Endothelial to mesenchymal transition in the interleukin-1 pathway during aortic aneurysm formation.

OBJECTIVE: Endothelial to mesenchymal transition may represent a key link between inflammatory stress and endothelial dysfunction seen in aortic aneurysm disease. Endothelial to mesenchymal transition is regulated by interleukin-1ß, and previous work has demonstrated an essential role of interleukin-1 signaling in experimental aortic aneurysm models. We hypothesize that endothelial to mesenchymal transition is present in murine aortic aneurysms, and loss of interleukin-1 signaling attenuates this process. METHODS: Murine aortic aneurysms were created in novel CDH5-Cre lineage tracking mice by treating the intact aorta with peri-adventitial elastase. Endothelial to mesenchymal transition transcription factors as well as endothelial and mesenchymal cell markers were analyzed via immunohistochemistry and immunofluorescence (n = 10/group). To determine the role of interleukin-1 signaling, endothelial-specific interleukin-1 receptor 1 knockout and wild-type mice (n = 10/group) were treated with elastase. Additionally, C57/BL6 mice were treated with the interleukin-1 receptor 1 antagonist Anakinra (n = 7) or vehicle (n = 8). RESULTS: Elastase treatment yielded greater aortic dilation compared with controls (elastase 97.0% ± 34.0%; control 5.3% ± 4.8%; P < .001). Genetic deletion of interleukin-1 receptor 1 attenuated aortic dilation (control 126.7% ± 38.7%; interleukin-1 receptor 1 knockout 35.2% ± 14.7%; P < .001), as did pharmacologic inhibition of interleukin-1 receptor 1 with Anakinra (vehicle 146.3% ± 30.1%; Anakinra 63.5% ± 23.3%; P < .001). Elastase treatment resulted in upregulation of endothelial to mesenchymal transition transcription factors (Snail, Slug, Twist, ZNF) and mesenchymal cell markers (S100, alpha smooth muscle actin) and loss of endothelial cell markers (vascular endothelial cadherin, endothelial nitric oxide synthase, von Willebrand factor). These changes were attenuated by interleukin-1 receptor 1 knockout and Anakinra treatment. CONCLUSIONS: Endothelial to mesenchymal transition occurs in aortic aneurysm disease and is attenuated by loss of interleukin-1 signaling. Endothelial dysfunction through endothelial to mesenchymal transition represents a new and novel pathway in understanding aortic aneurysm disease and may be a potential target for future treatment.

IL-1 in Abdominal Aortic Aneurysms.

Abdominal Aortic Aneurysms (AAA) remain a clinically devastating disease with no effective medical treatment therapy. AAAs are characterized by immune cell infiltration, smooth muscle cell apoptosis, and extracellular matrix degradation. Interleukin-1 (IL-1) has been shown to play role in AAA associated inflammation through immune cell recruitment and activation, endothelial dysfunction, production of reactive oxygen species (ROS), and regulation of transcription factors of additional inflammatory mediators. In this review, we will discuss the principles of IL-1 signaling, its role in AAA specific inflammation, and regulators of IL-1 signaling. Additionally, we will discuss the influence of genetic and pharmacological inhibitors of IL-1 on experimental AAAs. Evidence suggests that IL-1 may prove to be a potential therapeutic target in the management of AAA disease.

Rectal cancer treatment and outcomes in elderly patients treated with curative intent.

The elderly population comprises a significant proportion of patients diagnosed with rectal cancer. However, there is a lack of evidence to guide treatment decisions in this group. Thus, this multicentre study compares the histopathology, treatment patterns and outcomes between the elderly and young populations with non-metastatic rectal cancer. The present study reported on the clinicopathological variables, treatment modalities and survival outcomes in 736 patients diagnosed with non-metastatic rectal cancer between 2006 and 2015. Patients were divided into the following two groups, <70 and ≥70 years of age, which were compared using Chi-square and survival outcome analysis using Kaplan-Meier. Elderly patients made up nearly half of the cohort and were less likely to undergo trimodality therapy or be discussed in a multidisciplinary meeting. Surgery in the elderly patients was associated with increased mortality. Elderly patients had worse cancer-specific survival (75 vs. 85%), which was particularly evident in stage III disease (hazard ratio, 2.1). Elderly patients in this subgroup treated with trimodality therapy had similar survival outcomes to younger patients. Elderly patients with locally advanced rectal cancer comprise a large proportion of the patient cohort. Consideration should be given for trimodality therapy in this group, taking into account biological age, especially in the context of increasing life expectancy and improvement in the management of age-related comorbidities.

Factors influencing recurrence of stage I-III rectal cancer in regional Australia.

