Paul A. Decker

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.

The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component–adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10−6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 × 10−8, replication P = 0.0038 and combined P = 1.85 × 10−10. On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 × 10−7, replication P = 0.00035 and combined P = 3.40 × 10−9. For both SNPs, the direction of association was the same in discovery and replication phases.

Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: Results of the American College of Surgery Oncology Group Z0030 Trial

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.

Video-assisted thoracic surgery versus open lobectomy for lung cancer: a secondary analysis of data from the American College of Surgeons Oncology Group Z0030 randomized clinical trial.

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.

Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts

Temozolomide (TMZ)-based therapy is the standard of care for patients with glioblastoma multiforme (GBM), and resistance to this drug in GBM is modulated by the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). Expression of MGMT is silenced by promoter methylation in approximately half of GBM tumors, and clinical studies have shown that elevated MGMT protein levels or lack of MGMT promoter methylation is associated with TMZ resistance in some, but not all, GBM tumors. In this study, the relationship between MGMT protein expression and tumor response to TMZ was evaluated in four GBM xenograft lines that had been established from patient specimens and maintained by serial subcutaneous passaging in nude mice. Three MGMT unmethylated tumors displayed elevated basal MGMT protein expression, but only two of these were resistant to TMZ therapy (tumors GBM43 and GBM44), while the other (GBM14) displayed a level of TMZ sensitivity that was similar in extent to that seen in a single MGMT hypermethylated line (GBM12). In tissue culture and animal studies, TMZ treatment resulted in robust and prolonged induction of MGMT expression in the resistant GBM43 and GBM44 xenograft lines, while MGMT induction was blunted and abbreviated in GBM14. Consistent with a functional significance of MGMT induction, treatment of GBM43 with a protracted low-dose TMZ regimen was significantly less effective than a shorter high-dose regimen, while survival for GBM14 was improved with the protracted dosing regimen. In conclusion, MGMT expression is dynamically regulated in some MGMT nonmethylated tumors, and in these tumors, protracted dosing regimens may not be effective.

Risk assessment of hemorrhagic complications associated with nonsteroidal antiinflammatory medications in ambulatory pain clinic patients undergoing epidural steroid injection.

We prospectively studied 1035 individuals undergoing 1214 epidural steroid injections to determine the risk of hemorrhagic complications. A history of bruising or bleeding was present in 176 (15%) patients. A platelet count was assessed in 77 patients before the epidural steroid injection; none was less than 100 × 109/L. Nonsteroidal antiinflammatory drugs (NSAIDs) were reported by 383 (32%) patients, including 34 patients on multiple medications. Aspirin was the most common NSAID and was noted by 158 patients, including 104 patients on 325 mg or less per day. There were no spinal hematomas (major hemorrhagic complications). Blood was noted during needle or catheter placement in 63 (5.2%) patients (minor hemorrhagic complications). NSAIDs did not increase the frequency of minor hemorrhagic complications. However, increased age, needle gauge, needle approach, needle insertion at multiple interspaces, number of needle passes, volume of injectant, and accidental dural puncture were all significant risk factors for minor hemorrhagic complications. There were 42 patients with new neurologic symptoms or worsening of preexisting complaints that persisted more than 24 h after injection; median duration of the symptoms was 3 days (range, 1–20 days). Our results confirm those of previous studies performed in obstetric and surgical populations that document the safety of neuraxial techniques in patients receiving NSAIDs. We conclude that epidural steroid injection is safe in patients receiving aspirin-like antiplatelet medications. Minor worsening of neurologic function may occur after epidural steroid injection and must be differentiated from etiologies requiring intervention.

Pleural Fluid Characteristics of Chylothorax

OBJECTIVE To determine the biochemical parameters of chylous pleural fluids and better inform current clinical practice in the diagnosis of chylothorax. PATIENTS AND METHODS We retrospectively reviewed 74 patients with chylothorax (defined by the presence of chylomicrons) who underwent evaluation during a 10-year period from January 1, 1997, through December 31, 2006. The biochemical parameters and appearance of the fluid assessed during diagnostic evaluation were analyzed. RESULTS The study consisted of 37 men (50%) and 37 women (50%), with a median age of 61.5 years (range, 20-93 years). Chylothorax was caused by surgical procedures in 51%. The chylous pleural fluid appeared milky in only 44%. Pleural effusion was exudative in 64 patients (86%) and transudative in 10 patients (14%). However, pleural fluid protein and lactate dehydrogenase levels varied widely. Transudative chylothorax was present in all 4 patients with cirrhosis but was also seen with other causes. The mean ± SD triglyceride level was 728±797 mg/dL, and the mean ± SD cholesterol value was 66±30 mg/dL. The pleural fluid triglyceride value was less than 110 mg/dL in 10 patients (14%) with chylothorax, 2 of whom had a triglyceride value lower than 50 mg/dL. CONCLUSION Chylothoraces may present with variable pleural fluid appearance and biochemical characteristics. Nonmilky appearance is common. Chylous effusions can be transudative, most commonly in patients with cirrhosis. Traditional triglyceride cutoff values used in excluding the presence of chylothorax may miss the diagnosis in fasting patients, particularly in the postoperative state.

Treatment of stage I lung cancer in high-risk and inoperable patients: Comparison of prospective clinical trials using stereotactic body radiotherapy (RTOG 0236), sublobar resection (ACOSOG Z4032), and radiofrequency ablation (ACOSOG Z4033)

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.

Tobacco Use Outcomes Among Patients With Lung Cancer Treated for Nicotine Dependence

PURPOSE There is a current lack of consensus about the effectiveness of nicotine dependence treatment for cancer patients. This retrospective study examined the 6-month tobacco abstinence rate among lung cancer patients treated clinically for nicotine dependence. PATIENTS AND METHODS A date-of-treatment matched case control design was used to compare lung cancer patients (201 lung cancer patients, 41% female) and nonlung cancer patients (201 controls, 45% female) treated in the Mayo Clinic Nicotine Dependence Center between 1988 and 2000. The intervention involves a brief consultation with a nicotine dependence counselor. A treatment plan individualized to the patients needs is then developed. The primary end point was the self-reported, 7-day point prevalence abstinence from tobacco at 6-month follow-up. RESULTS At baseline, compared with the controls, the lung cancer patients were significantly older (P <.001), reported higher motivation to stop smoking (P =.003), and were at a higher stage of change (P =.002). The 6-month tobacco abstinence rate was 22% for the lung cancer patients compared with 14% of the control patients (P =.024). After adjusting for age, sex, baseline cigarettes smoked per day, and stage of change, no significant difference was detected between lung cancer patients and controls on the tobacco abstinence rate. CONCLUSION The results suggest that nicotine dependence treatment is effective for patients with a diagnosis of lung cancer. The majority of lung cancer patients were motivated to stop smoking.

The impact of lung cancer on survival of idiopathic pulmonary fibrosis.

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.