Matthew Smeltzer

Prevalence, Prognostic Implications, and Survival Modulators of Incompletely Resected Non–Small Cell Lung Cancer in the U.S. National Cancer Data Base

Introduction The impact of incomplete lung cancer resection on survival has never been systematically quantified, nor has the value of postoperative adjuvant therapy in this setting been determined. Methods We evaluated lung cancer resections in the National Cancer Data Base from 2004 to 2011 to identify factors associated with margin involvement. We compared the survival of patients with and without positive margins and evaluated the impact of postoperative adjuvant therapy. Results Of 112,998 resections performed during the 8 years, 5,335 (4.7%) had positive margins. Patient demographic and clinical factors associated with an increased adjusted OR of incomplete resection included black race (p = 0.006), age‐based Medicare insurance (p = 0.006), urban residence (p = 0.01), histologic diagnosis of squamous cell carcinoma, high tumor grade, tumor overlapping more than one lobe, and advanced pathologic stage (p < 0.001 for all clinical factors). Community cancer programs (p = 0.002), institutions with high proportions of underinsured patients (p = 0.01), and institutions with a lower volume of cancer resections (p = 0.006) also had an increased adjusted OR. The crude 5‐year survival rates of patients with complete versus incomplete resections were 58.5% versus 33.8% (log‐rank p < 0.001). After an incomplete resection, adjuvant chemotherapy was associated with improved 5‐year survival across all stages (p < 0.01); radiotherapy was associated with worse survival in patients with stage I disease (p < 0.001). Conclusions Margin involvement significantly impaired survival after lung cancer resection irrespective of stage. Causative institutional and provider practices should be identified to minimize this adverse outcome. Postoperative adjuvant chemotherapy mitigated mortality risk independently of stage, whereas postoperative radiotherapy exacerbated the risk in patients with stage I disease. These findings need validation in prospective trials.

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long‐term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1–17·3) enrolled in the Hydroxyurea Study of Long‐Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3‐ to 6‐year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.

Amelioration of murine sickle cell disease by nonablative conditioning and γ-globin gene-corrected bone marrow cells

Patients with severe sickle cell disease (SCD) are candidates for gene therapy using autologous hematopoietic stem cells (HSCs), but concomitant multi-organ disease may contraindicate pretransplant conditioning with full myeloablation. We tested whether nonmyeloablative conditioning, a regimen used successfully for allogeneic bone marrow transplantation of adult SCD patients, allows engraftment of γ-globin gene-corrected cells to a therapeutic level in the Berkeley mouse model of SCD. Animals transplanted according to this regimen averaged 35% engraftment of transduced hematopoietic stem cells with an average vector copy < 2.0. Fetal hemoglobin (HbF) levels ranged from 20 to 44% of total hemoglobin and approximately two-thirds of circulating red blood cells expressed HbF detected by immunofluorescence (F-cells). Gene therapy treatment of SCD mice ameliorated anemia, reduced hyperleukocytosis, improved renal function, and reduced iron accumulation in liver, spleen, and kidneys. Thus, modest levels of chimerism with donor cells expressing high levels of HbF from an insulated γ-globin lentiviral vector can improve the pathology of SCD in mice, thereby illustrating a potentially safe and effective strategy for gene therapy in humans.

Association of Pathologic Nodal Staging Quality With Survival Among Patients With Non-Small Cell Lung Cancer After Resection With Curative Intent.

