Peter E. DeWitt

The Impact of Definitive Local Therapy for Lymph Node-Positive Prostate Cancer: A Population-Based Study

PURPOSE To evaluate the survival outcomes for patients with lymph node-positive, nonmetastatic prostate cancer undergoing definitive local therapy (radical prostatectomy [RP], external beam radiation therapy [EBRT], or both) versus no local therapy (NLT) in the US population in the modern prostate specific antigen (PSA) era. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results database was queried for patients with T1-4N1M0 prostate cancer diagnosed from 1995 through 2005. To allow comparisons of equivalent datasets, patients were analyzed in separate clinical (cN+) and pathologically confirmed (pN+) lymph node-positive cohorts. Kaplan-Meier overall survival (OS) and prostate cancer-specific survival (PCSS) estimates were generated, with accompanying univariate log-rank and multivariate Cox proportional hazards comparisons. RESULTS A total of 796 cN+ and 2991 pN+ patients were evaluable. Among cN+ patients, 43% underwent EBRT and 57% had NLT. Outcomes for cN+ patients favored EBRT, with 10-year OS rates of 45% versus 29% (P<.001) and PCSS rates of 67% versus 53% (P<.001). Among pN+ patients, 78% underwent local therapy (RP 57%, EBRT 10%, or both 11%) and 22% had NLT. Outcomes for pN+ also favored local therapy, with 10-year OS rates of 65% versus 42% (P<.001) and PCSS rates of 78% versus 56% (P<.001). On multivariate analysis, local therapy in both the cN+ and pN+ cohorts remained independently associated with improved OS and PCSS (all P<.001). Local therapy was associated with favorable hazard ratios across subgroups, including patients aged ≥70 years and those with multiple positive lymph nodes. Among pN+ patients, no significant differences in survival were observed between RP versus EBRT and RP with or without adjuvant EBRT. CONCLUSIONS In this large, population-based cohort, definitive local therapy was associated with significantly improved survival in patients with lymph node-positive prostate cancer.

A systematic review and meta-analysis of ambient temperature and diarrhoeal diseases

BACKGROUND Global climate change is expected to increase the risk of diarrhoeal diseases, a leading cause of childhood mortality. However, there is considerable uncertainty about the magnitude of these effects and which populations bear the greatest risks. METHODS We conducted a systematic review using defined search terms across four major databases and, additionally, examined the references of 54 review articles captured by the search. We evaluated sources of heterogeneity by pathogen taxon, exposure measure, study quality, country income level and regional climate, and estimated pooled effect estimates for the subgroups identified in the heterogeneity analysis, using meta-analysis methods. RESULTS We identified 26 studies with 49 estimates. Pathogen taxa were a source of heterogeneity. There was a positive association between ambient temperature and all-cause diarrhoea (incidence rate ratio (IRR) 1.07; 95% confidence interval (CI) 1.03, 1.10) and bacterial diarrhoea (IRR 1.07; 95% CI 1.04, 1.10), but not viral diarrhoea (IRR 0.96; 95% CI 0.82, 1.11). These associations were observed in low-, middle- and high-income countries. Only one study of protozoan diarrhoea was identified. CONCLUSIONS Changes in temperature due to global climate change can and may already be affecting diarrhoeal disease incidence. The vulnerability of populations may depend, in part, on local pathogen distribution. However, evidence of publication bias and the uneven geographical distribution of studies limit the precision and generalizability of the pooled estimates.

