Ann Am Thorac Soc
RATIONALE: Lung cancer screening with low-dose chest CT decreases mortality for high-risk current or former smokers. An essential eligibility criteria, lifetime smoking intensity (cigarette pack-years) is poorly recorded in electronic health records (EHRs), which may contribute to the overall low appropriate utilization of screening. OBJECTIVES: We sought to assess whether elements commonly extractable from the EHR may be useful as pre-screening tools to identify individuals for formal assessment of eligibility. METHODS: This is a cross-sectional cohort study of the National Health and Nutrition Examination Survey (NHANES) continuous survey, years 2011-2016. We included all adult participants with complete smoking interview data, weighted to construct a nationally representative cohort. We determined test characteristics for 5 criteria including eligibility age, smoking status (current, former or never) and current smoking intensity to predict lung cancer screening eligibility as defined by the United States Preventive Services Task Force and Centers for Medicare and Medicaid Services. RESULTS: Almost 9 million individuals, 3.8% of the population, may qualify for screening. Simplified criteria including the appropriate age range (55-77) and smoking status correctly discriminated individuals eligible for screening in most cases (AUC 0.92). When restricting to those of eligible age, smoking status retained fair predictive value (AUC 0.85). Incorporating additional information about current smoking behavior would allow for refinement in approaches to identify specific populations for screening. CONCLUSIONS: These simplified criteria may be useful in identifying individuals who are eligible for lung cancer screening. Applying these criteria as a pre-screening tool may improve appropriate referral and implementation of screening.
Eur Urol Oncol
BACKGROUND: The effect of local treatment on survival in advanced-stage patients has gained interest in several malignancies; however, limited data exist regarding urothelial carcinoma (UC). OBJECTIVE: To test the impact of surgery of the primary tumor site on cancer-specific mortality (CSM) and overall mortality (OM) in patients affected by metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: Individual patient-level data from a multicenter collaboration, including metastatic UC patients treated with first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011 from hospitals in the USA, Europe, Israel, and Canada. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox regression analyses were used to assess the effect of surgery on CSM and OM in patients affected by metastatic UC using 3-mo landmark analyses. Subgroup analyses were performed on the basis of the number of metastasis sites involved and including only patients treated with surgery before the start of chemotherapy. RESULTS AND LIMITATIONS: Of the 326 patients included in the study, 47 (14%) were treated with surgery of the primary tumor site. Median (interquartile range) follow-up was 43 (33-45)mo. Of the patients treated with surgery, 28 (60%) were affected by a primary bladder cancer and 19 (40%) by a primary upper urinary tract tumor. On multivariable analyses, surgery was associated with a protective effect on CSM (hazard ratio [HR]: 0.59, confidence interval [CI]: 0.35-0.98, p=0.04) and OM (HR: 0.45, CI: 0.37-0.99, p=0.04) compared with patients treated with chemotherapy only. Similar results were found considering patients only surgically treated before the start of chemotherapy. After stratifying according to the number of metastatic sites, surgery has an effect on survival in patients with only one metastatic site, while no survival benefit was observed in patients with two or more metastatic sites. The study is limited by its retrospective nature. CONCLUSIONS: We found that surgery of the primary tumor site is associated with improved survival in patients with metastatic UC who received standard chemotherapy. This effect disappears in patients affected by two or more metastatic sites. Our results need to be validated in a high-quality prospective trial. PATIENT SUMMARY: In our multicenter, retrospective series, surgery in metastatic urothelial cancer patients improve survival compared with patients treated with chemotherapy only. This effect was evident in patients with limited disease extent, identified as one metastatic site.
J Thorac Oncol
PURPOSE: Lung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous non-small cell lung cancer (sqNSCLC). The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a CDK 4/6 inhibitor, in patients with cell cycle gene abnormalities. METHODS: Patients with sqNSCLC, Performance status (PS) 0-2, normal organ function, who had progressed after at least one prior platinum-based chemotherapy with CDK 4 or CCND1/2/3 amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib to docetaxel, but was modified to a single arm phase II trial with primary endpoint of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 pts, then the study would cease enrollment. RESULTS: Eighty-eight patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to docetaxel). One patient registered to docetaxel was re-registered to receive palbociclib after progression on docetaxel. The frequency of cell cycle gene alterations in the eligible palbociclib patients (N=32) were: CCND1 (n=26, 81%), CCND2 (n=3, 9%), CCND3 (n=2, 6%), CDK4 (n=1, 3%). Thirty-two eligible patients received palbociclib. There were two partial responses (6% RR, 95% CI: 0%-15%), both with CCND1 amplification. Twelve patients had stable disease (38%, 95% CI: 21%-54%). Median progression-free survival was 1.7 months (95% CI: 1.6-2.9 months) and median overall survival was 7.1 months (95% CI: 4.2-12.5). CONCLUSIONS: Palbociclib as monotherapy failed to demonstrate the pre-specified criteria for advancement to phase III testing.
