Discrepancy between treatment goals documentation by oncologists and their understanding among cancer patients under active treatment with chemotherapy.

OBJECTIVE/BACKGROUND: Discussion of treatment goals between oncologists and patients is challenging. Patients frequently misunderstand goals of therapy. There are several methods to document goals of chemotherapy, however, and are frequently not incorporated into patient charts. METHODS/DESIGN: Cancer patients receiving their first cycle of chemotherapy were interviewed. Patients' recall of discussions with their oncologist regarding therapy intent was assessed and compared to documentation. An adjusted McNemar's test was utilised. A one-sample proportion test was used to evaluate whether the overall observed rate of discordance was significantly different from the proposed 33% rate; a rate posited as a threshold too high in the clinical sense. RESULTS: Two hundred and seven eligible patients were interviewed. Oncologist identified treatment goals were not documented in 24.6% of cases and had to be excluded. There was not a significant difference in the directionality of discordance present. Inter-rater agreement between patient and oncologist was found to be adequate (κ = 0.64). The overall rate of discordance (17.29%) was found to be significantly less than the proposed acceptable level of 33% (p < 0.01). Upon univariable analysis, age, gender, marital and employment status were not found to be associated with discordance. CONCLUSIONS: Discordance between treatment goals documentation and their understanding exists, indicating continued miscommunication between the patient and oncologist.

Integrating independent spatio-temporal replications to assess population trends in disease spread.

Glaucoma is the second leading cause of blindness in the USA. A visual field test (perimetry) is used to sample and quantitate visual field function in preselected regions in the eye. These regions can be considered a spatial field with replications across independently measured individuals. At return visits, a new set of visual field measurements is obtained producing a subject specific spatio-temporal dataset. We develop a Bayesian hierarchical modeling framework to analyze these spatio-temporal datasets both for individual level spread and as aggregate population level trends. Our model extends previous research utilizing a dimension reduction matrix and individual specific latent variables. Human characteristics are incorporated into the model to help explain glaucoma progression. One beneficial product of our model is smoothed estimates for individuals. We also specify how progression rates are computed for monitoring purposes so that clinicians can track changes and predict forward in time. Copyright © 2016 John Wiley & Sons, Ltd.

Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction.

BACKGROUND: Diagnosis of chronic obstructive pulmonary disease is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended fixed ratio of forced expiratory volume in the first second/forced vital capacity<0.70 with LLN in diagnosing smoking-related airflow obstruction using CT-defined emphysema and gas trapping as the disease gold standard. METHODS: Data from a large multicentre study (COPDGene), which included current and former smokers (age range 45-80 years) with and without airflow obstruction, were analysed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard. RESULTS: 7743 subjects were included. There was very good agreement between the two spirometric cutoffs (κ=0.85; 95% CI 0.83 to 0.86, p<0.001). 7.3% were discordant. Subjects with airflow obstruction by fixed ratio only had a greater degree of emphysema (4.1% versus 1.2%, p<0.001) and gas trapping (19.8% vs 7.5%, p<0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9% and 19.8% vs 10.9%, respectively, p<0.001). On follow-up, the fixed ratio only group had more exacerbations than smoking controls. CONCLUSIONS: Compared with the fixed ratio, the use of LLN fails to identify a number of patients with significant pulmonary pathology and respiratory morbidity.

A matched case-control study of IBD-associated colorectal cancer: IBD portends worse outcome.

BACKGROUND AND OBJECTIVES: The effect of inflammatory bowel disease (IBD) on outcome in patients with colorectal cancer (CRC) remains unclear. Our objective is to evaluate oncologic outcomes of patients with IBD-associated CRC. METHODS: We retrospectively reviewed a prospectively maintained database to identify patients with IBD-associated CRC. Clinicopathologic variables and overall survival were compared to patients with sporadic CRC using a 2:1 matched-controlled analysis. RESULTS: Fifty-five patients with IBD and CRC were identified. On univariate analysis, CRC patients with IBD had a significantly shorter median overall survival (68.2 months vs. 204.3 months, P = 0.01) compared to patients with sporadic CRC. On multivariate analysis, after adjusting for N and M stage, IBD was associated with an increased risk of death compared to sporadic CRC (HR = 2.011, 95% CI 1.24-3.23, P = 0.004). Stage 3 CRC patients with IBD in particular showed significantly decreased survival (23.0 vs. 133.9 months, P = 0.008). CONCLUSIONS: In this study, patients with node-positive IBD-associated CRC had a significant increased risk of death and a shorter overall survival than those with sporadic disease and may require tailored adjuvant therapy and surveillance protocols. Continued investigation to elucidate the mechanisms that contribute to these observations is justified.

An algorithm for utilizing peripheral blood CD34 count as a predictor of the need for plerixafor in autologous stem cell mobilization--cost-effectiveness analysis.

Certain patients who receive granulocyte colony-stimulating factor (GCSF) for autologous hematopoietic stem cell (AHSC) collection fail to mobilize well enough to proceed with transplant. When plerixafor is used with GCSF, the likelihood of achieving the CD34⁺ stem cell target in fewer collections is higher; plerixafor use in all patients is unlikely to be cost-effective. This study retrospectively evaluated the effectiveness of utilizing a peripheral blood CD34⁺ stem cell count (PBCD34) ≤8/µL on day 4 of GCSF-based AHSC mobilization as a threshold for plerixafor administration, and compared the efficacy of collection and cost analysis using historical controls. All patients in the study cohort reached their CD34⁺ targets in ≤3 collections. Significantly more patients who received plerixafor + GCSF versus GCSF alone reached their CD34⁺ target in one collection (P = 0.045); however, there were no significant differences in the number of collections or in cumulative product yields. The historical cohort had 10.3% mobilization failures; the number of collections per patient needed to reach the target was significantly higher in the historical cohort versus study cohort (P = 0.001) as was the number of patients requiring more than one collection to reach their target (P = 0.023). However, the average cost per patient was also significantly higher in the study cohort (P = 0.025). Further refinement of the algorithm may reduce the difference in cost between the two mobilization strategies.

Familial trends in a population with macular holes.

PURPOSE: To determine if patients with macular hole report an increased family history of macular hole compared with control patients and compare the report of family history between patients with unilateral and bilateral macular holes. METHODS: This was a multicenter case-control study. Charts of patients coded with diagnosis of macular hole were reviewed, and the diagnosis of idiopathic full-thickness macular hole was ascertained in 166 patients. The control group comprised 136 patients without macular hole or trauma who presented with senile cataract. Family history was obtained from all patients through a telephone interview. RESULTS: Six of 166 (3.6%) macular hole patients surveyed reported a history of macular hole in a primary relative compared with none of 136 (0.0%) control patients (odds ratio is infinity, with 95% confidence interval 1.295 to infinity); however, this finding may be explained by confounders such as age and number of family members. Two of the 142 (1.4%) patients with unilateral holes versus 4 of the 24 (16.7%) patients with bilateral holes reported a family history (odds ratio is 0.0714, with 95% confidence interval 0.0063 to 0.5537), and this finding remains significant when logistic regression is performed to evaluate variables of age and number of family members as potential confounders. CONCLUSION: There is an increased report of familial occurrence of macular hole in patients with macular holes compared with control patients; however, logistic regression relates this finding to variables of age and number of family members. Patients with bilateral macular holes are more likely to report a family history of macular hole than patients with unilateral macular holes, and this finding remains significant in the presence of age and number of family members. These findings may suggest a familial component to macular hole.

Single umbilical artery: Does side matter?

INTRODUCTION: The aim of this study was to determine if laterality of an absent umbilical artery (AUA) is associated with specific sonographic findings, chromosomal defects or postpartum birth defects. MATERIALS AND METHODS: In this retrospective cohort study, ultrasound reports and medical records of patients who received an obstetric ultrasound at the University of Iowa Hospitals and Clinics with an identified laterality of the AUA from 1989 to 2007 (n = 405) were reviewed. Rates of sonographic abnormalities between fetuses with a right versus left AUA were compared using Fisher's exact test. Adjustments for confounding were made using logistic regression modeling. The significance level was set at 0.05. RESULTS: Right AUAs on ultrasound demonstrate higher unadjusted rates of ultrasound abnormalities with a higher percentage of fetuses with >1 additional abnormality (51.1 vs. 37.0%; p = 0.0043). The left AUA group had a significantly higher percentage of isolated AUA (63.0 vs. 48.8%; p = 0.004). In a multivariate analysis, a sonographic right AUA was significantly associated with gastrointestinal (GI) and genitourinary (GU) abnormalities. No other ultrasonographic and umbilical artery Doppler abnormalities, chromosomal defects or postpartum birth defects were significantly associated with a specific laterality of the AUA. DISCUSSION: Our study identified a significant association between a right AUA and concomitant fetal GI and GU abnormalities. Contrary to previous reports, we conclude that laterality of the AUA may prove to be an easily identified early marker of fetal abnormalities.

Chitosan is a surprising negative modulator of cytotoxic CD8+ T cell responses elicited by adenovirus cancer vaccines.

Adjuvants modulate protective CD8(+) T cell responses generated by cancer vaccines. We have previously shown that immunostimulatory cytosine-phosphodiester-guanine (CpG) oligodeoxynucleotide (ODN) significantly augments tumor protection in mice given adenovirus cancer vaccines. Here, we examined the impact of chitosan, another candidate vaccine adjuvant, on protection conferred by adenovirus cancer vaccines. Unexpectedly, immunization of mice with adenovirus cancer vaccines in combination with chitosan provided little protection against tumor challenge. This directly correlated with the reduced detection of Ag-specific CD8(+) T cells, interferon-γ (IFN-γ) production, and cytotoxic T cell activity. We ruled out immunosuppressive regulatory T cells since the frequency did not change regardless of whether chitosan was delivered. In mammalian cell lines, chitosan did not interfere with adenovirus transgene expression. However, infection of primary murine bone marrow-derived dendritic cells with adenovirus complexed with chitosan significantly reduced viability, transgene expression, and upregulation of major histocompatability (MHC) class I and CD86. Our in vitro observations indicate that chitosan dramatically inhibits adenovirus-mediated transgene expression and antigen presenting cell activation, which could prevent CD8(+) T cell activation from occurring in vivo. These surprising data demonstrate for the first time that chitosan vaccine formulations can negatively impact the induction of CD8(+) T cell responses via its effect on dendritic cells, which is clinically important since consideration of chitosan as an adjuvant for vaccine formulations is growing.

Incidence, survival, and prevalence of neuroendocrine tumors versus neuroblastoma in children and young adults: nine standard SEER registries, 1975-2006.

BACKGROUND: The incidence, survival, and prevalence of neuroendocrine tumors (NETs) in children were determined as a first step in improving diagnosis and therapy. Outcomes were compared with neuroblastoma, a pediatric malignancy that shares several biomarkers. METHODS: Incidence rates, observed survival rates and 31-year limited duration prevalence counts were obtained from SEER*Stat for diagnosis years 1975 to 2006. These rates were compared between and within NETs and neuroblastoma for demographic and tumor-related variables from nine standard SEER registries for ages 0-29 years. Multivariate Cox regression was performed to identify prognostic factors for survival in NETs. RESULTS: The number of NETs was 1,073 compared to 1,664 neuroblastomas. The most common NET sites were lung, breast, and appendix. NET 5-year observed survival rates increased from 83% between 1975 and 1979 to 84% for the 2000-2006 period, while analogous neuroblastoma survival rates steadily increased from 45-73%. Five-year observed survival was less than 30% in females with NETs of the cervix and ovary. The estimated 31-year limited duration prevalence for NETs as of January 1, 2006 in the U.S. population was 7,724 compared to 9,960 for neuroblastomas. Age-adjusted multivariate Cox Regression demonstrated small cell histology, primary location in the breast, and distant stage as major predictors of decreased survival. CONCLUSIONS: While survivorship has significantly increased for neuroblastoma, those diagnosed with NETs have shown no increase in survival during this 31-year period. NETs constitute an unrecognized cancer threat to children and young adults comparable to neuroblastoma in both number of affected persons and disease severity.

A single-institution evaluation of factors important in fallopian tube carcinoma recurrence and survival.

OBJECTIVE: The aim of this study was to identify prognostic factors and markers that influence clinical outcomes in patients with primary fallopian tube carcinoma at a single tertiary health care center. These prognostic factors may be of clinical importance and can subsequently be included in future clinical trials. MATERIALS AND METHODS: A retrospective review of our Tumor Registry and Gynecologic Oncology database was conducted to include any patients with a diagnosis of fallopian tube carcinoma between the years 1994 and 2005. We identified clinicopathological data to evaluate factors important in recurrence, disease-specific and overall survival. Kaplan-Meier curves were generated, and log-rank tests were used to evaluate survival differences. RESULTS: Thirty-six patients had a diagnosis with primary fallopian tube carcinoma at a median age of 69 years. Patients most frequently presented with abdominal pain (19%) and a palpable mass (14%). The most common histological subtype was papillary serous adenocarcinoma in 56% of cases. Stage III disease (39%) and poorly differentiated tumors (81%) were most common. The median follow-up was 39.6 months. The 5-year cancer-specific survival was 42%, and the overall survival rate was 34%. Factors important in disease-free survival were International Federation of Gynecology and Obstetrics stage, tumor laterality, and serum CA-125, whereas International Federation of Gynecology and Obstetrics stage, serum CA-125, and residual disease were prognostic factors for overall survival. The most common locations of recurrence were pelvis and abdomen (63%) as opposed to distant sites. Factors associated with recurrence were stage, tumor laterality, and serum CA-125. CONCLUSIONS: Fallopian tube malignancies are rare. We have identified factors associated with recurrence, disease specific survival, and overall survival that could be further examined and included in larger clinical trials involving this uncommon malignancy.

Development and comparison of novel bioluminescent mouse models of pancreatic neuroendocrine neoplasm metastasis.

Pancreatic neuroendocrine neoplasms (pNENs) are slow growing cancers of increasing incidence that lack effective treatments once they become metastatic. Unfortunately, nearly half of pNEN patients present with metastatic liver tumors at diagnosis and current therapies fail to improve overall survival. Pre-clinical models of pNEN metastasis are needed to advance our understanding of the mechanisms driving the metastatic process and for the development of novel, targeted therapeutic interventions. To model metastatic dissemination of tumor cells, human pNEN cell lines (BON1 and Qgp1) stably expressing firefly luciferase (luc) were generated and introduced into NSG immunodeficient mice by intracardiac (IC) or intravenous (IV) injection. The efficiency, kinetics and distribution of tumor growth was evaluated weekly by non-invasive bioluminescent imaging (BLI). Tumors formed in all animals in both the IC and IV models. Bioluminescent Qgp1.luc cells preferentially metastasized to the liver regardless of delivery route, mimicking the predominant site of pNEN metastasis in patients. By comparison, BON1.luc cells most commonly formed lung tumors following either IV or IC administration and colonized a wider variety of tissues than Qgp1.luc cells. These models provide a unique platform for testing candidate metastasis genes and anti-metastatic therapies for pNENs.

Addition of 131I-MIBG to PRRT (90Y-DOTATOC) for Personalized Treatment of Selected Patients with Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131I-metaiodobenzylguanidine (131I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90Y-DOTATOC plus 131I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90Y-DOTATOC and 131I-MIBG.

Association of gallbladder hyperkinesia with acalculous chronic cholecystitis: A case-control study.

BACKGROUND: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis. METHODS: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups. RESULTS: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens. CONCLUSION: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults.

Prospective Analysis of the Impact of 68Ga-DOTATOC Positron Emission Tomography-Computerized Axial Tomography on Management of Pancreatic and Small Bowel Neuroendocrine Tumors.

OBJECTIVES: A prospective clinical trial evaluated the effect of Ga-DOTATOC positron emission tomography-computerized axial tomography (PET-CT) on change in management of patients with lung, pancreatic, and small bowel neuroendocrine tumors. The primary eligibility criterion was a histologically proven tumor with positive somatostatin receptor subtype 2A immunohistochemistry. The primary and secondary end points were change in patient management and safety. METHODS: Referring physicians completed questionnaires pre- and post-Ga-DOTATOC PET-CT, stating current and planned patient management, respectively, with tumor board adjudication of final management decisions. Change in management was categorized as follows: no change; minor change (additional imaging, supportive care); or major change (octreotide/lanreotide therapy, tumor biopsy, surgery, peptide receptor radiotherapy, chemotherapy, biological therapy, liver embolization). RESULTS: A major change in management was recommended for 54 (47.37%) of 114 subjects and a minor change for 6 (5.26%) of 114 subjects, with no change for 54 (47.37%) of 114 subjects. Grade 1 adverse events were observed in 26 of 114 subjects (nausea, headache, back pain, diarrhea); one grade 2 (petechiae) and one grade 3 (abdominal pain) adverse event were observed. No grade 2 or 3 adverse events were related to study drug and none required intervention. CONCLUSIONS: Imaging with Ga-DOTATOC PET-CT has a significant impact on management of patients with neuroendocrine tumors.

Morphological parameters for assessment of burn severity in an acute burn injury rat model.

Determination of burn severity (i.e. burn depth) is important for effective medical management and treatment. Using a recently described acute burn model, we studied various morphological parameters to detect burn severity. Anaesthetized Sprague-Dawley rats received burns of various severity (0- to 14-s contact time) followed by standard resuscitation using intravenous fluids. Biopsies were taken from each site after 5 h, tissues fixed in 10% neutral-buffered formalin, processed and stained with haematoxylin and eosin. Superficial burn changes in the epidermis included early keratinocyte swelling progressing to epidermal thinning and nuclear elongation in deeper burns. Subepidermal vesicle formation generally decreased with deeper burns and typically contained grey foamy fluid. Dermal burns were typified by hyalinized collagen and a lack of detectable individual collagen fibres on a background of grey to pale eosinophilic seroproteinaceous fluid. Intact vascular structures were identified principally deep to the burn area in the collagen. Follicle cell injury was identified by cytoplasmic clearing/swelling and nuclear pyknosis, and these follicular changes were often the deepest evidence of burn injury seen for each time point. Histological scores (epidermal changes) or dermal parameter depths (dermal changes) were regressed on burn contact time. Collagen alteration (r(2) = 0.91) correlated best to burn severity followed by vascular patency (r(2) = 0.82), epidermal changes (r(2) = 0.76), subepidermal vesicle formation (r(2) = 0.74) and follicular cell injury was useful in all but deep burns. This study confirms key morphological parameters can be an important tool for the detection of burn severity in this acute burn model.

The risk of developing arm lymphedema among breast cancer survivors: a meta-analysis of treatment factors.

BACKGROUND: As more women survive breast cancer, long-term complications that affect quality of life, such as lymphedema of the arm, gain greater importance. Numerous studies have attempted to identify treatment and prognostic factors for arm lymphedema, yet the magnitude of these associations remains inconsistent. METHODS: A PubMed search was conducted through January 2008 to locate articles on lymphedema and treatment factors after breast cancer diagnosis. Random-effect models were used to estimate the pooled risk ratio. RESULTS: The authors identified 98 independent studies that reported at least one risk factor of interest. The risk ratio (RR) of arm lymphedema was increased after mastectomy when compared with lumpectomy [RR = 1.42; 95% confidence interval (CI) 1.15-1.76], axillary dissection compared with no axillary dissection (RR = 3.47; 95% CI 2.34-5.15), axillary dissection compared with sentinel node biopsy (RR = 3.07; 95% CI 2.20-4.29), radiation therapy (RR = 1.92; 95% CI 1.61-2.28), and positive axillary nodes (RR = 1.54; 95% CI 1.32-1.80). These associations held when studies using self-reported lymphedema were excluded. CONCLUSIONS: Mastectomy, extent of axillary dissection, radiation therapy, and presence of positive nodes increased risk of developing arm lymphedema after breast cancer. These factors likely reflected lymph node removal, which most surgeons consider to be the largest risk factor for lymphedema. Future studies should consider examining sentinel node biopsy versus no dissection with a long follow-up time post surgery to see if there is a benefit of decreased lymphedema compared with no dissection.

Thromboembolic events in patients with cervical carcinoma: Incidence and effect on survival.

OBJECTIVES: The purpose of this study was to determine whether thromboembolic events (TE) in cervical cancer patients are associated with survival by comparing the survival of patients with and without thromboembolic events over a seven year period. METHODS: Utilizing a retrospective chart review we identified patients with any diagnosis of a TE, associated risk factors for TE development and overall survival. We also collected clinico-pathological data including stage, histology, height, weight, smoking history, radiation and chemotherapy treatment data and the temporal relationship of the development of TE to the time of cancer diagnosis. Data sources included the University of Iowa Hospitals and Clinics (UIHC) Tumor Registry and the UIHC Gynecologic Oncology Tumor Data Base as well as a search of UIHC medical record data bases using ICD-9 codes to initially identify all patients diagnosed with cervical carcinoma. RESULTS: In this study, the incidence of TE in cervical cancer patients was 11.7%. There was a clear and significant difference in survival between patients with and without TE. We identified an association between TE and stage, chemotherapy, brachytherapy, and radiation therapy. CONCLUSIONS: The major findings of our study are a significant incidence of thromboembolism in patients with cervical cancer, and a significant decrease in survival in patients who experience thromboembolism at presentation or during treatment. Deaths in these patients were overwhelmingly related to progressive cancer rather than the TE itself, suggesting that this adverse prognostic event may be related to aggressive tumor biology.

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth.

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

The impact of surgery on survival of elderly women with endometrial cancer in the SEER program from 1992-2002.

OBJECTIVES: Few population-based studies have evaluated surgical treatment and outcomes in elderly patients with endometrial cancer. The National Cancer Institute's SEER, Surveillance, Epidemiology and End Results, Program provides a database to examine this issue. The objective of this study was to determine the extent to which elderly women with endometrial cancer receive surgical treatment and to evaluate the impact of surgery on survival. METHODS: Data were obtained from the SEER registries for expanded races from 1992-2002. The inclusion criteria were women ages 50 to 95 with pathologically confirmed endometrial cancer. Cases with multiple primaries were excluded. The data were examined with respect to histology, radiotherapy use, extent of surgery and FIGO stage. The survival data were analyzed using a Cox proportional hazard model. Chi-squared tests were used to examine the extent to which elderly women with endometrial cancer receive surgical treatment, hysterectomy at minimum. Endometrial cancer-specific mortality was analyzed. RESULTS: 27,517 women were analyzed with 94% of the cohort receiving surgical treatments. There is a significant trend that suggests elderly women, aged 65+ years at time of endometrial cancer diagnosis, received surgical treatment less often than younger women (p<0.001). The age-adjusted hazard of death was reduced with surgical intervention. After adjustment for stage at diagnosis, histology, and radiotherapy, the hazard ratios for endometrial cancer-specific mortality were decreased when surgery was undertaken. CONCLUSIONS: In this population-based study, the poor prognosis associated with advanced age may be in part associated with the decreased frequency of surgical treatment. The reasons need to be further investigated. Continued efforts should be directed at providing surgical treatment for elderly patients with endometrial cancer.

The Effective Dynamic Ranges for Glaucomatous Visual Field Progression With Standard Automated Perimetry and Stimulus Sizes III and V.

Purpose: It has been shown that threshold estimates below approximately 20 dB have little effect on the ability to detect visual field progression in glaucoma. We aimed to compare stimulus size V to stimulus size III, in areas of visual damage, to confirm these findings by using (1) a different dataset, (2) different techniques of progression analysis, and (3) an analysis to evaluate the effect of censoring on mean deviation (MD). Methods: In the Iowa Variability in Perimetry Study, 120 glaucoma subjects were tested every 6 months for 4 years with size III SITA Standard and size V Full Threshold. Progression was determined with three complementary techniques: pointwise linear regression (PLR), permutation of PLR, and linear regression of the MD index. All analyses were repeated on "censored'' datasets in which threshold estimates below a given criterion value were set to equal the criterion value. Results: Our analyses confirmed previous observations that threshold estimates below 20 dB contribute much less to visual field progression than estimates above this range. These findings were broadly similar with stimulus sizes III and V. Conclusions: Censoring of threshold values < 20 dB has relatively little impact on the rates of visual field progression in patients with mild to moderate glaucoma. Size V, which has lower retest variability, performs at least as well as size III for longitudinal glaucoma progression analysis and appears to have a larger useful dynamic range owing to the upper sensitivity limit being higher.