Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort.

OBJECTIVES: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. METHODS: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier's curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. RESULTS: Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0-4) and higher (5-7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (≥24) groups (p = 0.19 for both). CONCLUSIONS: Despite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT.

Labial vibrotactile somatosensory perception: a pilot study in healthy aging versus young adult participants.

The purpose of this pilot study was to begin characterizing changes in labial vibrotactile somatosensation in healthy older adults as a foundational step in determining how changes in orofacial sensation can affect functional behaviors, such as speech and feeding. Labial vibrotactile perception capacity of healthy older adults (n = 15) was compared to a cohort of healthy young adults (n = 5). Vibrotactile inputs were delivered to the glabrous surface of the left lower lip at 5, 10, 50, and 150 Hz. A modified von Bekesy (staircase) method was used to identify participants' thresholds and response standard deviations for each test frequency. Consistent with findings in other body regions, a decrease in labial vibrotactile detection sensitivity was expected in healthy older adults. The threshold values for the 5 and 10 Hz test frequencies were higher in the older group and the differences in response standard deviations at these frequencies were statistically significant. This pilot study identified changes in labial perception among healthy older adults.

Cervical cancer screening: exploring Appalachian patients' barriers to follow-up care.

This article describes a community-based Patient Navigation (PN) project conducted to identify potential barriers to seeking follow-up cervical cancer care in southeastern Kentucky. Patient navigators (PNs) were placed in cervical cancer programs within county public health departments where they interviewed patients about their perceived barriers to seeking follow-up care after receiving a positive Pap test result. Participants identified various potential barriers at three levels: the individual/personal level, the health care system level and the community/environmental level. One identified barrier that was unique to this study was a lack of consistency between follow-up recommendations and follow-up guidelines for patients under age 21. Implications are discussed.

A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure.

Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.

Effectiveness of a primary care practice intervention for increasing colorectal cancer screening in Appalachian Kentucky.

OBJECTIVE: This report describes findings from a randomized controlled trial of an intervention to increase colorectal cancer (CRC) screening in primary care practices in Appalachian Kentucky. METHODS: Sixty-six primary care practices were randomized to early or delayed intervention groups. The intervention was provided at practices using academic detailing, a method of education where providers receive information on a specific topic through personal contact. Data were collected in cross-sectional surveys of medical records at baseline and six months post-intervention. RESULTS: A total of 3844 medical records were reviewed at baseline and 3751 at the six-month follow-up. At baselines, colonoscopy was recommended more frequently (43.4%) than any other screening modality, followed by fecal occult blood testing (18.0%), flexible sigmoidoscopy (0.4%), and double-contrast barium enema (0.3%). Rates of documented screening results were higher for all practices at the six-month follow-up for colonoscopy (31.8% vs 29.6%) and fecal occult blood testing (12.2% vs 11.2%). For early intervention practices that recommended screening, colonoscopy rates increased by 15.7% at six months compared to an increase of 2.4% in the delayed intervention practices (p=.01). CONCLUSIONS: Using academic detailing to reach rural primary care providers with a CRC screening intervention was associated with an increase in colonoscopy.

Effectiveness of an Intervention for Adherence to Follow-up Recommendations for Abnormal Pap Tests in Appalachian Kentucky.

OBJECTIVE: In collaboration with rural county health departments (CHDs), we developed a patient navigation intervention to increase adherence to follow-up recommendations for women with abnormal Pap tests. METHODS: Local women were recruited, trained and placed in CHDs. Navigation was tailored to the follow-up care recommended. Effectiveness was evaluated in a quasi-experimental trial that included 13 intervention CHDs and 13 comparison group CHDs. Participants were enrolled from September 2008 through July 2010. RESULTS: A total of 478 participants were enrolled. The proportion that received recommended follow-up care was greater in the intervention CHDs (91.6%) than in the comparison group CHDs (80.8%) (p = .01). CONCLUSIONS: These results suggest that development of policy to promote navigation with rural health care delivery systems has great potential to improve patient outcomes.

Total target volume is a better predictor of whole brain dose from gamma stereotactic radiosurgery than the number, shape, or location of the lesions.