Gleason stratifications prognostic for survival in men receiving definitive external beam radiation therapy for localized prostate cancer

PURPOSE Histologic grade analyses for prostate cancer (PCa) have traditionally included Gleason scores (GS) of ≤6, 7, and 8-10. Stratified biochemical progression-free survival has increasingly been reported within these groups on analyses of primary-secondary patterns (PSPs) (e.g., 3+4 vs. 4+3) and overall GS (e.g., 8 vs. 9 vs. 10) but with limited data regarding stratified survival outcomes. In this analysis, outcomes for biopsy-assigned GS 6 to 10 were comprehensively evaluated to identify stratifications prognostic for survival in patients undergoing external beam radiation therapy (EBRT). METHODS The Surveillance, Epidemiology, and End Results database was examined for T1-4 N0 M0, GS 6 to 10 PCa managed with EBRT alone from 2004 to 2006. GS and PSP variations were analyzed for PCa-specific survival (PCSS) and overall survival (OS). RESULTS Overall, 26,885 patients were evaluated. Preliminary PSP analyses identified stratifications for 3+4 vs. 4+3 = 7 and 4+4 = 8 vs. GS 8 with pattern 5 (P5) (i.e., 3+5 and 5+3) as significant; however, no differences were observed for 4+5 vs. 5+4 = 9. The primary analysis included stratifications for GS 6, 3+4, 4+3, 4+4, 8 w/P5, 9, and 10, where the 7.5-year PCSS rates were 99%, 97%, 95%, 91%, 86%, 81%, and 78% and 7.5-year OS rates were 83%, 76%, 72%, 67%, 66%, 58%, and 54%, respectively. PCSS differences for sequential score increases were all significant on univariate analyses (all P<0.05). In sequential multivariate analyses of PCSS accounting for age, prostate-specific antigen, T stage, year, marital status, race, and tumor registry, the identified GS stratifications remained significant (all P<0.05), with the exception of GS 8 w/P5 vs. 9 (P = 0.11). In overall multivariate analyses, the identified GS stratifications represented the strongest prognostic factor for survival. Subgroup analyses demonstrated that presence of any P5 was an independent prognostic factor for survival. CONCLUSION In the largest reported survival analysis of Gleason stratifications, biopsy-assigned GS 6, 3+4, 4+3, 4+4, 8 w/P5, 9, and 10 represented sequential prognostic factors for survival in patients managed with definitive EBRT.

Management of Male Breast Cancer in the United States: A Surveillance, Epidemiology and End Results Analysis

PURPOSE To analyze the stage-specific management of male breast cancer (MBC) with surgery and radiation therapy (RT) and relate them to outcomes and to female breast cancer (FBC). METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results database was queried for all primary invasive MBC and FBC diagnosed from 1973 to 2008. Analyzable data included age, race, registry, grade, stage, estrogen and progesterone receptor status, type of surgery, and use of RT. Stage was defined as localized (LocD): confined to the breast; regional (RegD): involving skin, chest wall, and/or regional lymph nodes; and distant: M1. The primary endpoint was cause-specific survival (CSS). RESULTS A total of 4276 cases of MBC and 718,587 cases of FBC were identified. Male breast cancer constituted 0.6% of all breast cancer. Comparing MBC with FBC, mastectomy (M) was used in 87.4% versus 38.3%, and breast-conserving surgery in 12.6% versus 52.6% (P<10(-4)). For males with LocD, CSS was not significantly different for the 4.6% treated with lumpectomy/RT versus the 70% treated with M alone (hazard ratio [HR] 1.33; 95% confidence interval [CI] 0.49-3.61; P=.57). Postmastectomy RT was delivered in 33% of males with RegD and was not associated with an improvement in CSS (HR 1.11; 95% CI 0.88-1.41; P=.37). There was a significant increase in the use of postmastectomy RT in MBC over time: 24.3%, 27.2%, and 36.8% for 1973-1987, 1988-1997, and 1998-2008, respectively (P<.0001). Cause-specific survival for MBC has improved: the largest significant change was identified for men diagnosed in 1998-2008 compared with 1973-1987 (HR 0.73; 95% CI 0.60-0.88; P=.0004). CONCLUSIONS Surgical management of MBC is dramatically different than for FBC. The majority of males with LocD receive M despite equivalent CSS with lumpectomy/RT. Postmastectomy RT is greatly underutilized in MBC with RegD, although a CSS benefit was not demonstrated. Outcomes for MBC are improving, attributable to improved therapy and its use in this unscreened population.

