Indigenizing and Ruralizing NCI Screen to Save Program: Resources, Optimizing Outreach, Teaching, Science (ROOTS).

Colorectal cancer (CRC) is a complex health disparity in many Indigenous and rural populations. While it affects anyone regardless of race, age, gender, or other common differences among people, Indigenous and rural populations are at a higher risk of dying from colorectal cancer. An NCI Screen to Save (S2S) program was culturally tailored to promote awareness and knowledge of colorectal cancer and screening in both Indigenous and rural communities across a sector in Northeastern USA. Indigenous and rural community outreach teams at an NCI-designated cancer center partnered with a community advisory board to provide an indigenized/ruralized version of the NCI Screen to Save program delivered to both Indigenous and rural/suburban communities. In total, n = 79 pre/post surveys were obtained from n = 82 participants, who had an average age of 49 years. Findings demonstrated that Indigenous/rural participants in both off-territory/non-reservation communities and a tribal community that received a culturally tailored version of NCI's S2S program were able to identify both smoking and tobacco use along with lack of physical activity as risk factors for colorectal cancer. Post-intervention, participants reported being more likely to increase physical activity. Most importantly, participants said they would be more likely to be screened for colorectal cancer along with their family and friends based on their cancer screening experiences. Culturally tailored CRC messaging is an effective means for increasing screening intentions and decreasing cancer health disparities among both indigenous and rural populations. Future research should include the relationship of diet to obesity-related cancers, greater integration of Indigenous-rural patient navigation programs, creation of more information on genetic screening, and quality improvement to service translational science initiatives.

Bayesian optimization of tacrolimus exposure in stable kidney transplant patients.

STUDY OBJECTIVE: The objective was to compare tacrolimus AUC0-12 determined by Non-Compartmental Analysis (NCA) using intensive sampling to Maximum a Posteriori-Bayesian (MAP-Bayesian) estimates from robust (n = 9 samples/subject) and sparse (n = 2 samples/subject) sampling in 67 stable KTRs and a validation group of similar patients. DESIGN: This open-label, prospective, single center 12-h PK study included nine serial samples collected in KTRs to determine steady-state NCA tacrolimus AUC0-12 . SETTING: This study was conducted at a single site within a large, urban hospital in the western New York area. PATIENTS: This study described tacrolimus pharmacokinetics in stable kidney transplant recipients on maintenance tacrolimus therapy. INTERVENTION: Robust and sparse AUC0-12 estimates by a MAP-Bayesian approach were obtained using the Advanced Dosing Solutions (AdDS) and ADAPT5 freeware. Limited sampling strategies were evaluated using the original population PK model (n = 67), which was also assessed using a validation group (n = 15). AUC0-12 agreement was tested by paired t-tests with intraclass correlation coefficient (ICC) and Bland Altman analysis. MEASUREMENTS AND MAIN RESULTS: A total of 35 Black and 32 White stable KTRs (estimated glomerular filtration rate [eGFR] = 55.2 ± 15.7 mL/min/1.73m2 ) received the tacrolimus dose of 3.4 ± 1.7 mg/study with troughs of 6.8 ± 1.8 ng/mL. The NCA-AUC0-12 was 123.8 ± 33.6 µg·h/L compared to MAP-Bayesian estimates for Robust-AUC0-12 of 124.7 ± 33.3 µg·h/L and optimal 2-specimen Sparse-AUC0-12 of 119.7 ± 32.7 µg·h/L for the training group. Comparison of Robust-AUC0-12 to NCA-AUC0-12 had an ICC of 0.96 (p = 0.99) while comparison of Robust-AUC0-12 to Sparse-AUC0-12 using Pre-dose trough [C(t0h )] and 1 h [C(t1h )] resulted in an ICC of 0.93 (p = 0.014). In the validation group, 5 Black and 10 White KTRs (eGFR = 56.4 ± 16.8 mL/min/1.73m2 ) received a mean tacrolimus dose of 1.9 ± 1.2 mg/study with a trough of 6.0 ± 1.7 ng/mL. The validation group's NCA-AUC0-12 (88.4 ± 33.1 µg·h/L) was comparable to Robust-AUC0-12 (85.1 ± 33.8 µg·h/L, ICC = 0.93; p = 0.12) and Sparse-AUC0-12 determined from C(t0h ) and C(t4h ) (86.7 ± 33.9 µg·h/L, ICC = 0.91; p = 0.61). CONCLUSION: MAP-Bayesian estimation for patient-specific AUC0-12 using sparse, two-specimen sampling is comparable to NCA and may enhance tacrolimus TDM in stable KTRs.

