Summary Background Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with ...untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). Methods In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov , number NCT02085070. Findings Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7–48) of 18 patients with melanoma and six (33%; 14–59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3–4 adverse events were grade 3 elevated aminotransferases (n=1 6%) in the melanoma cohort, and grade 3 colitis (n=1 6%), grade 3 pneumonitis (n=1 6%), grade 3 fatigue (n=1 6%), grade 4 hyperkalemia (n=1 6%), and grade 2 acute kidney injury (n=1 6%) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1–2 seizures (n=3 17%) in the melanoma cohort. Interpretation Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.
Thymic carcinoma outcomes and prognosis: Results of an international analysis Ahmad, Usman, MD; Yao, Xiaopan, PhD; Detterbeck, Frank, MD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
2015, January 2015, 2015-Jan, 2015-01-00, 20150101, Letnik:
149, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Objectives The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free ...survival (RFS). Methods Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures. Results In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval CI, 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS. Conclusions R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS.
Objective Primary neuroendocrine tumors of the thymus (TNET) are exceedingly rare. We studied a large series of TNET identified through the International Thymic Malignancy Interest Group and the ...European Society of Thoracic Surgeons databases. Methods This was a retrospective multicenter study of patients undergoing operation for TNET between 1984 and 2012. Outcome measures were: overall survival (OS) and cumulative incidence of recurrences (CIR). OS was analyzed using the Kaplan-Meier method and CIR was analyzed using competing risk analysis. Associations with clinical and prognostic factors for OS and CIR were evaluated using the log rank test and Gray test. Results Two hundred five patients with TNET were treated: 25 patients received induction therapy (19 chemotherapy CT and 6 radiotherapy RT). Data about resection status were available in 47% of cases: complete resection was performed in 52 patients (54%). Masaoka-Koga stages I, II, III, and IV were observed in 12, 33, 56, and 47 patients, respectively. Atypical carcinoid was the commonest histologic subtype (71 cases; 40%). One hundred one patients with TNET received adjuvant treatment; 52 patients died and 36 experienced a recurrence. The median OS was 7.5 years; 5-year OS was 68%, and 5-year CIR was 39%. OS was significantly influenced by Masaoka-Koga stage ( P = .02) and completeness of resection ( P = .03). CIR significantly increased in high Masaoka-Koga stages ( P = .04). Histologic subtype was not associated with either OS or CIR. Conclusions Our results confirm the high biologic aggressiveness of these rare neoplasms; pathologic stage and completeness of resection were demonstrated to be strong prognostic factors, whereas histology did not influence patients outcome.
Background The survival of untreated non-small cell lung cancer (NSCLC), or the natural history, is an important perspective for patients considering resection for NSCLC. The National Cancer Database ...(NCDB) allows untreated NSCLC patients who were recommended to undergo surgical resection (ie, “operable”) to be identified. The survival of untreated NSCLC patients in the NCDB was studied to determine the natural history of operable NSCLC. Methods The NCDB was queried for untreated clinical stage I to IIIA NSCLC patients diagnosed between 2003 and 2009. The natural history cohort was defined as patients who were recommended to undergo resection but went untreated. Results We identified 1,693 untreated patients with operable NSCLC. The median survival for clinical stage I, II, and IIIA was 16.6, 9.4, and 8.4 months, respectively. The 5-year Kaplan-Meier estimates of survival for clinical stage I, II, and IIIA NSCLC were 10.1%, 7.3%, and 4.9%, respectively. At each stage (I to IIIA), the survival of untreated operable NSCLC patients was superior to that of untreated NSCLC patients not recommended to undergo resection (nonoperable, p < 0.001). A multivariable Cox regression model identified increasing age, male gender, white (vs black) race, increasing comorbidity, squamous cell or large cell histology, and increasing stage as predictors of decreased survival. Conclusions The natural history of operable NSCLC, although poor, varies with clinical stage and is superior to that of nonoperable NSCLC.
Background Preoperative chemotherapy improves the survival of surgically managed stage III non-small cell lung cancer (NSCLC). A proportion of stage III NSCLC patients in the United States have ...undergone operations primarily and been given chemotherapy postoperatively. It is unclear whether postoperative chemotherapy is as effective as preoperative chemotherapy. Our objective was to determine the survival of resected stage III NSCLC according to the timing of chemotherapy. Methods The National Cancer Database (NCDB) was queried for clinical T1–4N2M0 NSCLC (cstage III–cN2) undergoing lobectomy or pneumonectomy between 2003 and 2006. Results 1,356 patients with surgically managed cstage III–cN2 disease who received preoperative chemotherapy were compared with 649 patients receiving postoperative chemotherapy. In a Cox proportional hazards model with adjustment for demographics, comorbidities, and tumor attributes, the results of postoperative chemotherapy appeared similar to those of preoperative chemotherapy (hazard ratio HR = 1.05, 95% confidence interval CI 0.93–1.19, p = 0.438). In separate Cox models, the results of postoperative chemotherapy alone were similar to those of preoperative chemotherapy alone (HR = 1.106, 95% CI 0.91–1.344, p = 0.3124). The results of postoperative chemotherapy + radiation were similar to those of preoperative chemotherapy + radiation (HR = 1.125, 95% CI 0.949–1.333, p = -0.175). Conclusions Adjusted comparison of preoperative and postoperative chemotherapy results for cstage III–N2 NSCLC in the NCDB failed to identify a superior chemotherapy approach. This suggests that a more rigorous examination of the widely held view that preoperative chemotherapy is superior may be warranted.
Background The role of leptin in mediating calcium-related metabolic processes is not well understood. Study Design We enrolled patients with hyperparathyroidism undergoing parathyroidectomy in a ...prospective study to assess postoperative changes to serum leptin and parathyroid hormone levels and to determine the presence of LEPR (leptin receptor) polymorphisms. Patients undergoing hemithyroidectomy under identical surgical conditions were enrolled as controls. Wilcoxon signed-rank test was used to analyze changes in leptin. Pearson correlations and Bland-Altman methods were used to examine the between-subject and within-subject correlations in changes in leptin and parathyroid hormone levels. Five single-nucleotide polymorphisms in the LEPR gene were genotyped, and linear regression analysis was performed for each polymorphism. Results Among the 71 patients included in the clinical study, after-surgery leptin levels decreased significantly in the parathyroid adenoma (p < 0.001) and parathyroid hyperplasia subgroups (p = 0.002) and increased in the control group (p = 0.007). On multivariate analysis, parathyroid disease subtype, baseline leptin levels, age, body mass index, and calcium at diagnosis was associated with changes in leptin. Among the 132 patients included in the genotyping analysis, under a recessive model of inheritance, single-nucleotide polymorphism rs1137101 had a significant association with the largest parathyroid gland and total mass of parathyroid tissue removed (p = 0.045 and p = 0.040, respectively). When analyzing obese patients only, rs1137100 and rs1137101 were significantly associated with total parathyroid size (p = 0.0343 and p = 0.0259, respectively). Conclusions Our results suggest a role for the parathyroid gland in regulating leptin production. Genetic contributions from the leptin pathway might predispose to hyperparathyroidism.
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