Multiplex array proteomics detects increased MMP-8 in CSF after spinal cord injury

IntroductionA variety of methods have been used to study inflammatory changes in the acutely injured spinal cord. Recently novel multiplex assays have been used in an attempt to overcome limitations in numbers of available targets studied in a single experiment. Other technical challenges in developing pre-clinical rodent models to investigate biomarkers in cerebrospinal fluid (CSF) include relatively small volumes of sample and low concentrations of target proteins. The primary objective of this study was to characterize the inflammatory profile present in CSF at a subacute time point in a clinically relevant rodent model of traumatic spinal cord injury (SCI). Our other aim was to test a microarray proteomics platform specifically for this application.MethodsA 34 cytokine sandwich ELISA microarray was used to study inflammatory changes in CSF samples taken 12 days post-cervical SCI in adult rats. The difference between the median foreground signal and the median background signal was measured. Bonferroni and Benjamini-Hochburg multiple testing corrections were applied to limit the False Discovery Rate (FDR), and a linear mixed model was used to account for repeated measures in the array.ResultsWe report a novel subacute SCI biomarker, elevated levels of matrix metalloproteinase-8 protein in CSF, and discuss application of statistical models designed for multiplex testing.ConclusionsMajor advantages of this assay over conventional methods include high-throughput format, good sensitivity, and reduced sample consumption. This method can be useful for creating comprehensive inflammatory profiles, and biomarkers can be used in the clinic to assess injury severity and to objectively grade response to therapy.

Vitamin D deficiency does not increase the rate of postoperative hypocalcemia after thyroidectomy

BACKGROUND Hypocalcemia is a frequent complication of thyroidectomy. Although typically mild and temporary, it can lead to an increased length of stay, readmission, and in some cases be permanent. Controversy exists as to whether vitamin D deficiency (VDD) contributes to post-thyroidectomy hypocalcemia. METHODS This is a retrospective study of 152 patients who underwent thyroidectomy. Patients with or without VDD were compared. Data were analyzed for demographics, operative procedure, calcium levels, and complications of hypocalcemia. RESULTS There was no difference in the rates of biochemical or symptomatic hypocalcemia or in the need for readmission between the VDD and non-VDD groups. A multivariate analysis controlling for central neck dissection, parathyroid autotransplant, and preoperative diagnosis confirmed no association between VDD and post-thyroidectomy hypocalcemia. CONCLUSIONS Despite VDD being common in patients undergoing thyroidectomy, our results do not suggest that this increases the rate of hypocalcemia. Thus, preoperative evaluation/repletion of VDD is unlikely to reduce post-thyroidectomy hypocalcemia rates.

Sparing the larynx and esophageal inlet expedites feeding tube removal in patients with stage III-IV oropharyngeal squamous cell carcinoma treated with intensity-modulated radiotherapy†

To evaluate the effect of larynx and esophageal inlet sparing on dysphagia recovery after intensity‐modulated radiotherapy (IMRT) for stage III‐IV oropharyngeal squamous cell carcinoma.

Functional Status Scale in children with traumatic brain injury: a prospective cohort study