PURPOSE: To assess the hypothesis that the volume of whole brain that receives a certain dose level is primarily dependent on the treated volume rather than on the number, shape, or location of the lesions. This would help a physician validate the suitability of GammaKnife(®) based stereotactic radiosurgery (GKSR) prior to treatment. METHODS: Simulation studies were performed to establish the hypothesis for both oblong and spherical shaped lesions of various numbers and sizes. Forty patients who underwent GKSR [mean age of 54 years (range 7-80), mean number of lesions of 2.5 (range 1-6), and mean lesion volume of 4.4 cm(3) (range 0.02-22.2 cm(3))] were also studied retrospectively. Following recommendations of QUANTEC, the volume of brain irradiated by the 12 Gy (VB12) isodose line was measured and a power-law based relation is proposed here for estimating VB12 from the known tumor volume and the prescription dose. RESULTS: In the simulation study on oblong, spherical, and multiple lesions, the volume of brain irradiated by 50%, 10%, and 1% of maximum dose was found to have linear, linear, and exponentially increasing dependence on the volume of the treated region, respectively. In the retrospective study on 40 GKSR patients, a similar relationship was found to predict the brain dose with a Spearman correlation coefficient >0.9. In both the studies, the volume of brain irradiated by a certain dose level does not have a statistically significant relationship (p ≥ 0.05) with the number, shape, or position of the lesions. The measured VB12 agrees with calculation to within 1.7%. CONCLUSIONS: The results from the simulation and the retrospective clinical studies indicate that the volume of whole brain that receives a certain percentage of the maximum dose is primarily dependent on the treated volume and less on the number, shape, and location of the lesions.

Inconsistencies between medical records and patient-reported recommendations for follow-up after abnormal Pap tests.

PURPOSE: Adherence with recommended follow-up after an abnormal Pap test is a critical step in the prevention of cervical cancer. Here, we focused on identifying inconsistencies between self-reported and health department record recommendations for follow-up. METHODS: Self-reported recommendations for follow-up were collected by questionnaire from 519 women with abnormal Pap tests in rural Appalachia as part of a trial of the efficacy of patient navigation. Health department medical records were reviewed to collect healthcare provider recommendations. Measures of inconsistency (discordance) were calculated for overall recommendations and each of three particular follow-up recommendations: repeat Pap test, referral for further tests, and other gynecologist referral. RESULTS: The inconsistencies between the recommendation from the health department records and self-reports ranged from 15.0% (repeat Pap test) to 35.3% (gynecologist referral). Inconsistencies were most common among women with a history of abnormal Pap tests and those with more severe initial results. Recommendations for repeat Pap tests were correctly reported most often when the women recalled receiving a letter stating the results. Of greatest concern were the inconsistencies regarding recommendations for referral to a gynecologist. The more severe the Pap test result, the greater the odds of inaccurate self-reports of receiving a referral to a gynecologist for follow-up, p<0.001. CONCLUSIONS: Clinicians should be aware that patients with a history of abnormal results and severe Pap test abnormalities are at risk of misreporting recommendations for follow up.

Low-dose fractionated radiation with induction chemotherapy for locally advanced head and neck cancer: 5 year results of a prospective phase II trial.

OBJECTIVE: This study aims to report the long-term outcomes of a novel treatment approach utilizing induction low-dose fractionated radiation therapy (LDFRT) and chemotherapy for locally advanced squamous cell carcinoma of head and neck (SCCHN). METHODS: We prospectively enrolled 40 patients with locally advanced SCCHN (77 % stage IV) on a phase II clinical trial and treated with induction paclitaxel (225 mg/m2), carboplatin (AUC 6), and LDFRT (80 cGy BID on days 1 and 2) every 21 days for two cycles. RESULTS: Forty patients enrolled; 39 were evaluable. The acute toxicity and response data have been previously reported; overall response rate (RR) was 82 %. After induction, definitive therapy was concurrent chemoradiation (CRT) in 51 %, XRT alone in 39 %, surgery in 5 %, and surgery and XRT in 5 %. The long-term outcomes are now reported with a median follow-up of 83 months. Locoregional control (LRC) is 80 % and distant control (DC) is 77 %. Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively. CONCLUSION: Induction chemotherapy with LDFRT has a high initial RR, comparable toxicity to two-drug induction regimens, but adds a third novel and effective agent, LDFRT. Five-year follow-up shows favorable outcomes compared to historical controls and excellent compliance with definitive therapy. This novel treatment approach is now planned for phase 3 trial evaluation.

Dose-finding clinical trial design for ordinal toxicity grades using the continuation ratio model: an extension of the continual reassessment method.

