Physical activity levels and quality of life relate to collagen turnover and inflammation changes after running.

The purpose of this study was to determine whether an association existed between self-reported symptom and function scores and tissue turnover or inflammatory biomarker changes after a running bout among individuals with and without an acute knee-injury history. A pre-test/post-test prospective cohort study design (Level II) of 22 participants was conducted. Eleven physically active individuals with a history of anterior cruciate ligament surgery and/or meniscus surgery within 4 years of study participation were matched to 11 healthy control participants. All participants completed self-reported outcome measures (Knee Osteoarthritis Outcomes Score and Tegner activity level) assessing knee symptoms and functional levels prior to the run. Blood samples were taken both pre- and post-30-minute run at a prescribed pace on a treadmill to determine serum biomarker concentration changes. Tegner activity levels were inversely related to type II collagen/type II collagen synthesis marker ratio biomarker changes after the run (r = -0.45, p = 0.01). Quality-of-life scores pre-exercise were inversely related to interleukin-1ß changes after the run (r = -0.50, p = 0.02). No other correlation coefficients were statistically significant (r = -0.39 to 0.36). Ultimately, individuals with lower activity and quality-of-life scores experienced greater increases in collagen turnover and inflammation after a running bout, respectively. A gradual increase in activity (e.g., frequency, duration, intensity) may be warranted in this group prior to returning to activities that involve running. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:612-617, 2017.

DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma.

Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and the 8th most common cancer overall in the US. RCC survival rates drop precipitously with regional and distant spread and recent studies have demonstrated that RCC presents an epithelial-mesenchymal transition (EMT) phenotype linked to increased recurrence and decreased survival. EMT is a key characteristic of tumor stem cells (TSCs) along with chemo-resistance and radio-resistance, which are also phenotypic of RCC. Targeting these factors is key to increasing the survival of RCC patients. Doublecortin-like kinase 1 (DCLK1) marks TSCs in pancreatic and colorectal cancer and regulates EMT and stemness. Analysis of the Cancer Genome Atlas' RCC dataset revealed that DCLK1 is overexpressed and dysregulated on the mRNA and epigenetic level in more than 93% of RCC tumors relative to adjacent normal tissue. Immunohistochemistry using α-DCLK1 antibody confirmed overexpression and demonstrated a major increase in immunoreactivity in stage II-III tumors compared to normal kidney and stage I tumors. Small-interfering RNA (siRNA) mediated knockdown of DCLK1 resulted in decreased expression of EMT and pluripotency factors and significantly reduced invasion, migration, focal adhesion, drug-resistance, and clonogenic capacity. These findings suggest that DCLK1 is a novel, overexpressed factor in RCC progression that may be targeted to suppress EMT, metastasis, and stemness in early-stage and advanced RCC to increase patient survival. Moreover, the possibility that DCLK1 may mark a population of tumor stem-like cells in RCC should be further investigated in light of these findings.

The impact of Smad3 loss of function on TGF-ß signaling and radiation-induced capsular contracture.

BACKGROUND: Capsular contracture remains a major problem following prosthetic breast implantation, especially in patients undergoing irradiation. Recent studies suggest that such radiation injuries are a cascading process of cytokine activation, with transforming growth factor (TGF)-ß acting as the "master switch." Because TGF-ß signals through phosphorylation of Smad3, a plausible approach to abate TGF-ß-induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wild-type and Smad3 knockout mice was compared using micro-computed tomographic and histologic examination. METHODS: On day 0, 48 mice were implanted with bilateral silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomographic scanning. Animals in the radiation arm then received a 10-Gy directed radiation dose. On postoperative days 21, 28, 35, and 42, animals were imaged again. Histologic evaluation was performed at necropsy. RESULTS: Irradiated implants in the wild-type mice demonstrated shape and contour deformation on micro-computed tomographic scanning beginning on postoperative day 21 and progressing through day 42. Conversely, micro-computed tomographic scanning of irradiated implants in knockout mice demonstrated few changes from day 0 through day 42. Corresponding histologic specimens from wild-type mice demonstrated irregular capsules composed of disorganized collagen that became thicker from day 21 to day 42. Irradiated knockout specimen maintained thin capsules from day 21 through day 42. CONCLUSIONS: In this work, inhibiting TGF-ß signaling led to a reduction in radiation-induced capsular contracture as measured by micro-computed tomographic and histologic evaluation. The results of this study suggest a promising target for the prevention of capsular contracture through the development of anti-Smad3/TGF-ß-based therapies.

A novel animal model for studying silicone gel-related capsular contracture.

