Ten Hills Farm tells the powerful saga of five generations of slave owners in colonial New England. Settled in 1630 by John Winthrop--who would later become governor of the Massachusetts Bay ...Colony--Ten Hills Farm was a six-hundred-acre estate just north of Boston. Winthrop, famous for envisioning his ’city on the hill’ and lauded as a paragon of justice, owned slaves on that ground and passed the first law in North America condoning slavery. In this mesmerizing narrative, C. S. Manegold exposes how the fates of the land and the families that lived on it were bound to America’s most tragic and tainted legacy. Challenging received ideas about America and the Atlantic world, Ten Hills Farm digs deep to bring the story of slavery in the North full circle--from concealment to recovery.
Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report ...the final overall survival (OS) analysis from the phase III AVAiL trial.
Patients (n=1043) received cisplatin 80 mg/m2 and gemcitabine 1250 mg/m2 for up to six cycles plus bevacizumab 7.5 mg/kg (n=345), bevacizumab 15 mg/kg (n=351) or placebo (n=347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point.
Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) 95% confidence interval (CI) 0.75 (0.64–0.87), P=0.0003 and 0.85 (0.73–1.00), P=0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab HR (95% CI) 0.93 (0.78–1.11), P=0.420 and 1.03 (0.86–1.23), P=0.761 for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients (∼62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported.
Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin–gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.
Bone matters in lung cancer Brodowicz, T.; O'Byrne, K.; Manegold, C.
Annals of oncology,
09/2012, Letnik:
23, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Bone metastases are a significant and undertreated clinical problem in patients with advanced lung cancer.
We reviewed the incidence of bone metastases and skeletal-related events (SREs) in patients ...with lung cancer and examined the burden on patients' lives and on health care systems. Available therapies to improve survival and lessen the impact of SREs on quality of life (QoL) were also investigated.
Bone metastases are common in lung cancer; however, owing to short survival times, data on the incidences of SREs are limited. As with other cancers, the costs associated with treating SREs in lung cancer are substantial. Bisphosphonates reduce the frequency of SREs and improve measures of pain and QoL in patients with lung cancer; however, nephrotoxicity is a common complication of therapy. Denosumab, a recently approved bone-targeted therapy, is superior to zoledronic acid in increasing the time to first on-study SRE in patients with solid tumours, including lung cancer. Additional roles of bone-targeted therapies beyond the prevention of SREs are under investigation.
With increasing awareness of the consequences of SREs, bone-targeted therapies may play a greater role in the management of patients with lung cancer, with the aim of delaying disease progression and preserving QoL.
To determine the prevalence and clinicopathological features of ROS1 fusions in Chinese patients with non-small-cell lung cancer (NSCLC).
Formalin-fixed and paraffin-embedded (FFPE) tissue sections ...from 392 patients with NSCLC were screened for ROS1 fusions by multiplex RT–PCR and all ROS1 fusions were validated by direct sequencing. The relationship between ROS1 fusions and clinicopathological features and the prognostic effect of the ROS1 fusion status on survival were analyzed.
In this study, 8 of 392 (2.0%) evaluable samples were found to harbor ROS1 fusions. Of the ROS1-positive patients, seven presented with adenocarcinoma, and one with adenosquamous carcinoma. The ratio of female to male and never smoker to smokers in a ROS1 fusion-positive group was 5:3. There was no statistically significant difference in age, sex, smoking history, histological type and pathological stage between ROS1 fusion-positive and ROS1 fusion-negative patients. ROS1 fusion-negative patients had a significantly longer survival when compared with ROS1 fusion-positive patients (P = 0.041). Lower pathological stage, younger age and ROS1 fusion-negative status were significantly associated with better prognosis on multivariate analysis.
ROS1 fusions occurred in ∼2.0% of Chinese patients with NSCLC and had no specific clinicopathological feature. ROS1 fusion-negative patients may have a better survival than ROS1 fusion-positive patients.
To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency.
Clinical and ...biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time.
In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%).
Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.
