately 2%-6% will require hemodialysis. The development of ...AKI after cardiac surgery portends poor short- and long-term prognoses, with those developing RIFLE failure or AKI Network stage III having an almost 2-fold increase in the risk of death. AKI is caused by a variety of factors, including nephrotoxins, hypoxia, mechanical trauma, inflammation, cardiopulmonary bypass, and hemodynamic instability, and it may be affected by the clinician's choice of fluids and vasoactive agents as well as the transfusion strategy used. The risk of AKI may be ameliorated by avoidance of nephrotoxins, achievement of adequate glucose control preoperatively, and use of goal-directed therapy hemodynamic strategies. Remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation. Unfortunately, there are no pharmacologic agents known to reduce the risk of AKI or treat established AKI.
Surgeons are increasingly asked to operate on patients with residual disease after immunotherapy. The safety and utility of lung resection in this setting are unknown.
We retrospectively reviewed ...patients who underwent lung resection within 6 months of treatment with checkpoint blockade agents for metastatic or unresectable cancer. Survival was estimated from the first resection using the Kaplan-Meier approach.
Database query identified 19 patients who underwent 22 resections for suspected residual disease with therapeutic intent after immunotherapy between 2012 and 2016. Lung cancer was the most common diagnosis (47%), followed by metastatic melanoma (37%). The most frequently used agents were nivolumab (32%), pembrolizumab (32%), and ipilimumab (16%). Patients received a mean of 21 doses (range, 1 to 70 doses). The final dose was administered at an average of 75 days (range, 7 to 183 days) before the operation. Anatomic resection (lobectomy or greater) was performed in 11 patients (50%). Four lobectomies were attempted minimally invasively, and one required conversion to thoracotomy. Of the resected patients, 68% had viable tumor remaining. R0 resection was achieved in 95%. Mean operative time for lobectomy was 227 minutes (range, 150 to 394 minutes). Complications occurred in 32% of patients; all but 1 were minor (grade 1/2). The 2-year overall and disease-free survival were 77% and 42%, respectively.
In patients with previously metastatic or unresectable cancer, lung resection for suspected residual disease after immunotherapy is feasible, with high rates of R0 resection. Operations can be technically challenging, but significant morbidity appears to be rare. Outcomes are encouraging, with reasonable survivals during short-interval follow-up.
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of ...circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (
= 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders 5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35;
= 0.007 and HR 6.91; 95% CI, 1.37-34.97;
= 0.02, respectively, which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (
= 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.
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To minimize the stress of operations, improve the patient experience, reduce variability, and optimize resource utilization, we implemented a thoracic enhanced recovery after surgery (ERAS) protocol ...and evaluated progress after 1 year.
Two protocols were developed: video-assisted thoracic surgery (ERAS-VATS) and thoracotomy (ERAS-T). Each incorporated preoperative patient education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, and early ambulation. Patient outcomes, length of stay, pain scores, opioid use, fluid administration, and cost for ERAS patients were compared with historic controls from the year before program initiation.
Historic VATS (n = 162) were compared with 81 ERAS-VATS patients. Median postoperative morphine equivalents (86 versus 22 mg, p < 0.0001), total fluid balance (1279 versus 227 mL, p < 0.0001), and mean inflation adjusted hospital costs ($20,169 versus $14,870, p = 0.0003) all decreased significantly. Historic thoracotomy patients (n = 62) were compared with 58 ERAS-T patients. Median postoperative morphine equivalents (130 versus 54 mg, p < 0.0001), total fluid balance (788 versus −489 mL, p = 0.012), length of stay (6.0 versus 4.0 days, p = 0.009), and mean inflation adjusted hospital costs ($41,950 versus $26,089, p < 0.00001) all decreased significantly.
Implementation of thoracic ERAS is a dynamic process with potential to improve outcomes in thoracic surgical procedures. In the first year we shortened length of stay, decreased opioid usage, minimized fluid overload, and decreased hospital costs.
We conducted a phase I trial of neoadjuvant nivolumab, a monoclonal antibody to the programmed cell death protein 1 checkpoint receptor, in patients with resectable non–small cell lung cancer. We ...analyzed perioperative outcomes to assess the safety of this strategy.
Patients with untreated stage I-IIIA non–small cell lung cancer underwent neoadjuvant therapy with 2 cycles of nivolumab (3 mg/kg), 4 and 2 weeks before resection. Patients underwent invasive mediastinal staging as indicated and post-treatment computed tomography. Primary study end points were safety and feasibility of neoadjuvant nivolumab followed by pulmonary resection. Data on additional surgical details were collected through chart review.