Comparison of P-glycoprotein function in peripheral blood mononuclear cells ex vivo in stable Black and White male and female kidney transplant recipients.

Kidney allograft survival remains poorer in Black compared to White recipients due to racial differences in calcineurin inhibitor (CNI) pharmacology. P-glycoprotein (P-gp), an ABC efflux transporter expressed in peripheral blood mononuclear cells (PBMCs), modulates CNI pharmacokinetics and intracellular pharmacology. This study investigated P-gp function in PBMC ex vivo at 0 (trough), 4, 8, and 12 h in stable Black and White male and female kidney transplant recipients (n = 67) receiving tacrolimus and mycophenolic acid. Tacrolimus doses were adjusted to troughs of 4-10 ng/ml. P-gp function was quantified with flow cytometric measurement of cyclosporine (CYA; 2.5 µM)-reversible efflux of P-gp substrate, 3,3'-Diethyloxacarbocyanine iodide by determining the percentage change of mean fluorescent intensity (MFI) with CYA (% ΔMFI). The composite parameter of area under the concentration versus time (AUC)0-12h % ΔMFI estimated P-gp function. Data analysis examined race, sex, and race-sex associations to P-gp function. A secondary aim analyzed ABCB1 genotypes: 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), and P-gp function. P-gp function (% ΔMFI) was higher in White patients at troughs (p = 0.031) compared to Black counterparts with similar trends at 4 and 8 h. Reduced AUC0-12h % ΔMFI was noted in Black recipients (N = 32) compared with Whites (N = 35, p = 0.029) with notable pairwise adjusted differences between Black and White women (p = 0.021). Higher AUC0-12h % ΔMFI was associated with ABCB1 2677 TT compared to GG variants (p = 0.035). The AUC0-12h % ΔMFI was greater in White than Black subjects. P-gp function was higher at troughs in White subjects and differed between race-sex groups. P-gp function in PBMC may influence intracellular tacrolimus exposure and inter-relating pharmacodynamic responses which may support race and sex pharmacologic differences.

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center.

BACKGROUND: A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-). PATIENTS AND METHODS: A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies. RESULTS: In this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002). CONCLUSIONS: The real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

Visceral Obesity Promotes Lung Cancer Progression-Toward Resolution of the Obesity Paradox in Lung Cancer.

INTRODUCTION: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. METHODS: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. RESULTS: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. CONCLUSIONS: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

Concomitant Mediastinoscopy Increases the Risk of Postoperative Pneumonia After Pulmonary Lobectomy.

BACKGROUND: Mediastinoscopy is considered the gold standard for preresectional staging of lung cancer. We sought to examine the effect of concomitant mediastinoscopy on postoperative pneumonia (POP) in patients undergoing lobectomy. METHODS: All patients in our institutional database (2008-2015) undergoing lobectomy who did not receive neoadjuvant therapy were included in our study. The relationship between mediastinoscopy and POP was examined using univariate (Chi square) and multivariate analyses (binary logistic regression). In order to validate our institutional findings, lobectomy data in the National Surgical Quality Improvement Program (NSQIP) from 2005 to 2014 were analyzed for these associations. RESULTS: Of 810 patients who underwent a lobectomy at our institution, 741 (91.5%) surgeries were performed by video-assisted thoracic surgery (VATS) and 487 (60.1%) patients underwent concomitant mediastinoscopy. Univariate analysis demonstrated an association between mediastinoscopy and POP in patients undergoing VATS [odds ratio (OR) 1.80; p = 0.003], but not open lobectomy. Multivariate analysis retained mediastinoscopy as a variable, although the relationship showed only a trend (OR 1.64; p = 0.1). In the NSQIP cohort (N = 12,562), concomitant mediastinoscopy was performed in 9.0% of patients, with 44.5% of all the lobectomies performed by VATS. Mediastinoscopy was associated with POP in patients having both open (OR1.69; p < 0.001) and VATS lobectomy (OR 1.72; p = 0.002). This effect remained in multivariate analysis in both the open and VATS lobectomy groups (OR 1.46, p = 0.003; and 1.53, p = 0.02, respectively). CONCLUSIONS: Mediastinoscopy may be associated with an increased risk of POP after pulmonary lobectomy. This observation should be examined in other datasets as it potentially impacts preresectional staging algorithms for patients with lung cancer.