BACKGROUND: As treatments for rectal cancer improve with developments in surgical techniques, radiotherapy and chemotherapy, the nature of recurrences are evolving. We used a comprehensive database of a large Australian population with stage I-III rectal adenocarcinoma to identify timing and prognostic significance of recurrences, and factors associated with risk of developing recurrent disease. METHODS: All patients with locoregional rectal cancer treated with curative intent in our health district from 2006 to 2017 were included. Multivariate analysis using Cox regression models were used to identify factors associated with recurrence. RESULTS: A total of 483 patients were included. Recurrence occurred in 117 (24.2%) of 483 patients, being locoregional in 15 (3.1%) patients, distant in 85 patients (17.6%) and both locoregional and distant in 17 (3.5%) patients. Compared to those with locoregional recurrence, those with both locoregional and distant recurrence had worse cancer-specific survival. On univariate analysis, factors associated with recurrence included stage, grade, radiotherapy, chemotherapy, surgery type and distal tumour location. Factors which remained significant on multivariate analysis included higher grade and stage. CONCLUSION: In the era of multimodality therapy for rectal cancer, recurrences are predominantly distant. Traditional predictors including higher stage, grade and distal tumour location remain independently associated with recurrence, despite current treatment paradigms.

68Ga-Prostate-Specific Membrane Antigen Uptake in Cerebral Tuberculosis.

A 71-year-old man with a history of high-risk prostate adenocarcinoma (Gleason score 4 + 5 = 9) treated with brachytherapy in 2016 was referred for a Ga-prostate-specific membrane antigen (PSMA)-HBED-CC PET/CT scan for suspected cancer recurrence on a background of slowly rising serum prostate-specific antigen (0.95 ng/mL; reference, <0.2 ng/mL). This revealed PSMA-avid dura-based hyperdense lesions in the brain, suggestive of cerebral metastases. Biopsy demonstrated the presence of acid-fast bacilli, and with further clinical and microbiological testing, a diagnosis of PSMA-avid cerebral tuberculous mycobacterium infection was made.

Patterns of follow-up care after curative radiotherapy ± chemotherapy for stage I-III non-small cell lung cancer.

OBJECTIVES: To describe patterns of follow-up care for non-small cell lung cancer patients treated with curative radiotherapy and to evaluate the role of routine imaging. MATERIALS AND METHODS: We retrospectively analyzed follow-up care of patients with stage I-III non-small cell lung cancer treated with curative radiotherapy (minimum dose of 50 Gy) between 2007 and 2011 at three Sydney institutions. Patient demographics, tumor characteristics and treatment factors were collected from oncology and hospital records. Follow-up visits were recorded until an event (recurrence or new primary) was diagnosed or censor date was reached (December 31, 2016). Univariate and multivariate analyses were performed to identify factors associated with subsequent curative treatment and survival. RESULTS: Two-hundred and eighty-three patients were identified with a median age of 72 (36-91) years. Median number of follow-up visits was 6, and median time to first event was 10.8 months. Follow-up visits were by routine appointment in 74%, and symptomatic presentation in 26%. Variation in follow-up was seen across the three institutions in terms of imaging conducted and specialist seen. Recurrences were diagnosed in 175 patients of whom 85 were symptomatic and 90 diagnosed on routine imaging. New primaries were diagnosed in 23 patients, 18 with symptoms and 5 on routine imaging. Subsequent treatment was curative in 17 (10%) patients with recurrent disease and 18 (78%) with new primaries. On multivariable analysis, symptomatic diagnosis (P = 0.006) was associated with subsequent curative treatment but not with overall survival (P > 0.05). CONCLUSION: The follow-up of patients showed considerable variation between institutions. Routine imaging was not associated with subsequent curative treatment of events or improved overall survival.

The impact of breast cosmetic and functional outcomes on quality of life: long-term results from the St. George and Wollongong randomized breast boost trial.

The aims of this study were to evaluate the impact of cosmetic and functional outcomes after breast-conserving surgery (BCS) and radiation on quality of life (QOL). In this exploratory analysis; baseline, 5 and 10 years data of patient's assessment of breast cosmesis, arm swelling/pain, limitation of movement, loss of feeling in fingers and breast sensitivity/tenderness were dichotomized and their impact on QOL (QLQ-C30) were assessed. Multivariable modelling was also performed to assess associations with QOL. The St. George and Wollongong randomized trial randomized 688 patients into the boost and no boost arms. 609, 580, and 428 patients had baseline, 5 and 10 years cosmetic data available, respectively. Similar numbers had the various functional assessments in the corresponding period. By univariate analysis, cosmesis and a number of functional outcomes were highly associated with QOL. Adjusted multivariate modelling showed that cosmesis remained associated with QOL at 5 and 10 years. Breast sensitivity, arm pain, breast separation, age and any distant cancer event were also associated with QOL on multivariate modelling at 10 years. This study highlights the importance of maintaining favorable cosmetic and functional outcomes following BCS. In addition, the clinically and statistically significant relationship between functional outcomes and QOL shows the importance for clinicians and allied health professionals in identifying, discussing, managing, and limiting these effects in women with breast cancer in order to maintain QOL.

Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel.

