Immune and Circulating Tumor DNA Profiling After Radiation Treatment for Oligometastatic Non-Small Cell Lung Cancer: Translational Correlatives from a Mature Randomized Phase II Trial.

PURPOSE: NCT01725165 was a phase II prospective trial in which patients with non-small cell lung cancer were randomized to local consolidative therapy (LCT) versus maintenance therapy or observation (MT/O). METHODS AND MATERIALS: Peripheral blood from patients enrolled on NCT01725165 were labeled as (1) baseline, (2) early follow-up (FU) if obtained in the first or second FU evaluation (6-18 weeks), and (3) late FU if obtained in the third to sixth FU evaluations (22-50 weeks). All patients who underwent LCT and were included in this analysis received radiation. Among 49 randomized patients, 21 patients underwent T cell CDR3 variable region sequencing using immunoSEQ, 31 patients underwent circulating tumor DNA (ctDNA) analysis using next-generation sequencing with a 1021 cancer gene panel, and cytokine concentration was assayed in 19 patients using enzyme-linked immunosorbent assay. All analyses were exploratory and not corrected for multiple testing. RESULTS: No associations were identified between baseline T cell repertoire and ctDNA metrics with patient outcomes. Among baseline cytokines, interleukin 1α was the only cytokine associated with both overall survival (hazard ratio, 0.02; 95% confidence interval, 0.1-0.5; P = .0006) and progression-free survival (hazard ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .03). At early FU, LCT was associated with decreased ctDNA burden, including lower number of detected mutations (median, 2 [interquartile range {IQR}, 1-6] vs 6 [IQR, 4-18]) and decreased average variable allele frequency (VAF; median, 0.006 [IQR, 0.003-0.010] vs 0.011 [IQR, 0.007-0.014]) compared with MT/O. Among 6 patients with serial ctDNA analysis, a rise in ctDNA detected mutation burden preceded clinical progression by 6.7 months. At early FU, LCT was associated with changes in T cell clonality that suggested oligoclonal expansion specifically increased T cell clonality (median, 0.15 [IQR, 0.12-0.24] vs 0.10 [IQR, 0.05-0.13]) and frequency of top 10 clones (median, 0.14 [IQR, 0.06-0.18] vs 0.21[IQR, 0.19-0.28]). CONCLUSION: LCT was associated with decreased ctDNA burden and oligoclonal expansion at early FU timepoints. Baseline interleukin 1α was associated with improved patient outcomes.

Postoperative Urinary Tract Infection Quality Assessment and Improvement: The S.T.O.P. UTI Program and Its Impact on Hospitalwide CAUTI Rates.

BACKGROUND: Postoperative urinary tract infection (UTI) is a frequent complication that diminishes patient experience and incurs substantial costs. The purpose of this project was to develop a urinary tract care assessment tool that would lead to actionable quality improvement initiatives. METHODS: Multidisciplinary teams at a single institution developed the S.T.O.P. UTI algorithm to assess elements related to urinary catheter care: Sterile catheter placement, Timely catheter removal, Optimal collection bag position, and Proper urine sampling for urinalysis and culture. Based on this evaluation, a targeted intervention was applied to address deficient areas in surgical patients. UTI rates were monitored. RESULTS: The assessment revealed that best practice for sterile placement was being performed but that time to removal, optimal positioning, and proper sampling could be improved. Providers were educated on best practice for catheter removal, nurses placed a reminder note on the chart, personnel were taught about optimal catheter positioning, and nursing assistants were educated on best practices for collection of urine. From 2012 to 2015, non-risk-adjusted UTI rates in surgical patients decreased from 2.90% to 0.46% (p = 0.0003), and the American College of Surgeons National Surgical Quality Improvement Program risk-adjusted comparison improved from the 8th to the 4th decile. Simultaneously, hospitalwide catheter-associated UTI rates also decreased, from 2.24/1,000 catheter-days in 2014 to 0.70/1,000 catheter-days in 2016 (p < 0.001). CONCLUSION: The S.T.O.P. UTI algorithm is a tool that hospitals can use to systematically assess UTI processes. The program can identify areas for improvement specific to an institution, directing the allocation of quality improvement resources to decrease both surgical and medical UTIs.

Validation of a proliferation-based expression signature as prognostic marker in early stage lung adenocarcinoma.