BACKGROUND: Capsular contracture remains one of the major problems following prosthetic implantation of the breast, especially in postmastectomy breast reconstruction patients receiving radiation therapy. Advances in this area have been hampered by the absence of an acceptable animal model. This study evaluates a new murine model with which to facilitate research into the cellular and molecular pathways underlying capsular contracture and provides a surrogate for evaluating potential therapies. METHODS: On day 0, mice were implanted with silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomography. Animals in the irradiation group then received a 10-Gy directed radiation dose from a slit-beam cesium source. On days 21, 28, 35, and 42, both irradiated and nonirradiated animals were imaged again and histologic evaluation was performed. RESULTS: Nonirradiated implants demonstrated little change in contour from day 0 through day 42 on micro-computed tomography, whereas irradiated implants demonstrated consistent shape deformation and irregularities in contour at these time points. Histologic evaluation showed that irradiated specimens developed thicker capsules and more disorganized capsules than nonirradiated specimens at each time point. CONCLUSIONS: In this article, the authors introduce a novel animal model with which to study capsular contracture. This model is the first of its kind to use radiation to induce, and live-scan micro-computed tomography to evaluate, capsular contracture. Radiation was shown to cause reproducible changes that can be consistently evaluated with micro-computed tomography and histology. Future studies with this model will study the cellular and molecular mechanisms underlying capsular contracture using knockout and transgenic mouse strains.

Acute toxicity of postoperative IMRT and chemotherapy for endometrial cancer.

PURPOSE: The aim of this study was to determine the acute toxicity of postoperative intensity-modulated radiotherapy (IMRT) with and without chemotherapy in patients with endometrial cancer. MATERIALS AND METHODS: A total of 19 patients with stages IB-IVB endometrial cancer who underwent surgery and postoperative IMRT were reviewed. The treatment planning goal was to cover the tissue at risk and minimize the dose to the bladder, bowel, and bone marrow. Median dose was 50.4 Gy (range 49.6-51.2 Gy). Altogether, 14 patients underwent chemotherapy; most were given carboplatin and paclitaxel. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). RESULTS: The prescribed radiation treatment was completed in all patients. The prescribed cycles of chemotherapy were completed in all 14 patients, except one who received five of six cycles limited by prolonged thrombocytopenia. Chemotherapy was delayed in two patients (14%). Three patients required growth factor support during chemotherapy, and one patient required a blood transfusion. Acute grades 3-4 hematological toxicity occurred in 9 of the 14 patients (64%) who underwent chemotherapy. None experienced acute grade 3 or 4 genitourinary or gastrointestinal toxicity. CONCLUSION: Adjuvant IMRT and chemotherapy following surgery in patients with endometrial cancer is well tolerated and did not lead to treatment modification in most patients.

Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.

PURPOSE: Small-cell lung cancer (SCLC) is a histologic subtype of lung cancer with a distinct biology and clinical course. It has been observed that the incidence of SCLC has been decreasing over the last several years. METHODS: We used the Surveillance, Epidemiologic, and End Results (SEER) database to determine the incidence of SCLC over the last 30 years. In addition, we sought to determine sex- and stage-based differences in the incidence and survival of SCLC among a proportion of reported cases of lung cancer over the last 30 years (1973 to 2002). Joinpoint analyses were applied to test the trends in annual percentage change for statistical significance. RESULTS: The proportion of SCLC (among all lung cancer histologic types) decreased from 17.26% in 1986 to 12.95% in 2002. Of all patients with SCLC, the proportion of women with SCLC increased from 28% in 1973% to 50% in 2002. A modest but statistically significant improvement in 2- and 5-year survival was noted among both limited-stage SCLC and extensive-stage SCLC cohorts during the study period. CONCLUSION: Our analysis indicates that the incidence of SCLC is decreasing in the United States, and only modest improvements have been seen in survival over the last 30 years. Possible explanations for the decreasing incidence include the decrease in the percentage of smokers and the change to low-tar filter cigarettes. Despite trends toward modest improvement in survival, the outcome remains very poor.

A prospective study of differences in duodenum compared to remaining small bowel motion between radiation treatments: implications for radiation dose escalation in carcinoma of the pancreas.

PURPOSE: As a foundation for a dose escalation trial, we sought to characterize duodenal and non-duodenal small bowel organ motion between fractions of pancreatic radiation therapy. PATIENTS AND METHODS: Nine patients (4 women, 5 men) undergoing radiation therapy were enrolled in this prospective study. The patients had up to four weekly CT scans performed during their course of radiation therapy. Pancreas, duodenum and non-duodenal small bowel were then contoured for each CT scan. On the initial scan, a four-field plan was generated to fully cover the pancreas. This plan was registered to each subsequent CT scan. Dose-volume histogram (DVH) analyses were performed for the duodenum, non-duodenal small bowel, large bowel, and pancreas. RESULTS: With significant individual variation, the volume of duodenum receiving at least 80% of the prescribed dose was consistently greater than the remaining small bowel. In the patient with the largest inter-fraction variation, the fractional volume of non-duodenal small bowel irradiated to at least the 80% isodose line ranged from 1% to 20%. In the patient with the largest inter-fraction variation, the fractional volume of duodenum irradiated to at least the 80% isodose line ranged from 30% to 100%. CONCLUSION: The volume of small bowel irradiated during four-field pancreatic radiation therapy changes substantially between fractions. This suggests dose escalation may be possible. However, dose limits to the duodenum should be stricter than for other segments of small bowel.

