BACKGROUND Lung cancer (LC) is frequently associated with idiopathic pulmonary fibrosis (IPF). Despite this well-known association, the outcome of LC in patients with IPF is unclear. The objective of ...this study was to evaluate the impact of LC on survival of patients with associated IPF. METHODS A total of 260 patients with IPF were reviewed, and 186 IPF cases had complete clinical and follow-up data. Among these, five cases were excluded because LC was radiologically suspected but not histologically proven. The remaining 181 cases were categorized in two groups: 23 patients with biopsy-proven LC and IPF (LC-IPF) and 158 patients with IPF only (IPF). Survival and clinical characteristics of the two groups were compared. RESULTS Prevalence of histologically proven LC was 13%, and among those with LC-IPF cumulative incidence at 1 and 3 years was 41% and 82%. Patients with LC were more frequently smokers (91.3% vs 71.6%, P = .001), with combined pulmonary fibrosis and emphysema (52% vs 32%, P = .052). Survival in patients with LC-IPF was significantly worse than in patients with IPF without LC (median survival, 38.7 months vs 63.9 months; hazard ratio = 5.0; 95% CI, 2.91-8.57; P < .001). Causes of death in the study group were respiratory failure in 43% of patients, LC progression in 13%, and LC treatment-related complications in 17%. CONCLUSIONS In patients with IPF, LC has a significant adverse impact on survival. Diagnosis and treatment of LC in IPF are burdened by an increased incidence of severe complicating events, apparently as lethal as the cancer itself.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of ...the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
Objective The purpose of the present study was to compare the selection criteria and short-term outcomes among 3 prospective clinical trials using stereotactic body radiotherapy (Radiation Therapy ...Oncology Group RTOG trial 0236), sublobar resection (American College of Surgeons Oncology Group ACOSOG trial Z4032), and radiofrequency ablation (ACOSOG trial Z4033). Methods The selection criteria and outcomes were compared among RTOG 0236 (n = 55), ACOSOG Z4032 (n = 211), and ACOSOG Z4033 (n = 51). Age, Eastern Cooperative Oncology Group performance status, percentage of predicted forced expiratory volume in 1 second, and percentage of predicted carbon monoxide diffusing capacity of the lung were used to perform a propensity-matched analysis among patients with clinical stage 1A in RTOG 0236 and ACOSOG Z4032. Results The patients in ACOSOG Z4033 undergoing radiofrequency ablation were older (75.6 ± 7.5 years) than those in RTOG 0236 (72.5 ± 8.8 years) and ACOSOG Z4032 (70.2 ± 8.5 years; P = .0003). The pretreatment percentage of predicted forced expiratory volume in 1 second was 61.3% ± 33.4% for RTOG 0236, 53.8% ± 19.6% for ACOSOG Z4032, and 48.8% ± 20.3% for ACOSOG Z4033 ( P = .15). The pretreatment percentage of predicted carbon monoxide diffusing capacity of the lung was 61.6% ± 30.2% for RTOG 0236, 46.4% ± 15.6% for ACOSOG Z4032, and 43.7% ± 18.0% for ACOSOG Z4033 ( P = .001). The overall 90-day mortality for stereotactic body radiotherapy, surgery, and radiofrequency ablation was 0%, 2.4% (5/211), and 2.0% (1/51), respectively ( P = .5). Overall, the unadjusted 30-day grade 3+ adverse events were more common with surgery than with stereotactic body radiotherapy (28% vs 9.1%, P = .004), although no difference was between the 2 groups at 90 days. Among the patients with clinical stage IA in ACOSOG Z4032, 29.3% had a more advanced pathologic stage at surgery. A propensity-matched comparison showed no difference between stereotactic body radiotherapy and surgery for 30-day grade 3+ adverse events (odds ratio, 2.37; 95% confidence interval, 0.75-9.90; P = .18). Conclusions Among appropriately matched patients, no difference was seen in early morbidity between sublobar resection and stereotactic body radiotherapy. These results underscore the need for a randomized trial to delineate the relative survival benefit of each modality and to help stratify patients considered high risk.