PURPOSE: New prognostic markers to guide treatment decisions in early stage non-small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer-related death in patients with early stage lung adenocarcinoma. EXPERIMENTAL DESIGN: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Director's Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. RESULTS: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Director's Consortium cohort (P = 0.00014; HR = 2.08; 95% CI, 1.43-3.02) and GSE31210 (P = 0.0010; HR = 2.25; 95% CI, 1.42-3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables (P = 0.0022; HR = 2.02; 95% CI, 1.29-3.17 in Director's Consortium, P = 0.0026; HR = 2.16; 95% CI, 1.32-3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate (P = 0.00033; HR = 2.10; 95% CI, 1.39-3.17) and multivariate analyses (P = 0.0071; HR = 1.92; 95% CI, 1.18-3.10). CONCLUSIONS: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and may be a valuable tool in selecting patients for adjuvant treatment.

Diaphragmatic hernia after esophagectomy in 440 patients with long-term follow-up.

BACKGROUND: Postesophagectomy diaphragmatic hernia (PDH) is a recognized but severely under-reported and potentially hazardous event. Information regarding the natural course of this condition and guidelines regarding indications for reoperative intervention are lacking. In this study we aim to describe the frequency, predictors of incidence, and indications for repair. METHODS: Cross-sectional imaging (computed tomography scan) from patients who underwent esophagectomy between January 2001 and December 2007 at a single center were reviewed by two radiologists blinded to previous reports and clinical outcomes. Patients with PDH were compared with a similar cohort who did not have hernia. Patient characteristics, outcomes, and hernia descriptors including longitudinal progression were recorded. Multivariable logistic regression analyses identified predictors of PDH and need for repair. RESULTS: Of a total of 440 patients who underwent esophagectomy, 67 (15%) were radiologically diagnosed with PDH. Of these, only 7 of 67 cases (10%) were prospectively reported by the radiologist. Median time interval from esophagectomy to hernia was 2 years. Type of esophagectomy was an independent predictor for hernia developing (p = 0.027). Patients with high body mass index were less prone to have PDH (p = 0.043). Thus far, 9 patients (2%) have required surgical intervention, all for hernia-related symptoms or progression. Despite mesh repair, 4 of 9 have recurred and 2 were re-repaired. There was 1 PDH-associated death, 8 years after transhiatal resection. CONCLUSIONS: Variables contributing to PDH are both technical and patient dependent. Whereas the majority of patients with PDH have not required repair, a small portion who became symptomatic or had large, progressive hernia required remedial surgery. Postesophagectomy patients require long-term surveillance for PDH.

Esophageal cancer dose escalation using a simultaneous integrated boost technique.

PURPOSE: We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer. METHODS AND MATERIALS: Treatment plans were generated using four different approaches (two-dimensional conformal radiotherapy [2D-CRT] to 50.4 Gy, 2D-CRT to 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure. RESULTS: The 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). CONCLUSIONS: The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation.

Propensity-matched analysis of three techniques for intrathoracic esophagogastric anastomosis.

BACKGROUND: A cervical side-to-side stapled esophagogastric anastomosis appears to decrease morbidity compared with traditional hand-sewn techniques. We evaluated our experience with this novel technique in intrathoracic anastomoses and compared the outcome with circular-stapled or hand-sewn techniques. METHODS: All patients undergoing transthoracic esophagectomy from 1999 to 2005 for esophageal cancer with gastric replacement were reviewed. A prospective quality improvement database, telephone interview, and chart review were used to collect data. A side-to-side stapled anastomosis was done in 44 patients, circular-stapled anastomosis in 147, and hand-sewn anastomosis in 23. Propensity scores were generated from 14 variables, which were then used to generate 23 patient triplets. End points included leak, dysphagia, stricture, other major complications, and overall survival. Follow-up was available on all patients. RESULTS: For matched triplet comparison, no significant difference was noted in anastomotic leaks (8.7% with side-to-side stapled, 4.3% with circular-stapled, and 4.3% with hand-sewn; p = 0.78). Postoperative dysphagia was significantly higher in hand-sewn anastomoses at 56.5% versus 26.1% with side-to-side stapled and 21.7% with circular-stapled (p = 0.04). Stricture requiring esophageal dilation was also increased in hand-sewn at 34.8% versus 8.7% with side-to-side stapled and 8.7% with circular-stapled (p = 0.04). No difference was noted in perioperative mortality, long-term survival, or locoregional recurrences between techniques. CONCLUSIONS: In this carefully matched group of patients, intrathoracic use of the side-to-side stapled esophagogastric anastomosis in esophageal cancer patients is safe and effective. Postoperative dysphagia and need for stricture dilation may be decreased using a stapled compared with a traditional hand-sewn anastomosis.