Importance Pathologic nodal stage is the most significant prognostic factor in resectable non–small cell lung cancer (NSCLC). The International Association for the Study of Lung Cancer NSCLC staging project revealed intercontinental differences in N category–stratified survival. These differences may indicate differences not only in cancer biology but also in the thoroughness of the nodal examination. Objective To determine whether survival was affected by sequentially more stringent definitions of pN staging quality in a cohort of patients with NSCLC after resection with curative intent. Design This observational study used the Mid-South Quality of Surgical Resection cohort, a population-based database of lung cancer resections with curative intent. A total of 2047 consecutive patients who underwent surgical resection at 11 hospitals with at least 5 annual lung cancer resections in 4 contiguous US Dartmouth hospital referral regions in northern Mississippi, eastern Arkansas, and western Tennessee (>90% of the eligible population) were included. Resections were performed from January 1, 2009, through January 25, 2016. Survival was evaluated with the Kaplan-Meier method and Cox proportional hazards models. Exposures Eight sequentially more stringent pN staging quality strata included the following: all patients (group 1); those with complete resections only (group 2); those with examination of at least 1 mediastinal lymph node (group 3); those with examination of at least 10 lymph nodes (group 4); those with examination of at least 3 hilar or intrapulmonary and at least 3 mediastinal lymph nodes (group 5); those with examination of at least 10 lymph nodes, including at least 1 mediastinal lymph node (group 6); those with examination of at least 1 hilar or intrapulmonary and at least 3 mediastinal nodal stations (group 7); and those with examination of at least 1 hilar or intrapulmonary lymph node, at least 10 total lymph nodes, and at least 3 mediastinal nodal stations (group 8). Main Outcomes and Measures N category–stratified overall survival. Results Of the total 2047 patients (1046 men [51.1%] and 1001 women [48.9%]; mean [SD] age, 67.0 [9.6] years) included in the analysis, the eligible analysis population ranged from 541 to 2047, depending on stringency. Sequential improvement in the N category–stratified 5-year survival of pN0 and pN1 tumors was found from the least stringent group (0.63 [95% CI, 0.59-0.66] for pN0 vs 0.46 [95% CI, 0.38-0.54] for pN1) to the most stringent group (0.71 [95% CI, 0.60-0.79] for pN0 vs 0.60 [95% CI, 0.43-0.73] for pN1). The pN1 cohorts with 3 or more mediastinal nodal stations examined had the most striking survival improvements. More stringently defined mediastinal nodal examination was associated with better separation in survival curves between patients with pN1 and pN2 tumors. Conclusions and Relevance The prognostic value of pN stratification depends on the thoroughness of examination. Differences in thoroughness of nodal staging may explain a large proportion of intercontinental survival differences. More thorough nodal examination practice must be disseminated to improve the prognostic value of the TNM staging system. Future updates of the TNM staging system should incorporate more quality restraints.

Evolution in the Surgical Care of Patients With Non–Small Cell Lung Cancer in the Mid-South Quality of Surgical Resection Cohort

Surgery is the most important curative treatment modality for patients with early-stage non-small cell lung cancer (NSCLC). We examined the pattern of surgical resection for NSCLC in a high incidence and mortality region of the United States over a 10-year period (2004-2013) in the context of a regional surgical quality improvement initiative. We abstracted patient-level data on all resections at 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions in North Mississippi, East Arkansas, and West Tennessee. Surgical quality measures focused on intraoperative practice, with emphasis on pathologic nodal staging. We used descriptive statistics and trend analyses to assess changes in practice over time. To measure the effect of an ongoing regional quality improvement intervention with a lymph node specimen collection kit, we used period effect analysis to compare trends between the preintervention and postintervention periods. Of 2566 patients, 18% had no preoperative biopsy, only 15% had a preoperative invasive staging test, and 11% underwent mediastinoscopy. The rate of resections with no mediastinal lymph nodes examined decreased from 48%-32% (P < 0.0001), whereas the rate of resections examining 3 or more mediastinal stations increased from 5%-49% (P < 0.0001). There was a significant period effect in the increase in the number of N1, mediastinal, and total lymph nodes examined (all P < 0.0001). A quality improvement intervention including a lymph node specimen collection kit shows early signs of having a significant positive effect on pathologic nodal examination in this population-based cohort. However, gaps in surgical quality remain.

Birth Prevalence of Sickle Cell Trait and Sickle Cell Disease in Shelby County, TN

Accurate quantification of the regional burden of sickle cell disease (SCD) is vital to allocating health‐related resources. Shelby County, TN, which includes the city of Memphis and the regional pediatric SCD treatment center at St. Jude Childrens Research Hospital, is home to a large population of African Americans.