Objective Video-assisted thoracoscopic lobectomy remains controversial. We compared outcomes from participants in a randomized study comparing lymph node sampling versus dissection for early-stage ...lung cancer who underwent either video-assisted thoracoscopic or open lobectomy. Methods Data from 964 participants in the American College of Surgeons Oncology Group Z0030 trial were used to construct propensity scores for video-assisted thoracoscopic versus open lobectomy (based on age, gender, histology, performance status, tumor location, and T1 vs T2). Propensity scores were used to estimate the adjusted risks of short-term outcomes of surgery. Patients were classified into 5 equal-sized groups and compared using conditional logistic regression or repeated measures analysis of variance. Results A total of 752 patients (66 video-assisted and 686 open procedures) were analyzed on the basis of propensity score stratification. Median operative time was shorter for video-assisted thoracoscopic lobectomy (video-assisted thoracoscopy 117.5 minutes vs open 171.5 minutes; P < .001). Median total number of lymph nodes retrieved (dissection group only) was similar (video-assisted thoracoscopy 15 nodes vs open 19 nodes; P = .147), as were instances of R1/R2 resection (video-assisted thoracoscopy 0% vs open 2.3%; P = .368). Patients undergoing video-assisted thoracoscopic lobectomy had less atelectasis requiring bronchoscopy (0% vs 6.3%, P = .035), fewer chest tubes draining greater than 7 days (1.5% vs 10.8%; P = .029), and shorter median length of stay (5 days vs 7 days; P < .001). Operative mortality was similar (video-assisted thoracoscopy 0% vs open 1.6%, P = 1.0). Conclusion Patients undergoing video-assisted lobectomy had fewer respiratory complications and shorter length of stay. These data suggest video-assisted thoracoscopic lobectomy is safe in patients with resectable lung cancer. Longer follow-up is needed to determine the oncologic equivalency of video-assisted versus open lobectomy.
Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it ...differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain.
We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing.
Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation.
In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.
Objective To determine whether mediastinal lymph node dissection improves survival compared with mediastinal lymph node sampling in patients undergoing resection for N0 or nonhilar N1, T1, or T2 ...non–small cell lung cancer. Methods Patients with non–small cell lung cancer underwent sampling of 2R, 4R, 7, and 10R for right-sided tumors and 5, 6, 7, and 10L for left-sided tumors. If all tumors were negative for malignancy, patients were randomized to no further lymph node sampling (mediastinal lymph node sampling) or complete mediastinal lymph node dissection. Results Of 1111 patients randomized, 1023 (mediastinal lymph node sampling in 498, mediastinal lymph node dissection in 525) were eligible and evaluable. There were no significant differences between the 2 groups in terms of demographics, Eastern Cooperative Oncology Group status, histology, cancer location, type or extent of resection, and pathologic stage. Occult N2 disease was found in 21 patients in the mediastinal lymph node dissection group. At a median follow-up of 6.5 years, 435 patients (43%) have died: mediastinal lymph node sampling in 217 (44%) and mediastinal lymph node dissection in 218 (42%). The median survival is 8.1 years for mediastinal lymph node sampling and 8.5 years for mediastinal lymph node dissection ( P = .25). The 5-year disease-free survival was 69% (95% confidence interval, 64–74) in the mediastinal lymph node sampling group and 68% (95% confidence interval, 64–73) years in the mediastinal lymph node dissection group ( P = . 92). There was no difference in local ( P = . 52), regional ( P = . 10), or distant ( P = . 76) recurrence between the 2 groups. Conclusions If systematic and thorough presection sampling of the mediastinal and hilar lymph nodes is negative, mediastinal lymph node dissection does not improve survival in patients with early stage non–small cell lung cancer, but these results are not generalizable to patients staged radiographically or those with higher stage tumors.