Differential prognostic impact of comorbidity.

PURPOSE: Cancer patients with concurrent comorbid conditions have worse outcomes than patients with no comorbidities. We hypothesized that the prognostic impact of comorbidities would be greatest for patients with cancers associated with a long natural history and least in patients with aggressive cancers. PATIENTS AND METHODS: Using the Barnes-Jewish Hospital Oncology Data Services cancer registry, we grouped 11,558 patients with breast, lung, colon, or prostate cancer by morphologic stage at diagnosis and then determined the 1-year overall survival rate for each group. Overall, severity of comorbidity was assessed from chart review and classified into one of four groups: none, mild, moderate, or severe. The relative prognostic impact of comorbidity was measured by the hazard ratio and adjusted for the prognostic impact of age, race, and sex. RESULTS: One-year overall survival rate ranged from 20% for 1,005 patients with distant spread of lung cancer to 98% for 3,325 patients with localized prostate cancer. Adjusted hazard ratio of moderate/severe comorbidity (relative to none/mild) ranged from 1.04 to 4.48. The correlation between overall survival rate and severity of comorbidity was statistically significant (r2 = 0.56; P < .001). The proportion of variance in outcome explained by comorbidity ranged from less than 1% to almost 9%, depending on tumor site and stage. CONCLUSION: Concurrent comorbidities had the greatest prognostic impact among groups with the highest survival rate and the least impact in groups with the lowest survival rate. These findings can be used to help determine the role comorbidity information should play in studies of cancer outcomes.

The epidemiology of bronchioloalveolar carcinoma over the past two decades: analysis of the SEER database.

Bronchioloalveolar carcinoma of the lung (BAC) is a subtype of adenocarcinoma of the lung. Although traditionally grouped with other non-small cell lung carcinomas (NSCLC), BAC has unique morphological features and clinical behavior such as bilateral lung involvement, indolent course and lack of association with smoking. Some epidemiologic studies report a significant increase in the incidence of BAC. We used the SEER database to compare the incidence, demographics, and overall survival of BAC patients as compared to other NSCLC types over the past two decades (1979-1998). Although the incidence of BAC has increased over the past two decades, BAC represents less than 4% of all NSCLC in every time period evaluated. The 1 year survival rate is significantly better for BAC patients relative to other histological subtypes of NSCLC. There has not been a marked increase in the incidence of BAC reported to SEER over the past 20 years.

Prognostic importance of comorbidity in a hospital-based cancer registry.

CONTEXT: Patients with cancer often have other medical ailments, referred to as comorbidity. Comorbidity may impact treatment decision-making, prognosis, and quality of care assessment. OBJECTIVE: To assess whether comorbidity information can provide important prognostic information in a hospital-based cancer registry. DESIGN, SETTING, AND PARTICIPANTS: An observational prospective cohort study using comorbidity data collected by trained hospital-based cancer registrars. Comorbidity was obtained through medical record review using the Adult Comorbidity Evaluation 27, a validated chart-based comorbidity instrument. A total of 17,712 patients receiving care between January 1, 1995, and January 31, 2001, for the primary diagnosis of new cancer of the prostate, lung (nonsmall cell), breast, digestive system, gynecological, urinary system, or head and neck were included. MAIN OUTCOME MEASURE: Duration in months of overall survival. RESULTS: A total of 19,268 patients were included in the study; median duration of follow-up was 31 months. Of these patients, 1556 (8.0%) were excluded due to missing or unknown data. Severity of comorbidity strongly influenced survival in a dose-dependent fashion and the impact of comorbidity was independent of cancer stage. Compared with patients without comorbidity, the adjusted hazard ratio associated with mild comorbidity was 1.21 (95% confidence interval [CI], 1.13-1.30), moderate comorbidity was 1.86 (95% CI, 1.73-2.00), and severe comorbidity was 2.56 (95% CI, 2.35-2.81). Adjusted Kaplan-Meier survival curves revealed that at any point in time the patients with more severe levels of comorbidity had worse survival (partial chi2(3) due to comorbidity, 523.54; P<.001). Model discrimination ranged from 0.71 for head and neck to 0.86 for prostate cancers. CONCLUSIONS: Comorbidity is an important independent prognostic factor for patients with cancer. The inclusion of comorbidity in hospital-based cancer registries will increase the value and use of observational research.