BACKGROUND: Various dose-finding clinical trial designs, including the continual reassessment method (CRM), dichotomize toxicity outcomes based on prespecified dose-limiting toxicity (DLT) criteria. This loss of toxicity information is particularly inefficient due to the small sample sizes in phase I trials, especially when Common Terminology Criteria for Adverse Events (CTCAE v4.0) are an established ordinal toxicity grading classification already used in the clinical practice. PURPOSE: The purpose of this simulation study is to incorporate ordinal toxicity grades as specified by CTCAE v4.0 using a continuation ratio (CR) model in the likelihood-based CRM. METHODS: This simulation study compares the CR model design to the dichotomous CRM as well as an ordinal CRM that implements the proportional odds (PO) model. We compare six scenarios for model performance based on various safety and efficiency criteria and consider a range of dose-toxicity relationship models, including CR models, PO models, and models that violate the PO assumption. RESULTS: The ordinal CRM performs as well as the dichotomous CRM in all scenarios considered, especially in situations where the starting dose is overly toxic, the ordinal designs show slight improvement in the estimation of the maximum tolerated dose (MTD) and fewer median patients exposed to excessively toxic dose levels as compared to the binary CRM. We also find slight discrepancies in the performance between the PO model and CR model; however, the differences were not substantial enough to strongly recommend one model over the other. LIMITATIONS: The CR model design does require slightly more input from clinical investigators prior to the start of the trial as compared to the dichotomous CRM. Investigators must specify the distribution of toxicity grades at the expected dose levels for a 10% and 90% DLT rate in this CR design. However, an R package will help with the implementation of this ordinal design. CONCLUSIONS: While the ordinal designs did not perform significantly better than the binary counterpart, we were able to incorporate maximal toxicity information available into a feasible dose-finding design without compromising overall design performance.

Proportional odds model for dose-finding clinical trial designs with ordinal toxicity grading.

Currently many dose-finding clinical trial designs, including the continual reassessment method (CRM) and the standard ' 3 + 3' design, dichotomize toxicity outcomes based on the pre-specified dose-limiting toxicity (DLT) criteria. This loss of information is particularly inefficient due to the small sample sizes in phase I trials. Common Toxicity Criteria (CTCAEv3.0) classify adverse events into grades 1-5, which range from 1 as a mild adverse event to 5 as death related to an adverse event. In this paper, we extend the CRM to include ordinal toxicity outcomes as specified by CTCAEv3.0 using the proportional odds model (POM) and compare results with the dichotomous CRM. A sensitivity analysis of the new design compares various target DLT rates, sample sizes, and cohort sizes. This design is also assessed under various dose-toxicity relationship models including POMs as well as those that violate the proportional odds assumption. A simulation study shows that the proportional odds CRM performs as well as the dichotomous CRM on all criteria compared (including safety criteria such as percentage of patients treated at highly toxic or suboptimal dose levels) and with improved estimation of the maximum tolerated dose when the PO assumption is not violated. These findings suggest that it is beneficial to incorporate ordinal toxicity endpoints into phase I trial designs.

An evaluation of edge effects in nutritional accessibility and availability measures: a simulation study.

BACKGROUND: This paper addresses the statistical use of accessibility and availability indices and the effect of study boundaries on these measures. The measures are evaluated via an extensive simulation based on cluster models for local outlet density. We define outlet to mean either food retail store (convenience store, supermarket, gas station) or restaurant (limited service or full service restaurants). We designed a simulation whereby a cluster outlet model is assumed in a large study window and an internal subset of that window is constructed. We performed simulations on various criteria including one scenario representing an urban area with 2000 outlets as well as a non-urban area simulated with only 300 outlets. A comparison is made between estimates obtained with the full study area and estimates using only the subset area. This allows the study of the effect of edge censoring on accessibility measures. RESULTS: The results suggest that considerable bias is found at the edges of study regions in particular for accessibility measures. Edge effects are smaller for availability measures (when not smoothed) and also for short range accessibility CONCLUSIONS: It is recommended that any study utilizing these measures should correct for edge effects. The use of edge correction via guard areas is recommended and the avoidance of large range distance-based accessibility measures is also proposed.

Post-hematopoietic stem cell transplant immunization practices in the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND: A survey of National Marrow Donor Program transplant centers in 1995 demonstrated a wide range of immunization practices in post-hematopoietic stem cell transplant (HSCT) recipients, which led to the 2000 Centers for Disease Control and Prevention (CDC) recommendations for vaccination after HSCT. We surveyed the principal investigators of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) to identify immunization practice patterns after HSCT and assess compliance with the 2000 CDC guidelines. PROCEDURE: Approval was obtained from the Medical University of South Carolina Institutional Review Board. A 33 question survey using surveymonkey.com was distributed by email to principal investigators in the PBMTC. RESULTS: Forty-one (40%) of the 102 pediatric HSCT centers participating in the PBMTC responded. Thirty of the responding centers completed the entire survey. For individual vaccines, compliance with the CDC guidelines ranged from 22% to 93%. Less than 20% of the centers reported schedules consistent with the 2000 CDC recommendations for both allogeneic and autologous HSCT recipients. CONCLUSION: Despite the 2000 CDC guidelines, wide variation in post-HSCT immunization practices still exists. Updated guidelines have been needed, particularly to address the use of the pneumococcal conjugate vaccine. In conjunction with multiple other groups, the CDC recently released new immunization guidelines in October 2009. Additional data are still needed to adequately address the utility of incorporating immunologic parameters with the timing of vaccination after HSCT.