Impact of cyclin D1 A870G polymorphism in esophageal adenocarcinoma tumorigenesis.

The dramatically increased incidence and poor survival rates of esophageal adenocarcinoma (EAC) underscore the need for novel targets useful for risk assessment and therapeutic intervention. Altered expression of cyclin D1 has been proposed as an early predictor for malignant transformation in EAC; however, the mechanisms underlying cyclin D1 deregulation have not been identified. A single nucleotide polymorphism, A870G, of the cyclin D1 gene has been associated with the preferential encoding of a protein with an extended half-life. We investigated the association of the cyclin D1 A870G polymorphism with cyclin D1 protein expression and clinical characteristics and outcome in 124 patients treated at our institution for EAC. Our results indicate that the cyclin D1 AA/AG genotype is associated with earlier age of cancer onset, cyclin D1 protein deregulation in the primary tumors, and increased frequency of distant metastasis. Our findings suggest that cyclin D1 status could be useful to assess risk of progression to EAC, and strategies directed to modulate cyclin D1 expression may prove useful for interventions to slow or interrupt the EAC tumorigenesis process.

Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report.

PURPOSE: To evaluate tumor resectability after induction chemotherapy and to determine disease-free and overall survival rates of patients with locally advanced unresectable thymoma that received a multimodal treatment regimen. PATIENTS AND METHODS: Twenty-two patients (9 men, 13 women) with histologically confirmed invasive thymoma were treated with a multidisciplinary regimen consisting of three courses of induction chemotherapy, surgical resection, and radiation therapy, followed by three courses of consolidation chemotherapy. The median age was 47 years (range, 25-70). Eleven patients had stage III disease, 10 patients, stage IVA, and one patient, IVB. The most common histologic type was lymphocytic. Induction chemotherapy consisted of 500 mg/m(2) of cyclophosphamide on day 1; doxorubicin (20 mg/m(2) per day) on days 1-3 via continuous infusion (a total of 60 mg/m(2)); cisplatin (30 mg/m(2) per day) on days 1-3 (a total of 90 mg/m(2)); and prednisone (100 mg per day) on days 1-5. This cycle was repeated three times at 3-4-week intervals. Patients then underwent surgery for tumor resection and received radiotherapy. Consolidation chemotherapy given at 80% of the induction chemotherapy doses of cyclophosphamide, doxorubicin, and cisplatin and 100% of the dose of prednisone was then repeated every 3-4 weeks for a total of three courses. RESULTS: Induction chemotherapy produced major responses in 17 (77%) of the 22 patients including 3 (14%) complete responses (CR) and 14 (63%) partial responses (PR). Twenty-one patients underwent surgical exploration: 16 (76%) had complete resection and 5 (24%) had incomplete resection; one patient refused surgery. All 22 patients received radiation therapy. Nineteen of 22 patients completed the planned therapy, and all but one had completed consolidation chemotherapy at the time of analysis. With a median follow-up time of 50.3 months, 18 of the 19 patients who completed the multidisciplinary approach were disease-free. Of the 22 patients originally registered, 20 were alive at the time of analysis (one patient died of endocarditis, and one died of recurrent disease). The overall survival rate was 95% at 5 years (95% confidence interval (CI), 0.87-1.0) and 79% at 7 years (95% CI, 0.55-1.0). The progression-free survival rates were 77% at 5 years (95% CI, 0.58-1.0) and 77% at 7 years (95% CI, 0.58-1.0). The major side effect from induction and consolidation chemotherapy was myelosuppression. Nine patients experienced grade III/IV neutropenia, which included neutropenic fever in two patients, and grade III thrombocytopenia in two patients. The most common nonhematologic side effects were fatigue, nausea and vomiting, and decreased appetite. One patient experienced acute respiratory distress syndrome after surgical resection and required a prolonged hospitalization. No patients developed cardiac toxic effects, and no surgical mortality occurred. CONCLUSIONS: The use of induction chemotherapy to optimize surgical resectability of thymoma followed by radiation therapy and consolidation chemotherapy lead to good control of residual disease and high overall survival rates. We believe that this combined multidisciplinary approach prolongs lives and may cure locally advanced unresectable malignant thymomas. Future prospective multi-institutional studies are needed to further verify or define the best treatment for this patient population.