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose‐dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long‐term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient‐years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow‐up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso‐occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 106/L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

Distance from an Urban Sickle Cell Center and its Effects on Routine Healthcare Management and Rates of Hospitalization.

Abstract The St. Jude Children’s Research Hospital (St. Jude) comprehensive sickle cell center serves a 150 mile catchment radius around Memphis, TN, USA. Full travel expenses are provided for routine and acute care visits for sickle cell disease patients living ≥35 miles from St. Jude. We compared hospitalization rates to national estimates and assessed if driving distance was a barrier to sickle cell healthcare despite the travel reimbursement policy. We evaluated the associations between hospitalizations and routine clinic visits and distance from St. Jude using negative binomial models and we conducted bias analyses by Monte Carlo simulation. We followed 545 patients (2550 patient-years) aged ≤18 years with sickle cell disease (Hb SS only) from 2007 to 2012. The hospitalization rate per patient-year was 0.65 [95% CI (confidence interval): 0.62, 0.68), significantly lower than the national rate of 1.16 (95% CI: 1.14, 1.18). Children living <35 miles from St. Jude had 1.75 (95% CI: 1.41, 2.17) times the rate of hospitalization and 1.22 (95% CI: 1.07, 1.39) times the rate of clinic visits compared to those ≥35 miles. Bias analysis suggested that under-reporting could explain the observed difference in hospitalization rates if 30.0% of patients who lived ≥35 miles from the hospital under-reported six hospitalizations over 6 years. The hospitalization rate at St. Jude in children with sickle cell disease was lower than expected from national rates. Greater distance from the sickle cell center (>35 miles) was associated with decreased hospitalization rates, despite the travel allowances that are provided for those who live ≥35 miles from the hospital.

Pediatric to adult care co-location transitional model for youth with sickle cell disease

Among youth with sickle cell disease (SCD), morbidity and mortality substantially increase following departure from pediatric care. The purpose of this study was to investigate the efficacy of co-location transitional model by comparing the rate of health care utilization pre- and post-transfer to adult care and to evaluate the relation between disease specific knowledge and the co-location model. All patients transferring from pediatric to adult care between October 2011 and December 2013, opting for the co-location model to transition from pediatric to adult care in Memphis, TN were included in the analysis. Overall utilization, comprised of both acute care visits and hospitalizations, and health-maintenance visits were compared pre- and post-transfer. Additionally, the association between patient understanding of pain and all health care utilization were assessed. There were 59 participants who established adult care using the co-location transitional model. We found an increase in acute care visits, but a decrease in hospitalizations, that resulted in no change in overall utilization (IRR: 1.11; (95%CI: 0.76, 1.63) comparing pediatric to adult care. The overall utilization rate during adult care was below those previously reported (3.61 vs. 1.65 per person-year, p<0.001). Additionally, we found a significant decrease in hospitalizations and an increase in health-maintenance visits associated with higher pain knowledge after transfer. The co-location model for pediatric to adult care transition seems to provide benefits among youth with SCD by increasing disease knowledge and reducing health care utilization to levels below those seen at the national level. This article is protected by copyright. All rights reserved.

Comment on the Proposals for the Revision of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer

Comment on the Proposals for the Revision of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer Raymond U. Osarogiagbon, M.B.B.S.,* Matthew P. Smeltzer, MStat, PhD, Nicholas Faris, MDiv, Ramón Rami-Porta, MD, Peter Goldstraw, MD, Hisao Asamura, MD Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, Tennessee School of Public Health, University of Memphis, Memphis, Tennessee Thoracic Surgery Service, University Hospital Mutua Terrassa and Network of Biomedical Research Centers for Respiratory Diseases Lung Cancer Group, Terrassa, Barcelona, Spain Academic Department of Thoracic Surgery, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, London, United Kingdom Division of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan