Beyond the Network: A Holistic Perspective on State Cybersecurity Governance

I. Introduction II. Governance: The New Frontier of Information Assurance III. State Cybersecurity Governance Extends Beyond the Network IV. Centralizing Security Governance to Defend State Networks V. Governance Beyond Network Defense ... A. Disruption Response ... B. Law Enforcement ... C. Cybersecurity Centers VI. Conclusion Appendix: States and Indicator

Multifocal Renal Cell Carcinoma: Clinicopathologic Features and Outcomes for Tumors ≤4 cm

A significant increase in the incidental detection of small renal tumors has been observed with the routine use of cross-sectional abdominal imaging. However, the proportion of small renal tumors associated with multifocal RCC has yet to be established. Here then, we report our experience with the treatment of multifocal RCC in which the primary tumor was ≤4 cm. In our series of 1113 RCC patients, 5.4% (60/1113) had multifocal disease at the time of nephrectomy. Discordant histology was present in 17% (10/60) of patients with multifocal RCC. Nephron sparing surgery was utilized more frequently in patients with solitary tumors. Overall, cancer-specific, and distant metastasis-free survival appeared to be similar between multifocal and solitary tumors. These findings are consistent with previous series which evaluated multifocal RCC with tumors >4 cm. With the known incidence of multifocality RCC, careful inspection of the entire renal unit should be performed when performing nephron sparing surgery

Molecular Targets for Radiation Oncology in Prostate Cancer

Recent selected developments of the molecular science of prostate cancer (PrCa) biology and radiation oncology are reviewed. We present potential targets for molecular integration treatment strategies with radiation therapy (RT), and highlight potential strategies for molecular treatment in combination with RT for patient care. We provide a synopsis of the information to date regarding molecular biology of PrCa, and potential integrated research strategy for improved treatment of PrCa. Many patients with early-stage disease at presentation can be treated effectively with androgen ablation treatment, surgery, or RT. However, a significant portion of men are diagnosed with advanced stage/high-risk disease and these patients progress despite curative therapeutic intervention. Unfortunately, management options for these patients are limited and are not always successful including treatment for hormone refractory disease. In this review, we focus on molecules of extracellular matrix component, apoptosis, androgen receptor, RUNX, and DNA methylation. Expanding our knowledge of the molecular biology of PrCa will permit the development of novel treatment strategies integrated with RT to improve patient outcom

Frequent Disruption of Chromodomain Helicase DNA-Binding Protein 8 (CHD8) and Functionally Associated Chromatin Regulators in Prostate Cancer

AbstractAbnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared against a range of clinicopathologic variables. CHD8 expression was decreased in HGPIN, localized, and metastatic PCa compared to benign (P < .001). CHD8 promoter hypermethylation, assessed by Quantitative Pyrosequencing, occurred in over 45% of primary cancers in this population as well as the TGCA database. Treatment of cell lines with the demethylating agent 5-Aza-2′-deoxycytidine reinduced expression. An interesting dichotomy for CHD8 was observed within primary cancers, with higher nuclear protein expression associated with adverse clinical outcomes including extracapsular extension (P = .007), presence of metastases (P = .025) and worse PSA-recurrence free survival (P = .048). CHD8 outperformed Gleason score and predicted biochemical failure within intermediate grade prostate cancers. The BORIS/CTCF expression ratio increased in localized (P = .03) and metastatic PCa (P = .006) and was associated with higher Gleason score (P = .02), increased tumor volume (P = .02) and positive margins (P = .04). Per cell heterogeneity of expression revealed all protein expression to be more heterogeneous in cancerous tissue (both P < .001), especially high grade (P < .01). In the first detailed analysis in cancer, a marked loss of CHD8 expression and increased BORIS/CTCF ratio indicate frequent disruption of CTCF and its effector genes in PCa

Delayed Intervention of Small Renal Masses on Active Surveillance

Although surgical excision is the standard of therapy for small renal masses (SRMs), there is a growing recognition of active surveillance as an option in select patients who are poor surgical candidates or who have shorter life expectancy. A number of patients on expectant management, however, subsequently advance to definitive therapy. In this study, we systematically reviewed the literature and performed a pooled analysis of active surveillance series to evaluate the rate and indications for definitive treatment after initiating a period of active surveillance. Fourteen clinical series (1245 patients; 1364 lesions) met our selection criteria. Mean lesion size at presentation was 2.30 ± 0.40 cm with a mean follow-up of 33.6 ± 16.9 months. Collectively, 34.0% of patients underwent delayed intervention, which ranged in individual series from 3.6% to 70.3%. Of patients undergoing delayed intervention, the average time on active surveillance prior to definitive treatment was 27.8 ± 10.6 months. A pooled analysis revealed that 41.0% of patients underwent therapy secondary to tumor growth rate and 51.9% secondary to patient or physician preference in the absence of clinical progression. Overall, 1.1% of all patients progressed to metastatic disease during the average follow-up period. Thus, active surveillance may be an appropriate option for carefully selected patients with SRMs. However, delayed treatment is pursued in a significant percentage of patients within 3 years. Prospective registries and clinical trials with standardized indications for delayed intervention are needed to establish true rates of disease progressions and recommendations for delayed intervention.</p

Delayed Intervention of Small Renal Masses on Active Surveillance

Although surgical excision is the standard of therapy for small renal masses (SRMs), there is a growing recognition of active surveillance as an option in select patients who are poor surgical candidates or who have shorter life expectancy. A number of patients on expectant management, however, subsequently advance to definitive therapy. In this study, we systematically reviewed the literature and performed a pooled analysis of active surveillance series to evaluate the rate and indications for definitive treatment after initiating a period of active surveillance. Fourteen clinical series (1245 patients; 1364 lesions) met our selection criteria. Mean lesion size at presentation was 2.30 ± 0.40 cm with a mean follow-up of 33.6 ± 16.9 months. Collectively, 34.0% of patients underwent delayed intervention, which ranged in individual series from 3.6% to 70.3%. Of patients undergoing delayed intervention, the average time on active surveillance prior to definitive treatment was 27.8 ± 10.6 months. A pooled analysis revealed that 41.0% of patients underwent therapy secondary to tumor growth rate and 51.9% secondary to patient or physician preference in the absence of clinical progression. Overall, 1.1% of all patients progressed to metastatic disease during the average follow-up period. Thus, active surveillance may be an appropriate option for carefully selected patients with SRMs. However, delayed treatment is pursued in a significant percentage of patients within 3 years. Prospective registries and clinical trials with standardized indications for delayed intervention are needed to establish true rates of disease progressions and recommendations for delayed intervention

RNA-Seq identifies SPGs as a ventral skeletal patterning cue in sea urchins

The sea urchin larval skeleton offers a simple model for formation of developmental patterns. The calcium carbonate skeleton is secreted by primary mesenchyme cells (PMCs) in response to largely unknown patterning cues expressed by the ectoderm. To discover novel ectodermal cues, we performed an unbiased RNA-Seq-based screen and functionally tested candidates; we thereby identified several novel skeletal patterning cues. Among these, we show that SLC26a2/7 is a ventrally expressed sulfate transporter that promotes a ventral accumulation of sulfated proteoglycans, which is required for ventral PMC positioning and skeletal patterning. We show that the effects of SLC perturbation are mimicked by manipulation of either external sulfate levels or proteoglycan sulfation. These results identify novel skeletal patterning genes and demonstrate that ventral proteoglycan sulfation serves as a positional cue for sea urchin skeletal patterning

Predictive Nomogram for Recurrence following Surgery for Nonmetastatic Renal Cell Cancer with Tumor Thrombus

Purpose Following surgery for nonmetastatic renal cell carcinoma with tumor thrombus the risk of recurrence is significant but variable among patients. The purpose of this study was to develop and validate a predictive nomogram for individual estimation of recurrence risk following surgery for renal cell carcinoma with venous tumor thrombus. Materials and Methods Comprehensive data were collected on patients with nonmetastatic renal cell carcinoma and thrombus treated at a total of 5 institutions from 2000 to 2013. Independent predictors of recurrent renal cell carcinoma from a competing risks analysis were developed into a nomogram. Predictive accuracy was compared between the development and validation cohorts, and between the nomogram and the UISS (UCLA Integrated Staging System, SSIGN (Stage, Size, Grade and Necrosis) and Sorbellini models. Results A total of 636 patients were analyzed, including the development cohort of 465 and the validation cohort of 171. Independent predictors, including tumor diameter, body mass index, preoperative hemoglobin less than the lower limit of normal, thrombus level, perinephric fat invasion and nonclear cell histology, were developed into a nomogram. Estimated 5-year recurrence-free survival was 49% overall. Five-year recurrence-free survival in patients with 0, 1, 2 and more than 2 risk factors was 77%, 53%, 47% and 20%, respectively. Predictive accuracy was similar in the development and validation cohorts (AUC 0.726 and 0.724, respectively). Predictive accuracy of the thrombus nomogram was higher than that of the UISS (AUC 0.726 vs 0.595, p = 0.001), SSIGN (AUC 0.713 vs 0.612, p = 0.04) and Sorbellini models (AUC 0.709 vs 0.638, p = 0.02). Conclusions We present a predictive nomogram for postoperative recurrence in patients with nonmetastatic renal cell carcinoma with venous thrombus. Improving individual postoperative risk assessment may allow for better design and analysis of future adjuvant clinical trials

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression

Defining a standard set of patient-centered outcomes for men with localized prostate cancer

Background Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment. Objective To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value. Design, setting, and participants We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices. Outcome measurements and statistical analysis The group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set. Results and limitations We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons. Conclusions We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care. Patient summary Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed treatment decisions. We defined a set of outcomes that we recommend being tracked for every man being treated for localized prostate cancer