Management of Localized Prostate Cancer in Men With Human Immunodeficiency Virus: Analysis of a Large Retrospective Cohort.

INTRODUCTION: We aimed to characterize the clinicopathological characteristics and outcomes of HIV-positive patients with clinically localized, prostate cancer (PCa). METHODS: A retrospective study was conducted of HIV-positive patients from a single institution with elevated PSA and diagnosis of PCa by biopsy. PCa features, HIV characteristics, treatment type, toxicities, and outcomes were analyzed by descriptive statistics. Kaplan-Meier analysis was used to determine progression-free survival (PFS). RESULTS: Seventy-nine HIV-positive patients were included with a median age at PCa diagnosis of 61 years-old and median duration from HIV infection to PCa diagnosis of 21 years. The median PSA level at diagnosis and Gleason Score was 6.85 ng/mL and 7, respectively. The 5-year PFS was 82.5% with the lowest survival observed in patients treated with radical prostatectomy (RP) + radiation therapy (RT), followed by cryosurgery (CS). There were no reports of PCa-specific deaths, and the 5-year overall survival was 97.5%. CD4 count declined post-treatment in pooled treatment groups that included RT (P = .02). CONCLUSION: We present the characteristics and outcomes of the largest cohort of HIV-positive men with prostate cancer in published literature. RP and RT ± ADT is well-tolerated in HIV-positive patients with PCa as seen by the adequate biochemical control and mild toxicity. CS resulted in worse PFS compared to alternative treatments for patients within the same PCa risk group. A decline in CD4 counts was observed in patients treated RT, and further studies are needed to investigate this relationship. Our findings support the use of standard-of-care treatment for localized PCa in HIV-positive patients.

Prostate Cancer Outcomes in Patients Living With HIV/AIDS Treated With Radiation Therapy: A Systematic Review.

Purpose: A consensus has not been reached regarding the treatment and outcomes of prostate cancer (PCa) in people living with HIV/AIDS (PLWHA). This systematic review aims to summarize the evidence on the management of PCa with radiation therapy (RT) in PLWHA diagnosed with PCa. Methods and Materials: Searches were conducted in the PubMed, Cochrane Library, and Scopus databases during September 2021 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Articles reporting on outcomes of PLWHA treated for PCa with definitive RT were sought for inclusion. Results: A total of 9 studies with 187 patients with HIV who received diagnoses of PCa met inclusion criteria. The duration of HIV infection to PCa diagnosis ranged from 8.5 to 18.6 years with 69% to 100% of patients on highly active antiretroviral therapy at the time of diagnosis. Patients' prostate-specific antigen levels ranged from 8 to 82 ng/mL. The majority of patients (59%) were treated with external beam RT, followed by brachytherapy (20.5%). The 4- or 5-year biochemical failure-free rate was reported to be between 87% and 97% in 3 studies, and 2 studies reported an 84% to 97% 5-year cancer-specific survival. Using Common Terminology Criteria for Adverse Events criteria, 3 studies reported toxicities and grade 3 toxicity was observed in only 2 patients. Conclusions: RT is efficacious and well tolerated in PLWHA as supported by the comparable biochemical control, clinical outcome, and mortality to the general population as well as by the mild reports of radiotoxicity. There is mixed evidence regarding the effect of RT on CD4 count and viral load, and further studies are needed to better understand this relationship. These findings support the use of definitive RT in PLWHA with PCa.

Incidence, Mortality, and Treatment Patterns of Synchronous Lower Genital Tract Squamous Cell Carcinoma.

OBJECTIVE: The aim of the study was to define the incidence, prognosis, and treatment patterns associated with synchronous lower genital tract squamous cell carcinoma (LGTSCC) among women diagnosed with any LGTSCC. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results (SEER) database patients diagnosed with synchronous cervical, vaginal, vulvar, and/or anal SCC from 2000 to 2016 were included. Incidence and mortality were evaluated using Kaplan-Meier curves. Multivariable Cox proportional hazards regression was used to identify treatment patterns, risk factors, and mortality associated with LGTSCC. RESULTS: Among 15,424 women with LGTSCC, 138 had synchronous LGTSCC (0.89%). Vulvar and vaginal SCC was the most common combination (49.3%), and cervical with anal SCC was the least common (1.4%). Only one patient had 3 or more primary LGTSCC. Synchronous LGTSCC was independently associated with higher mortality compared with single-site LGTSCC (adjusted hazards ratio [aHR] = 1.67; p < .001). Synchronous LGTSCC was significantly associated with older age (63 vs. 58 years, p < .001) and lower stage (adjusted odds ratio [aOR] = 0.38; p < .001) and grade of disease (aOR = 0.32; p < .001). Patients with synchronous LGTSCC were more likely to receive radiation (aOR = 1.74; p = .005) and were more likely to receive adjuvant radiation after primary surgical resection compared with single-site LGTSCC (aOR = 1.88; p = .007). Receipt of any treatment including radiation (aHR = 0.85; p < .001), chemotherapy (aHR = 0.50; p < .001), and surgery (aHR = 0.70; p < .001) was independently associated with decreased mortality hazard. CONCLUSIONS: Synchronous LGTSCC is rare but is associated with increased mortality and higher rates of adjuvant radiation compared with single-site LGTSCC despite lower stage and grade at diagnosis. More research is needed to define optimal therapy for these patients.

Association Between Local Radiation Therapy to the Primary Bladder Tumor and Overall Survival for Patients with Metastatic Urothelial Cancer Receiving Systemic Chemotherapy.

There are limited data on the role of local therapy for metastatic urothelial carcinoma of the bladder (mUC). In this retrospective cohort analysis, we queried the National Cancer Data Base for patients with newly diagnosed mUC (cT1-4 N0-3 M1). Overall survival (OS) was compared between treatment with chemotherapy (CT) alone (n = 4122) and CT plus bladder-directed radiation therapy (CT + RT; n = 337). Multivariable Cox proportional-hazards analyses and matching and landmark analyses were performed. CT + RT was independently associated with better OS (hazard ratio 0.70, 95% confidence interval 0.62-0.79; p < 0.0001) and this result persisted in matched and landmark analyses. These findings are hypothesis-generating and limited by inherent confounding factors; however, a prospective trial evaluating the impact of bladder RT in mUC is warranted. PATIENT SUMMARY: For patients with bladder cancer that has already spread to other parts of the body, it is unclear if radiation therapy directed at the primary bladder tumor would provide any improvement in survival. In this study, we found that aggressive radiation therapy directed at the bladder combined with chemotherapy may provide a survival benefit in some patients with metastatic bladder cancer compared to chemotherapy alone.

A feasibility study to evaluate early treatment response of brain metastases one week after stereotactic radiosurgery using perfusion weighted imaging.

BACKGROUND: To explore if early perfusion-weighted magnetic resonance imaging (PWI) may be a promising imaging biomarker to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS). METHODS: This is a prospective pilot study of adult brain metastasis patients who were treated with SRS and imaged with PWI before and 1 week later. Relative cerebral blood volume (rCBV) parameter maps were calculated by normalizing to the mean value of the contralateral white matter on PWI. Cox regression was conducted to explore factors associated with time to LR, with Bonferroni adjusted p<0.0006 for multiple testing correction. LR rates were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS: Twenty-three patients were enrolled from 2013 through 2016, with 22 evaluable lesions from 16 patients. After a median follow-up of 13.1 months (range: 3.0-53.7), 5 lesions (21%) developed LR after a median of 3.4 months (range: 2.3-5.7). On univariable analysis, larger tumor volume (HR 1.48, 95% CI 1.02-2.15, p = 0.04), lower SRS dose (HR 0.45, 95% CI 0.21-0.97, p = 0.04), and higher rCBV at week 1 (HR 1.07, 95% CI 1.003-1.14, p = 0.04) had borderline association with shorter time to LR. Tumors >2.0cm3 had significantly higher LR than if ≤2.0cm3: 54% vs 0% at 1 year, respectively, p = 0.008. A future study to confirm the association of early PWI and LR of the high-risk cohort of lesions >2.0cm3 is estimated to require 258 patients. CONCLUSIONS: PWI at week 1 after SRS may have borderline association with LR. Tumors <2.0cm3 have low risk of LR after SRS and may be low-yield for predictive biomarker studies. Information regarding sample size and potential challenges for future imaging biomarker studies may be gleaned from this pilot study.

Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI).

BACKGROUND: Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) are two debilitating disorders that share similar symptoms of chronic pain, fatigue, and exertional exhaustion after exercise. Many physicians continue to believe that both are psychosomatic disorders and to date no underlying etiology has been discovered. As such, uncovering objective biomarkers is important to lend credibility to criteria for diagnosis and to help differentiate the two disorders. METHODS: We assessed cognitive differences in 80 subjects with GWI and 38 with CFS by comparing corresponding fMRI scans during 2-back working memory tasks before and after exercise to model brain activation during normal activity and after exertional exhaustion, respectively. Voxels were grouped by the count of total activity into the Automated Anatomical Labeling (AAL) atlas and used in an "ensemble" series of machine learning algorithms to assess if a multi-regional pattern of differences in the fMRI scans could be detected. RESULTS: A K-Nearest Neighbor (70%/81%), Linear Support Vector Machine (SVM) (70%/77%), Decision Tree (82%/82%), Random Forest (77%/78%), AdaBoost (69%/81%), Naïve Bayes (74%/78%), Quadratic Discriminant Analysis (QDA) (73%/75%), Logistic Regression model (82%/82%), and Neural Net (76%/77%) were able to differentiate CFS from GWI before and after exercise with an average of 75% accuracy in predictions across all models before exercise and 79% after exercise. An iterative feature selection and removal process based on Recursive Feature Elimination (RFE) and Random Forest importance selected 30 regions before exercise and 33 regions after exercise that differentiated CFS from GWI across all models, and produced the ultimate best accuracies of 82% before exercise and 82% after exercise by Logistic Regression or Decision Tree by a single model, and 100% before and after exercise when selected by any six or more models. Differential activation on both days included the right anterior insula, left putamen, and bilateral orbital frontal, ventrolateral prefrontal cortex, superior, inferior, and precuneus (medial) parietal, and lateral temporal regions. Day 2 had the cerebellum, left supplementary motor area and bilateral pre- and post-central gyri. Changes between days included the right Rolandic operculum switching to the left on Day 2, and the bilateral midcingulum switching to the left anterior cingulum. CONCLUSION: We concluded that CFS and GWI are significantly differentiable using a pattern of fMRI activity based on an ensemble machine learning model.

Radiologic Assessment of Groin Lymph Nodes in Pelvic Malignancies.

INTRODUCTION: Metastatic involvement of groin nodes can alter radiation therapy planning for pelvic tumors. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can identify nodal metastases; however, interpretation of PET/CT-positive nodes can be complicated by non-malignant processes. We evaluated quantitative metrics as methods to identify groin metastases in patients with pelvic tumors by comparison with standard subjective interpretive criteria, with pathology as the reference standard. METHODS: We retrospectively identified patients with vulvar, vaginal, or anal cancers who underwent 18F-FDG PET/CT before pathologic evaluation of groin nodes between 2007 and 2017. Because patho-radiologic correlation was not possible for every node, one index node identified on imaging was selected for each groin. For each index node, standardized uptake value measurements, total lesion glycolysis, metabolic tumor volume, CT-based volume, and short and long axes were measured. Multivariate logistic regression was used to identify metrics predictive for pathologically positive groins and generate a probabilistic model. Area under the receiver-operating characteristic curves (AUCs) for the model were compared with clinical interpretation from the diagnostic report via a Wald's χ2 test. RESULTS: Of 55 patients identified for analysis, 75 groins had pathologic evaluation resulting in 75 index groin nodes for analysis with 35 groins pathologically positive for malignancy. Logistic regression identified mean standardized-uptake-value (50% threshold) and short-axis length as the most predictive imaging metrics for metastatic nodal involvement. The probabilistic model performed better at predicting pathologic involvement compared with standard clinical interpretation on analysis (AUC 0.91, 95% CI 0.84 to 0.97 vs 0.80, 95% CI 0.71 to 0.89; p<0.01). DISCUSSION: Accuracy of 18F-FDG PET/CT for detecting groin nodal metastases in patients with pelvic tumors may be improved with the use of quantitative metrics. Improving prediction of nodal metastases can aid with appropriate selection of patients for pathologic node evaluation and guide radiation volumes and doses.

Logistic Regression Algorithm Differentiates Gulf War Illness (GWI) Functional Magnetic Resonance Imaging (fMRI) Data from a Sedentary Control.

Gulf War Illness (GWI) is a debilitating condition characterized by dysfunction of cognition, pain, fatigue, sleep, and diverse somatic symptoms with no known underlying pathology. As such, uncovering objective biomarkers such as differential regions of activity within a Functional Magnetic Resonance Imaging (fMRI) scan is important to enhance validity of the criteria for diagnosis. Symptoms are exacerbated by mild activity, and exertional exhaustion is a key complaint amongst sufferers. We modeled this exertional exhaustion by having GWI (n = 80) and sedentary control (n = 31) subjects perform submaximal exercise stress tests on two consecutive days. Cognitive differences were assessed by comparing fMRI scans performed during 2-Back working memory tasks before and after the exercise. Machine learning algorithms were used to identify differences in brain activation patterns between the two groups on Day 1 (before exercise) and Day 2 (after exercise). The numbers of voxels with t > 3.17 (corresponding to p < 0.001 uncorrected) were determined for brain regions defined by the Automated Anatomical Labeling (AAL) atlas. Data were divided 70:30 into training and test sets. Recursive feature selection identified twenty-nine regions of interest (ROIs) that significantly distinguished GWI from control on Day 1 and 28 ROIs on Day 2. Ten regions were present in both models between the two days, including right anterior insula, orbital frontal cortex, thalamus, bilateral temporal poles, and left supramarginal gyrus and cerebellar Crus 1. The models had 70% accuracy before exercise on Day 1 and 85% accuracy after exercise on Day 2, indicating the logistic regression model significantly differentiated subjects with GWI from the sedentary control group. Exercise caused changes in these patterns that may indicate the cognitive differences caused by exertional exhaustion. A second set of predictive models was able to classify previously identified GWI exercise subgroups START, STOPP, and POTS for both Days 1 and Days 2 with 67% and 69% accuracy respectively. This study was the first of its kind to differentiate GWI and the three sub-phenotypes START, STOPP, and POTS from a sedentary control using a logistic regression estimation method.

High expectations: The landscape of clinical trials of medical marijuana in oncology.

PURPOSE: Given the infancy and evolving complexity of medicinal marijuana, an evolving political landscape, and the growing frequency of its use in cancer care, it is important for oncologists to be actively engaged in developing and successfully implementing clinical trials focusing on medical marijuana. The purpose of this study was to analyze and evaluate trends in clinical trials focused on medical marijuana in oncology. PATIENTS AND METHODS: Using 3 web-based registries, Clinicaltrials.gov, European Union Clinical Trials Register (EU-CTR), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), we queried for search terms related to marijuana and oncology. This search identified approximately 48 oncology clinical trials involving medical marijuana. We restricted our selection to clinical trials registered between January 2002 and May 2019. Data were summarized using descriptive statistics, and qualitative data were represented as frequency and percentage. RESULTS: A total of 474,043 trials were queried in the databases and the search strategy returned 48 trials since 2002 that met criteria for analysis in the current study: 36 from ClinicalTrials.gov, 8 from EU CTR, and 4 from ICTRP. Mean trial enrollment was 370 participants, median 53, with range of 6-10000 participants. In total, 25 % trials were phase I, 12.5 % were phase I/II, 27.1 % were phase II, 4 % were phase II/III, 18.8 % were phase III, and 12.5 % were unknown. The recruitment status were "not yet recruiting", "recruiting", "active, not recruiting", "completed", "terminated/withdrawn", and "unknown" in 6 (12.5 %), 14 (29.2 %), 0 (0 %), 20 (41.7 %), 5 (10.4 %), and 3 (6.3 %) trials, respectively. The trial start years were "2002-2005″, 2006-2009, 2010-2013, 2014-2017, and 2018-Present in 4 (8.3 %), 5 (10.4 %), 10 (20.8 %), 15 (31.3 %), and 14 (29.2 %) of trials, respectively. Lastly, synthetic or branded compounds were investigated in 26 (54.2 %) of trials since 2002. CONCLUSION: Our results indicate that across oncology, there is growing interest in clinical research in the use of medical marijuana.

Effect of Radiation Treatment Volume Reduction on Lymphopenia in Patients Receiving Chemoradiotherapy for Glioblastoma.

PURPOSE: To evaluate whether reduction in glioblastoma radiation treatment volume can reduce risk of acute severe lymphopenia (ASL). METHODS AND MATERIALS: A total of 210 patients with supratentorial/nonmetastatic glioblastoma were treated with radiation therapy (RT) plus temozolomide from 2007 to 2016 and had laboratory data on total lymphocyte counts. Before 2015, 164 patients were treated with standard-field RT (SFRT), and limited-field RT (LFRT) was implemented thereafter for 46 patients to reduce treatment volume. Total lymphocyte counts were evaluated at baseline, during RT, and at approximately week 12 from initiating RT. Acute severe lymphopenia was defined as any total lymphocyte count < 500 cells/µL within 3 months (by week 12) of initiating RT. Multivariate analysis for overall survival (OS) was performed with Cox regression and with logistic regression for ASL. Propensity score matching was performed to adjust for variability between cohorts. Acute severe lymphopenia, progression-free survival (PFS), and OS were compared using the Kaplan-Meier method. RESULTS: Limited-field RT patients had higher gross tumor volume than SFRT patients yet lower brain dose-volume parameters, including volume receiving 25 Gy (V25 Gy: 41% vs 53%, respectively, P < .01). Total lymphocyte count at week 12 was significantly higher for LFRT than for SFRT (median: 1100 cells/µL vs 900 cells/µL, respectively, P = .02). On multivariate analysis, ASL was an independent predictor of OS, and brain V25 Gy was an independent predictor of ASL. The ASL rate at 3 months was 15.5% for LFRT and 33.8% for SFRT (P = .12). In a propensity-matched comparison of 45 pairs of LFRT and SFRT patients, PFS (median: 5.9 vs 6.2 months, respectively, P = .58) and OS (median: 16.2 vs 13.9 months, respectively, P = .69) were not significantly different. CONCLUSIONS: Limited-field RT is associated with less lymphopenia after RT plus temozolomide and does not adversely affect PFS or OS. Brain V25 Gy is confirmed as an important dosimetric predictor for ASL.

Impact of concurrent versus adjuvant chemotherapy on the severity and duration of lymphopenia in glioma patients treated with radiation therapy.

Prolonged severe lymphopenia has been shown to persist beyond a year in glioma patients after radiation therapy (RT) with concurrent and adjuvant chemotherapy. This study examines the differential impact of concurrent versus adjuvant chemotherapy on lymphopenia after RT. WHO grade II-III glioma patients who received RT with concurrent and/or adjuvant chemotherapy from 2007 to 2016 were retrospectively analyzed. Concurrent chemotherapy was temozolomide (TMZ), and adjuvant chemotherapy was either TMZ or procarbazine/lomustine/vincristine (PCV). Absolute lymphocyte count (ALC) was analyzed at baseline, 1.5, 3, 6, and 12 months after the start of RT. Univariable and multivariable logistic regression were used to identify the clinical variables in predicting acute or late lymphopenia. There were 151 patients with evaluable ALC: 91 received concurrent and adjuvant TMZ (CRT + ADJ), 32 received only concurrent TMZ (CRT), and 28 received only adjuvant TMZ or PCV (ADJ). There were 9 (10%) versus 6 (19%) versus 0 (0%) cases of grade 3 lymphopenia (ALC < 500/mm3) at 6 weeks and 4 (6%) versus 0 (0%) versus 3 (17%) cases at 12 months in CRT + ADJ, CRT and ADJ groups, respectively. On multivariable analyses, concurrent chemotherapy (odds ratio [OR] 72.3, p < 0.001), female sex (OR 10.8, p < 0.001), and older age (OR 1.06, p = 0.002) were the most significant predictors for any grade ≥ 1 lymphopenia (ALC < 1000/mm3) at 1.5 months. Older age (OR 1.08, p = 0.02) and duration of adjuvant chemotherapy (OR 1.19, p = 0.003) were significantly associated with grade ≥ 1 lymphopenia at 12 months. Thus, concurrent chemotherapy appears as the dominant contributor to the severity of acute lymphopenia after RT in WHO grade II-III glioma patients, and duration of adjuvant chemotherapy appears as the key factor to prolonged lymphopenia.

Patterns of care and outcomes of proton and eye plaque brachytherapy for uveal melanoma: Review of the National Cancer Database.

PURPOSE: To examine national practice patterns and outcomes of eye plaque brachytherapy compared to proton external beam radiotherapy in the treatment of choroid melanoma. METHODS AND MATERIALS: Demographic and clinical data for 1224 patients with choroid melanoma treated with either brachytherapy or proton beam therapy from 2004 to 2013 were obtained from the National Cancer Database. Logistic regression and propensity score matching was used to create a 1:1 matched cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate survival in brachytherapy and proton groups. RESULTS: Median followup was 37 and 29 months for brachytherapy and protons, respectively. Most patients were treated with brachytherapy (n = 996) vs. protons (n = 228). Proton patients came from more urban, affluent, and educated zip codes, and they were more likely to be treated at an academic center (all p < 0.004). In the propensity-score matched cohort, 2-year overall survival was 97% vs. 93%, and 5-year overall survival was 77% vs. 51% for brachytherapy and protons, respectively (p = 0.008). Multivariate Cox regression found older age (hazard ratio [HR] = 1.06, 95% confidence interval (CI) = 1.03-1.09), larger tumor diameter (12-18 mm, HR = 2.48, 95% CI = 1.40-4.42, >18 mm, HR = 6.41, 95% CI = 1.45-28.35), and protons (HR = 1.89, 95% CI = 1.06-3.37) were negative prognosticators of survival. CONCLUSIONS: Patients selected for proton treatment have inferior survival outcomes compared to brachytherapy in this retrospective analysis. There may be unaccounted variables that influence survival, warranting further prospective studies.

Impact of Time Interval between Radiation and Free Autologous Breast Reconstruction.

Background To evaluate whether the timing of surgery after radiation in autologous breast reconstruction affects major complications. Methods We performed a retrospective review of 454 free flaps (331 patients) for breast reconstruction at a single institution from 2003 to 2014. Charts were reviewed for age, BMI, laterality, flap type (TRAM, msTRAM, DIEP), surgeon, donor vessels (IMA, TD), chemotherapy, smoking, diabetes, hypertension, DVT, venous anastomoses, vein size, and time from radiation (none, < 12 months, or ≥ 12 months). The primary outcome of major complications was defined as partial/total flap loss, thrombosis, ischemia, or hematoma requiring return to the operating room. To identify independent predictors of major complications, a multivariate logistic regression was constructed. Alpha = 0.05 indicated significance in all tests. Results Average age was 47.4 ± 8.4. Free flaps consisted of msTRAM (41.1%), TRAM (29.6%), or DIEP (29.3%). The donor vessel was IMA in 66.9% of flaps or TD in 33.0% of patients with 90.7% using only one vein and 9.3% with two veins. The average IMA/TDV size was 2.5 cm ± 0.5. Preoperative radiation occurred in 31.2% of flaps. There were 54 flaps with at least one major complication (11.7%). On multivariate regression, only flap type (OR =4.04, p < .01) and vein size (OR = 0.13, p = 0.02) independently predicted major complications. Conclusion There was no significant difference in major complications between flaps who had reconstruction within 12 months and greater than 12 months after radiation. Only having a more muscle sparing technique or smaller vein size were independent risk factors for major complications.

Patterns of care and treatment outcomes of patients with Craniopharyngioma in the national cancer database.

To investigate the patterns of care and outcomes in patients with craniopharyngioma in the National Cancer Data Base (NCDB). This study included 697 patients (166 pediatric and 531 adult cases) treated for craniopharyngioma between 2004 and 2012 in the NCDB. Adjuvant radiotherapy (RT) was defined if within 6 months of surgery. Limited surgery (LS) was defined as biopsy or subtotal resection. Proportional-hazards models were used to evaluate associations between covariates and overall survival (OS). A time-dependent analysis of RT was performed to account for early deaths after surgery. Median follow-up was 46 months. Overall, 21% of patients received adjuvant RT. Of patients with known surgical extent (n = 195), 71% had LS. Utilization of adjuvant RT increased from 18% in 2004-2007 to 24% in 2008-2012. Patterns of care regarding adjuvant RT or LS were not significantly different between adult and pediatric patients. Tumor size, low comorbidity, and LS were associated with increased utilization of adjuvant RT. The 5-year OS among patients treated with LS, LS+RT, and gross total resection were 75, 85, and 82% (p = 0.02). On multivariate analysis of the 195 patients with known surgical extent, LS+RT was associated with improved OS compared to LS (HR 0.22, 95% CI 0.05-0.99, p = 0.04), but was not significant when early deaths (<2 months from surgery) were removed to adjust for immortal-time bias. Medical practice regarding surgical approach and adjuvant RT are similar for pediatric and adult craniopharyngiomas. Immortal-time bias may confound assessment of OS for adjuvant RT. Prospective studies comparing adjuvant RT versus observation after LS are warranted.

ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice.

Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). Cotreatment with ERK inhibitor PD98059 abrogated sildenafil-induced protection (31.8 +/- 4.4%). To further evaluate the role of ERK in delayed cardioprotection, mice were treated with sildenafil (ip) 24 h before global ischemia-reperfusion. PD98059 was administered (ip) 30 min before sildenafil treatment. Infarct size was reduced from 27.6 +/- 3.3% in controls to 7.1 +/- 1.5% in sildenafil-treated mice (P < 0.05). The delayed protective effect of sildenafil was also abolished by PD98059 (22.5 +/- 2.3%). Western blots revealed that sildenafil significantly increased phosphorylation of ERK1/2 and GSK-3beta and induced iNOS, eNOS, Bcl-2, and PKG activity in the heart 24 h after treatment. PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.