The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2-4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p=0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3-4 or pN1 disease who received AC (75% vs 54%; p<0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p=0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.
In this study, we report on major MRD or URD BMT outcomes in pediatric patients with SAA in Brazil. This was a retrospective study, which included 106 patients </=18 years old who received a first BMT for SAA. All patients received bone marrow as graft source from an MRD (n = 69) or a URD (n = 37). Conditioning regimen was non-myeloablative in 73.6% of cases, and GVHD prophylaxis comprised a calcineurin inhibitor plus methotrexate in 89.6% of patients. After a median follow-up of 4.5 years after BMT, 81 patients are alive, with a 4-year OS of 77% and no statistically significant difference between the MRD and URD groups (82% vs. 69%, respectively; P = .08). Grade III-IV aGVHD at 6 months and cGVHD at 2 years were observed in 8% and 14% of cases, respectively, and were not statistically different between the groups. Twenty-five (23%) patients died at a median of 2.9 months after BMT. Our study showed that 4-year OS after BMT was not statistically different between MRD and URD recipients. This study shows that the outcomes of pediatric patients transplanted for SAA with a URD in Brazil are approaching those of MRD transplants. In contrast, OS after MRD BMT was lower than we would expect based on previous reports. The wide range of preparatory regimens used by the study centers highlights the need for standardized protocols for these children. Our findings provide a benchmark for future studies focused on improving BMT outcomes in this setting in Brazil.
Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.
BACKGROUND: Survivors of childhood cancer are at risk of neurocognitive impairment, emotional distress, and poor health-related quality of life (HRQOL); however, the effect of race/ethnicity is understudied. The objective of this study was to identify race/ethnicity-based disparities in neurocognitive, emotional, and HRQOL outcomes among survivors of childhood cancer. METHODS: Self-reported measures of neurocognitive function, emotional distress (the Brief Symptom Inventory-18), and HRQOL (the Medical Outcomes Study Short Form-36 health survey) were compared between minority (Hispanic, n = 821; non-Hispanic black [NHB], n = 600) and non-Hispanic white (NHW) (n = 12,287) survivors from the Childhood Cancer Survivor Study (median age, 30.9 years; range, 16.0-54.1 years). By using a sample of 3055 siblings, the magnitude of same-race/same-ethnicity survivor-sibling differences was compared between racial/ethnic groups, adjusting for demographic and treatment characteristics and current socioeconomic status (SES). RESULTS: No clear pattern of disparity in neurocognitive outcomes by race/ethnicity was observed. The magnitude of the survivor-sibling difference in the mean score for depression was greater in Hispanics than in NHWs (3.59 vs 1.09; P = .004). NHBs and Hispanics had greater survivor-sibling differences in HRQOL than NHWs for mental health (NHBs: -5.78 vs -0.69; P = .001; Hispanics: -3.87 vs -0.69; P = .03), and social function (NHBs: -7.11 vs -1.47; P < .001; Hispanics: -5.33 vs -1.47; P = .001). NHBs had greater survivor-sibling differences in physical subscale scores for HRQOL than NHWs. In general, the findings were not attenuated by current SES. CONCLUSIONS: Although no pattern of disparity in neurocognitive outcomes was observed, differences across many HRQOL outcomes among minorities compared with NHWs, not attenuated by current SES, were identified. This suggests that further research into environmental and sociocultural factors during and immediately after treatment is needed.
Infect Control Hosp Epidemiol
This open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.
Journal for ImmunoTherapy of Cancer
Merkel cell carcinoma (MCC) is a rare but clinically aggressive cancer with a high mortality rate. In recent years, antibodies blocking the interactions among PD-1 and its ligands have generated durable tumor regressions in patients with advanced MCC. However, there is a paucity of data regarding effective therapy for patients whose disease is refractory to PD-1 pathway blockade. This retrospective case series describes a heterogeneous group of patients treated with additional immune checkpoint blocking therapy after MCC progression through anti-PD-1. Among 13 patients treated with anti-CTLA-4, alone or in combination with anti-PD-1, objective responses were seen in 4 (31%). Additionally, one patient with MCC refractory to anti-PD-1 and anti-CTLA-4 experienced tumor regression with anti-PD-L1. Our report - the largest case series to date describing this patient population - provides evidence that sequentially-administered salvage immune checkpoint blocking therapy can potentially activate anti-tumor immunity in patients with advanced anti-PD-1-refractory MCC and provides a strong rationale for formally testing these agents in multicenter clinical trials. Additionally, to the best of our knowledge, our report is the first to demonstrate possible anti-tumor activity of second-line treatment with a PD-L1 antibody in a patient with anti-PD-1-refractory disease.