Of 22 patients enrolled, 20 underwent resection. One was unresectable; another had small cell histologic subtype. There were no delays to surgical resection. Median time from first treatment to surgery was 33 (range, 17-43) days. There were 15 lobectomies, 2 pneumonectomies, 1 bilobectomy, 1 sleeve lobectomy, and 1 wedge resection. Of 13 procedures attempted via a video-assisted thoracoscopic surgery or robotic approach, 7 (54%) required thoracotomy. Median operative time was 228 (range, 132-312) minutes; estimated blood loss was 100 (range, 25-1000) mL; length of hospital stay was 4 (range, 2-17) days. There was no operative mortality. Morbidity occurred in 10 of 20 patients (50%). The most common postoperative complication was atrial arrhythmia (6/20; 30%). Major pathologic response was identified in 9 of 20 patients (45%).
Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality. More than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.
Purpose To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I ...non-small-cell lung cancer (NSCLC). Patients and Methods Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis. Results Of 2,186 patients, 1,532 (70.1%) were ≥ 65 years of age, including 638 (29.2%) ≥ 75 years of age. In patients < 65, 65 to 74, and ≥ 75 years of age, 5-year lung cancer-specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients ≥ 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer-specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients ≥ 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity ( P < .001), 1-year mortality ( P < .001), and noncancer-specific mortality ( P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer-specific mortality ( P = .002). Conclusion In patients who undergo curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases.
Acute kidney injury (AKI) occurs in 20% of patients following cardiac surgery. To reduce AKI in our institution, we instituted a quality improvement (QI) initiative using a goal-directed volume ...resuscitation protocol. Our protocol was designed to achieve quantifiable physiologic goals (eg, cardiac index > 2.5 L/min/m2, mean arterial pressure > 65 mm Hg) using fluid and vasoactive agents. The objective of this study was to evaluate AKI in the pre- and post-QI eras, hypothesizing that AKI incidence would decrease in the post-QI era.
In this observational retrospective cohort study, we identified patients who underwent cardiac operations from July 2011 to July 2015 with a risk score available. Kidney injury was determined using the lowest postoperative GFR within 7 days of surgery and standard Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease (RIFLE) classification criteria. The primary outcome was the rate of AKI, as defined by glomerular filtration rate-based RIFLE classification criteria injury, in the post- versus pre-QI eras.
A total of 1979 patients were included, of whom 725 were in the pre-QI cohort, and 1254 in the post-QI cohort. Overall, rates of RIFLE classification criteria risk, injury and failure were 27.5%, 5.9%, and 3.6%, respectively. RIFLE classification criteria injury saw the largest decrease in the post-QI cohort (8.1% vs 4.6%; P = .001). Multivariable analysis demonstrated a 37% reduction in the odds of AKI in the post-QI cohort (adjusted odds ratio, 0.63; 95% confidence interval, 0.43-0.90).
A goal-directed volume resuscitation protocol centered on patient fluid responsiveness is associated with significantly reduced risk for AKI after cardiac surgery. Protocol-driven approaches should be employed in intensive care units to improve outcomes.
Background Postoperative death is an important outcome after esophagectomy, and the Centers for Medicare & Medicaid Services currently uses 30-day mortality as a quality indicator for this operation. ...However, 30-day mortality may underestimate a patient's true postoperative death risk. The purpose of this study was to evaluate different mortality definitions using a large registry of patients undergoing esophagectomy for cancer. Methods Data were extracted from the Surveillance, Epidemiology and End Results-Medicare registry for patients with esophageal cancer who underwent esophagectomy between 2006 and 2009. Postoperative death was compared using four different definitions: 30-day, in-hospital, perioperative (in-hospital or 30-day), and 90-day mortality. Hierarchical logistic regression models evaluated the association between patient and tumor characteristics with survival at 30 and 90 days and the ability of death to differentiate between good hospitals and those that perform poorly. Results We identified 634 patients from 188 hospitals. The 90-day mortality rate (13.3%) was more than double the 30-day mortality rate (6.0%) in this patient population. Advanced age and diagnosis of chronic obstructive pulmonary disease were associated with an increased risk of 90-day mortality. Good or poor performers could not be determined using the 30-day or 90-day mortality rate. Conclusions There are clinically meaningful differences between postoperative mortality definitions after esophagectomy. Thirty-day mortality significantly underestimates a patient's true risk of death because this number more than doubles at 90 days in this elderly, Medicare population. Although neither 90-day nor 30-day mortality are adequate quality measures after esophagectomy, 90-day mortality is a better outcome measure because it provides a better understanding of true death risk for the surgeon and patient.
Abstract
Background
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity ...of prospective data to support its use.
Methods
Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided.
Results
Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI = 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI = 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI = 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI = 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response.
Conclusions
Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines.
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