PURPOSE: To determine the clinical utility of intrinsic molecular phenotype after breast-conserving therapy (BCT) with lumpectomy and whole-breast irradiation with or without a cavity boost. PATIENTS AND METHODS: Four hundred ninety-eight patients with invasive breast cancer were enrolled into a randomized trial of BCT with or without a tumor bed radiation boost. Tumors were classified by intrinsic molecular phenotype as luminal A or B, HER-2, basal-like, or unclassified using a five-biomarker panel: estrogen receptor, progesterone receptor, HER-2, CK5/6, and epidermal growth factor receptor. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ipsilateral breast tumor recurrence (IBTR), locoregional recurrence (LRR), distant disease-free survival (DDFS), and death from breast cancer. RESULTS: Median follow-up was 84 months. Three hundred ninety-four patients were classified as luminal A, 23 were luminal B, 52 were basal, 13 were HER-2, and 16 were unclassified. There were 24 IBTR (4.8%), 35 LRR (7%), 47 distant metastases (9.4%), and 37 breast cancer deaths (7.4%). The overall 5-year disease-free rates for the whole cohort were: IBTR 97.4%, LRR 95.6%, DDFS 92.9%, and breast cancer-specific death 96.3%. A significant difference was observed for survival between subtypes for LRR (P = .012), DDFS (P = .0035), and breast cancer-specific death (P = .0482), but not for IBTR (P = .346). CONCLUSION: The 5-year and 10-year survival rates varied according to molecular subtype. Although this approach provides additional information to predict time to IBTR, LRR, DDFS, and death from breast cancer, its predictive power is less than that of traditional pathologic indices. This information may be useful in discussing outcomes and planning management with patients after BCT.

Randomized, paired comparison of No-Sting Barrier Film versus sorbolene cream (10% glycerine) skin care during postmastectomy irradiation.

PURPOSE: Postmastectomy irradiation provides an excellent model for irradiated skin care practices because of the relatively uniform surface and radiation compared with other situations in which radiation-induced moist desquamation is common. We designed a study to test the effect of prophylactic 3M Cavilon No-Sting Barrier Film (No-Sting) on the rates of moist desquamation compared with sorbolene cream (with 10% glycerin). METHODS AND MATERIALS: The irradiated chest wall was divided into medial and lateral halves. Sixty-one women were randomized to have No-Sting applied to either the medial or lateral half, with the alternate half treated with sorbolene. RESULTS: For all patients, the skin toxicity, calculated as the area under the curve, mean No-Sting and sorbolene score was 8.1 vs. 9.2, respectively (p = 0.005, Wilcoxon signed rank test). The total number of weeks of moist desquamation for the 61 patients was 40 vs. 45, equating to a mean of 0.65 week vs. 0.74 week per patient in the No-Sting and sorbolene-treated areas, respectively. The rates of moist desquamation were 33% vs. 46% (p = 0.096, McNemar's Exact test). For 58 fully assessable patients (minimum of 7 weekly observations), the area under the curve and rates of moist desquamation were significantly different statistically (p = 0.002 and 0.049, respectively). No statistically significant differences were noted in the pain scores. The pruritus scores were significantly reduced in the No-Sting area (area under the curve, p = 0.011). CONCLUSION: No-Sting reduces the duration and frequency of radiation-induced moist desquamation.

Sites of local recurrence after surgery, with or without chemotherapy, for rectal cancer: implications for radiotherapy field design.

PURPOSE: To examine the sites of pelvic recurrence in patients with rectal cancer previously untreated with radiotherapy to determine the relative frequency and location of recurrence within the pelvis. METHODS AND MATERIALS: The records of patients with locally recurrent rectal cancer referred to three radiation oncology departments between 1984 and 1997 were reviewed. The data collected included the date and type of the initial resection and the pathologic findings. The site of recurrence within the pelvis, presence of metastasis, and date of recurrence were documented. RESULTS: A total of 269 patients were included. Tumor had invaded through the muscularis in 74% and involved other organs in 9%. Fifty-two percent of patients were node positive at initial surgery. The median time to local recurrence from surgery was 18 months (range 15-20) and from local recurrence to death was 14 months (range 12-17). Both the initial tumor stage and the resection type influenced the recurrence location within the pelvis (p <0.01). T4 tumors comprised only 9% of initial T stage tumors but accounted for 38% of anterior central pelvic recurrences (p <0.01). All perineal recurrences occurred after abdominoperineal resection. The sites of recurrence within the pelvis were the posterior central pelvis (47%) and anastomotic (21%). CONCLUSION: If those patients with T4 tumors at presentation were excluded, 89% had local recurrence at, or posterior to, the anastomosis. Furthermore, if we exclude both patients who underwent abdominoperineal resection and those with T4 tumors at presentation, the rate increases to 93%. The rate of recurrence anteriorly (7%) does not justify routine radiation of the anterior pelvis beyond that required to adequately cover the anastomotic site.