Objectives: In children with traumatic brain injury, 1) to describe the hospital discharge functional outcome and change from baseline function using the Functional Status Scale and 2) to determine any associations between discharge Functional Status Scale and age, injury mechanism, neurologic examination, imaging, and other predictors of outcome. Design: Prospective observational cohort study, May 2013 to November 2015. Setting: Two U.S. children’s hospitals designated as American College of Surgeons level 1 pediatric trauma centers. Patients: Children less than 18 years old admitted to an ICU with acute traumatic brain injury and either a surgical or critical care intervention within the first 24 hours or in-hospital mortality. Interventions: None. Measurements and Main Results: The primary outcome was hospital discharge Functional Status Scale. Most, 133 of 196 (68%), had severe traumatic brain injury (admission Glasgow Coma Scale, 3–8). Overall hospital mortality was 14%; 20% among those with severe traumatic brain injury. Hospital discharge Functional Status Scale had an inverse relationship with Glasgow Coma Scale: for each increase in admission Glasgow Coma Scale by 1, the discharge Functional Status Scale decreased by 0.5 (95% CI, 0.7–0.3). Baseline Functional Status Scale was collected at one site (n = 75). At that site, nearly all (61/62) of the survivors had normal or near-normal (⩽ 7) preinjury Functional Status Scale. More than one-third, 23 of 62 (37%), of survivors had new morbidity at hospital discharge (increase in Functional Status Scale, ≥ 3). Among children with severe traumatic brain injury who had baseline Functional Status Scale collected, 21 of 41 survivors (51%) had new morbidity at hospital discharge. The mean change in Functional Status Scale from baseline to hospital discharge was 3.9 ± 4.9 overall and 5.2 ± 5.4 in children with severe traumatic brain injury. Conclusions: More than one-third of survivors, and approximately half of survivors with severe traumatic brain injury, will have new morbidity. Hospital discharge Functional Status Scale, change from baseline Functional Status Scale, and new morbidity acquisition can be used as outcome measures for hospital-based care process improvement initiatives and interventional studies of children with traumatic brain injury.

Comparison of 3 Body Size Descriptors in Critically Ill Obese Children and Adolescents: Implications for Medication Dosing

OBJECTIVE To compare 3 methods of weight determination for medication dose calculations in obese children and to discuss feasibility for use in routine care. METHODS This was a patient safety and quality improvement study evaluating patients (2-19 years old) admitted to the pediatric intensive care unit during a 13-month period (July 2010-July 2011). Patients identified as obese (≥95th percentile body mass index [BMI] for age), including severely obese (≥99th percentile BMI for age), were included in the weight method comparison portion of this study. Lean body mass estimations, using equations derived by the Peters and Foster methods, were compared to ideal body weight estimates by using the BMI method. Absolute differences between values generated by the 3 methods, intraclass correlation (ICC), and Bland-Altman plots were calculated. RESULTS A total of 1369 patients met initial criteria; 176 met criteria for the dosing weight comparison (age ± SD = 9.28 ± 5 years; actual weight ± SD = 55.5 ± 33.9 kg; 46% female). Sixty were severely obese and 116 were obese. Mean ICC between methods was 0.968 (95% Confidence interval (CI): 0.959, 0.975). The Peters method estimated higher weights than the Foster or BMI method. Bland-Altman plots illustrated good agreement between methods in children with weight below 50 kg, but decreased agreement above 50 kg, which was influenced by sex. CONCLUSIONS All methods demonstrated strong correlation and acceptable agreement in children below 50 kg. Systematic biases were identified in children above 50 kg where variance was higher. The BMI method was least complex to calculate and the most feasible method for daily use.

Are We Appropriately Selecting Therapy For Patients With Cervical Cancer? Longitudinal Patterns-of-Care Analysis for Stage IB-IIB Cervical Cancer

PURPOSE We performed a patterns-of-care analysis evaluating the effects of newer technology and recent research findings on treatment decisions over 26 years to determine whether patients with cervical cancer are being appropriately selected for treatment to optimize the therapeutic ratio. METHODS AND MATERIALS A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) program from 1983 to 2009. We identified 10,933 women with stage IB-IIB cervical carcinoma. RESULTS Of the 10,933 subjects identified, 40.1% received surgery, 26.8% received radiation (RT), and 33.1% received surgery plus RT. RT use increased after 2000 compared to prior to 2000, with a corresponding decrease in surgery and surgery plus RT. Among patients with risk factors including tumor size >4 cm, positive parametria, and positive lymph nodes, declining use of surgery plus RT was observed. However, 23% of patients with tumors >4 cm, 20% of patients with positive parametria, and 55% of node-positive patients continued to receive surgery plus RT as of 2009. Factors associated with increased use of surgery plus RT included patient age <50 and node-positive status. CONCLUSIONS In this largest patterns-of-care analysis to date for patients with locally advanced cervical cancer, we found a substantial proportion of patients continue to undergo surgery followed by radiation, despite randomized data supporting the use of definitive radiation therapy, with lower morbidity than surgery and radiation.