Objectives
To investigate the correlation between maximum standardized uptake value (SUV
max
) of
18
FDG PET-CT and iodine-related attenuation (IRA) of dual energy CT (DECT) of primary tumours and
18
...FDG PET-CT positive thoracic lymph nodes (LN) in patients with lung cancer.
Methods
37 patients with lung cancer (27 NSCLC, 10 SCLC, 86
18
FDG PET-CT positive thoracic LN) who underwent both
18
FDG PET-CT and DECT were analyzed. The mean study interval between
18
FDG PET-CT and DECT was ≤21 days in 17 patients. The mean and maximum IRA of DECT as well as of virtual unenhanced and virtual 120 kV images of DECT was analyzed and correlated to the SUV
max
of
18
FDG PET-CT in all tumours and
18
FDG PET-CT positive thoracic lymph nodes. Further subgroup analysis was performed for histological subtypes in all groups.
Results
A moderate correlation was found between SUV
max
and maximum IRA in all tumours (
n
= 37;
r
= 0.507;
p
= 0.025) whereas only weak or no correlation were found between SUV
max
and all other DECT measurements. A strong correlation was found in patients with study intervals ≤21 days (
n
= 17;
r
= 0.768;
p
= 0.017). Analysis of histological subtypes of lung cancer showed a strong correlation between SUV
max
and maximum IRA in the analysis of all patients with NSCLC (
r
= 0.785;
p
= 0.001) and in patients with NSCLC and study intervals ≤21 days (
r
= 0.876;
p
= 0.024).
Thoracic LN showed moderate correlation between SUV
max
and maximum IRA in patients with study intervals ≤21 days (
r
= 0.654;
p
= 0.010) whereas a weak correlation was found between SUV
max
and maximum IRA in patients with study intervals >21 days (
r
= 0.299;
p
= 0.035).
Conclusions
DECT could serve as a valuable functional imaging test for patients with NSCLC as the IRA of DECT correlates with SUV
max
of
18
FDG PET-CT.
Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we ...aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor.
Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator’s choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS).
Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T.
In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.
•Adjuvant platinum-based chemotherapy is accepted as standard of care in stage II and III (NSCLC) patients.•Several studies addressed the question of whether molecular tumor markers may serve as predictive biomarkers.•ITACA was planned to evaluate the predictive utility of ERCC1 and TS mRNA expression levels in completely resected NSCLC.•ITACA results indicate that adjuvant chemotherapy customization based on ERCC1 and TS mRNA levels did not improve efficacy.•In terms of safety, the pharmacogenomic-driven arm was associated with better efficacy/toxicity ratio.
Background: The aim of this prognostic factor analysis was to investigate if a patient's self-reported health-related quality of life (HRQOL) provided independent prognostic information for survival ...in non-small cell lung cancer (NSCLC) patients. Patients and methods: Pretreatment HRQOL was measured in 391 advanced NSCLC patients using the EORTC QLQ-C30 and the EORTC Lung Cancer module (QLQ-LC13). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap validation technique was used to assess the stability of the outcomes. Results: The final multivariate Cox regression model retained four parameters as independent prognostic factors for survival: male gender with a hazard ratio (HR) = 1.32 (95% CI 1.03–1.69; P = 0.03); performance status (0 to 1 versus 2) with HR = 1.63 (95% CI 1.04–2.54; P = 0.032); patient's self-reported score of pain with HR= 1.11 (95% CI 1.07–1.16; P < 0.001) and dysphagia with HR = 1.12 (95% CI 1.04–1.21; P = 0.003). A 10-point shift worse in the scale measuring pain and dysphagia translated into an 11% and 12% increased in the likelihood of death respectively. A risk group categorization was also developed. Conclusion: The results suggest that patients' self-reported HRQOL provide independent prognostic information for survival. This finding supports the collection of such data in routine clinical practice.
This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung ...cancer (NSCLC).
Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS).
A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P = 0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade ≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade ≥3 AEs (experimental arm).
Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.
PDF