Patterns of Loss to Follow-Up Care Among Childhood Cancer Survivors.

PURPOSE: Surveillance for long-term complications related to previous cancer therapy can help diagnose/manage chronic health conditions in childhood cancer survivors and improve survivor quality of life. However, a challenge to delivering long-term care to childhood cancer survivors is loss to follow-up; many patients discontinue care at specialized survivor care centers. The purpose of this study was to examine patterns of loss to follow-up among a cohort of childhood cancer survivors. METHODS: This retrospective study examined follow-up patterns among a nonrandom representative sample of 370 childhood cancer survivors among 1116 patients from a single institution. The median age of patients at diagnosis was 10.2 years (range <1-21). Factors potentially related to follow-up were utilized to evaluate patterns of follow-up across 5-year intervals following completion of active therapy. The association between patient characteristics and follow-up was evaluated using univariate and multivariate binomial regression models. RESULTS: The probability of follow-up 1-5 years post-treatment was 91.2% (89.7%-92.5%) but dropped to 68.5% (66.2%-70.8%) during years 6-10, 47.7% (45.0%-50.3%) during years 11-15, and continued to steadily decrease over time. Overall, white race, diagnoses at younger ages, patients with lymphomas/leukemias, and decade of diagnosis were each associated with somewhat better rates of follow-up. CONCLUSIONS: These findings highlight the lack of follow-up by adult survivors of childhood cancer with only approximately one-half of patients returning for follow-up 10 years after completion of therapy. Interventions focused on educating both patients and primary care physicians may help to increase long-term follow-up care among this at-risk population.

HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma.

BACKGROUND: Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. METHODS: Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. RESULTS: Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. CONCLUSIONS: Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets.

Effect of Incorporation of Pretreatment Serum Carcinoembryonic Antigen Levels Into AJCC Staging for Colon Cancer on 5-Year Survival.

IMPORTANCE: The American Joint Committee on Cancer (AJCC) has proposed the inclusion of pretreatment serum carcinoembryonic antigen (CEA) levels (C stage) into the conventional TNM staging system of colon cancer. The latter proposal has yet to be widely adopted because of the lack of long-term survival estimates of after C-stage incorporation into AJCC staging. OBJECTIVES: To evaluate whether long-term overall and cancer-specific survival is affected by inclusion of C stage into the standard AJCC TNM staging and to study the implications on survival estimates. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective study of all patients diagnosed as having histologically proven colonic adenocarcinoma from January 1, 2004, through December 31, 2005, from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. We stratified each AJCC stage as C0 (normal) or C1 (elevated) based on the pretreatment serum CEA level. Median follow-up was 71 months. MAIN OUTCOME AND MEASURES: Five-year estimates of overall and disease-specific survival and hazard ratios (HRs) for estimates of risk of overall and disease-specific mortality. RESULTS: A total of 16 619 patients were evaluated, and of these, 8878 patients had C0 disease and 7741 had C1 disease. C1 stage was independently associated with a 51% and 59% increased risk of overall (HR, 1.51; 95% CI, 1.44-1.59; P < .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.49-1.69; P < . 001) at a median follow-up of 71 months. Analysis of survival of the AJCC stages subdivided as C0 or C1 revealed a significant worse prognosis of C1 AJCC stages compared with the respective C0 AJCC stages. The magnitude of change in survival was large enough to cause clustering of survival estimates of C1 vs C0 cancers across various AJCC stages. Analysis of patients with stage I, II, and III cancer revealed that node-negative C1 disease was associated with prognosis similar or worse than node-positive C0 disease. CONCLUSIONS AND RELEVANCE: Inclusion of C stage into the AJCC TNM staging of colon cancer revealed significant differences dependent on C stage in terms of 5-year survival. C-stage inclusion resulted in substantial change in survival estimates, with C1 status portending a prognosis to certain stages similar to or worse than higher AJCC TNM stages with C0 status. We recommend routine pretreatment CEA testing as standard of care in colon cancer and use of C stage for multimodality treatment planning and risk stratification in prospective studies and randomized clinical trials.

Race and drug formulation influence on mycophenolic acid pharmacokinetics in stable renal transplant recipients.