Accurate assessment of prognosis in idiopathic pulmonary fibrosis remains elusive due to significant individual radiological and physiological variability. We hypothesised that short-term ...radiological changes may be predictive of survival. We explored the use of CALIPER (Computer-Aided Lung Informatics for Pathology Evaluation and Rating), a novel software tool developed by the Biomedical Imaging Resource Laboratory at the Mayo Clinic Rochester (Rochester, MN, USA) for the analysis and quantification of parenchymal lung abnormalities on high-resolution computed tomography. We assessed baseline and follow-up (time-points 1 and 2, respectively) high-resolution computed tomography scans in 55 selected idiopathic pulmonary fibrosis patients and correlated CALIPER-quantified measurements with expert radiologists' assessments and clinical outcomes. Findings of interval change (mean 289 days) in volume of reticular densities (hazard ratio 1.91, p=0.006), total volume of interstitial abnormalities (hazard ratio 1.70, p=0.003) and per cent total interstitial abnormalities (hazard ratio 1.52, p=0.017) as quantified by CALIPER were predictive of survival after a median follow-up of 2.4 years. Radiologist interpretation of short-term global interstitial lung disease progression, but not specific radiological features, was also predictive of mortality. These data demonstrate the feasibility of quantifying interval short-term changes on high-resolution computed tomography and their possible use as independent predictors of survival in idiopathic pulmonary fibrosis.
Objective Surgical resection has been the mainstay of curative treatment of early stage lung cancer in selected patients. We evaluated survival and patterns of recurrence after surgical resection for ...early stage lung cancer from the American College of Surgeons Oncology Group Z0030/Alliance trial. Methods One thousand eighteen patients enrolled in the Z0030 trial were analyzed according to clinical T stage. Differences between groups were compared using the 2-sample rank test or χ2 test. Log rank test and Cox proportional hazards regression were used to compare survival and recurrence. To compare patients who underwent open versus video-assisted thoracoscopic surgery (VATS) resections, propensity-score matched analysis was performed. Seven hundred fifty-two patients (66 undergoing VATS and 686 undergoing open surgery) were classified into 5 equal-sized propensity-score groups. Proportional hazards regression was used to compare these outcomes. Results There were 578 patients with cT1 tumors and 440 patients with cT2 tumors. Median follow-up was 6.7 years. Median overall survival was 9.1 years (stage T1) and 6.5 years (stage T2). Overall survival at 5 years was 72% (stage T1) and 55% (stage T2). Local recurrence-free survival at 5 years was 95% (stage T1) and 91% (stage T2) ( P = .015). Among patients with stage T1 cancer, 4.2% (23 out of 542) had local recurrences, whereas 7.3% (30 out of 409) of those with stage T2 tumors had local failure. There was no difference in the development of new primary tumors between stage T1 and stage T2 groups. In the propensity-score matched analysis of VATS versus open lobectomy patients, there was no difference in overall survival, disease-free survival, and freedom from development of a new primary tumor. Conclusions Results of patients with resected early stage non–small cell carcinoma from a large-scale, multicenter trial serve as benchmarks against which to compare nonsurgical therapies for early stage lung cancer. Propensity-score matched analysis shows no difference in survival between patients undergoing VATS and open lobectomy.
Abstract Assessment of patient quality of life (QOL) requires balancing the details provided by multi-item assessments with the reduced burden of single-item assessments. In this project, we ...investigated the psychometric properties of single-item Linear Analog Scale Assessments (LASAs) for patients with newly diagnosed high-grade gliomas. Measures included QOL LASAs (overall, physical, emotional, spiritual, intellectual), Symptom Distress Scale (SDS), Profile of Mood States (POMS; overall, confusion, fatigue), and Functional Assessment of Cancer Therapy-Brain (FACT-Br; overall, brain, physical, emotional). Associations of LASA measures with SDS, POMS, and FACT-Br domains and with Eastern Cooperative Oncology Group performance score (PS) and Mini-Mental State Examination (MMSE) were assessed. Repeated measures ANOVA models compared the change over time of LASAs and SDS, POMS, and FACT-Br. Two hundred five patients completed the assessments across three time points. To allow comparison across measures, all scores were converted to a scale of 0–100, with higher scores indicating better QOL. LASA mean scores ranged from 60 to 78; SDS, POMS, and FACT-Br ranged from 62 to 81. FACT-Br physical ( P < 0.001) and POMS fatigue subscale ( P = 0.005) decreased over time, as did LASA physical ( P = 0.08). LASA scales were strongly associated with corresponding scales on SDS, POMS, and FACT-Br (0.44 < rho < 0.65; P < 0.001). LASA was negatively associated with PS and positively with MMSE, with associations similar in magnitude to the other QOL and psychosocial measures. The data suggest that the single-item LASA scales are valid for assessing QOL of cancer patients and are an appropriate alternative when a shorter instrument is warranted.
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