BACKGROUND: Limited mycophenolic acid (MPA) data are available comparing racial influence on mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) pharmacokinetics. METHODS: Intrapatient MPA pharmacokinetics of MMF versus EC-MPS were compared in 13 male African American (AA) and 14 Caucasian (C) renal transplant recipients (RTRs). RTRs were switched to equivalent doses of the alternate formulation for at least 10 days prior to the second study. Mycophenolic acid clearance and dose-normalized area under the concentration-time curve(0-12) (AUC*) were determined. Mixed model statistics evaluated the main effects of race, drug formulation, and interaction of race and drug formulation (R × D) with albumin, cyclosporine trough, renal function, and diabetes and enterhepatic recirculation. RESULTS: Significant R × D was identified for MPA AUC* for EC-MPS (AA, 0.056 ± 0.029 [mg·h/L]/mg; C, 0.080 ± 0.044 [mg·h/L]/mg) compared with MMF (AA, 0.053 ± 0.019 [mg·h/L]/mg; C, 0.060 ± 0.025 [mg·h/L]/mg), P = .022. Significant R × D was identified with albumin in the model for MPA clearance for MMF (AA, 21.7 ± 8.9 L/h; C, 20.5 ± 10.8 L/h) compared with EC-MPS (AA, 22.2 ± 10.1 L/h; C, 16.2 ± 9.1 L/h), P = .032. CONCLUSIONS: Race influences MPA exposure between MMF and EC-MPS and may warrant therapeutic monitoring during formulation conversion.

Comparison of 12-hour creatinine clearance and estimated glomerular filtration rate in renal transplant recipients.

Glomerular filtration rate (GFR) is an essential clinical assessment of renal function post-renal transplantation. Creatinine clearance (CrCl) measured over 12 h and estimated GFR (e-GFR) (calculated by the Modification of diet in renal disease equation) were compared in 28 stable renal transplant recipients (RTRs). This single center study included 14 African American (AA) and 14 Caucasian (CC) recipients. The 12-h creatinine clearance (CrCl-12 h) was determined by monitored urine collection and by e-GFR on two occasions (two phases) separated by at least 2 weeks. Statistics included mixed model analysis of CrCl-12 h and e-GFR relative to race, phase, and difference between parameters. In the first phase, the e-GFR was higher in AA males (58.4 ± 14.8 mL/min) than the CC males (46.2 ± 10.2 mL/min) (p = 0.032), whereas the CrCl-12 h of AA males (70.8 ± 8.7 mL/min) and CC males (63.3 ± 21.7 mL/min) was not different (p = 0.740). During the second phase, the e-GFR in AA and CC RTRs was 55.4 ± 10.1 mL/min and 47.6 ± 10.7 mL/min (p = 0.117), respectively, whereas CrCl-12 h in AAs was 64.71 ± 17.9 mL/min and in CCs was 62.0 ± 14.9 mL/min (p = 1.000). The CrCl-12 h was higher than the e-GFR (p < 0.001) irrespective of race or phase. CrCl-12 h was not different on both occasions (p = 0.289) in all the patients. CrCl-12 h was consistently greater than e-GFR. The difference between these e-GFR estimates may have an importance in the care of RTRs.

Mycophenolic acid pharmacokinetics during maintenance immunosuppression in African American and Caucasian renal transplant recipients.

Renal transplant recipients exhibit variability in mycophenolic acid (MPA) and MPA glucuronide (MPAG) pharmacokinetics, which are influenced by clinical and demographic factors. Racial influence on MPA and MPAG pharmacokinetics was investigated in 53 patients: 17 African American males, 22 Caucasian males, and 14 females receiving mycophenolate mofetil (MMF) and cyclosporine. A 12-hour steady-state pharmacokinetic study was conducted. Enterohepatic circulation of MPA was characterized by a second plasma concentration peak and was included in a novel statistical model with MPAG. MPA clearance in African American males was 26.5 ± 14.4 L/h versus 17.9 ± 6.1 L/h in Caucasian males (P = .035) and 16.1 ± 4.6 L/h in Caucasian females (P = .024) with no difference noted in MPA troughs. Enterohepatic circulation occurred less frequently in African American males (23%) compared with Caucasian males (42%) and Caucasian females (50%) (P > .05). Cyclosporine exposure was correlated with MPA and MPAG pharmacokinetics, whereas creatinine clearance influenced MPAG pharmacokinetics. A racial difference was noted with more rapid MPA clearance in African American males compared with Caucasians. The results support differential MPA dosing and the role of therapeutic drug monitoring in addition to considering the influence of renal function and concurrent immunosuppressives on MPA and MPAG pharmacokinetics.