American Gastroenterological Association-Proposed Fecal Calprotectin Cutoff of 50 ug/g is Associated With Endoscopic Recurrence in a Real-World Cohort of Patients With Crohn's Disease Post-ileocolic Resection.

Background: Fecal calprotectin (FC) is a reliable predictor of active bowel inflammation in postoperative Crohn's disease (CD), but cutoffs vary between studies. Recent guidelines recommend a cutoff of <50 ug/g to avoid routine endoscopy in patients at low pretest probability for CD recurrence. We evaluated the performance of this threshold in a real-world CD cohort after ileocolic resection (ICR). Methods: In this retrospective study, patients with CD post-ICR between 2009 to 2020 with FC > 60 days but < 1 year of surgery were included from a multicenter database. Established risk factors and/or biologic prophylaxis (biologic within 90 days of surgery) defined pretest probability. Those without postoperative colonoscopy were excluded. Rates of endoscopic recurrence, defined as Rutgeerts score ≥ i2b at any time after surgery, were compared between FC < 50 versus  ≥ 50 ug/g. Student's t-test and Fisher's exact test were utilized for statistical analysis. All postoperative FCs were matched to closest colonoscopy within 1 year to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Thirty-seven patients categorized as either low-risk or high-risk and received biologic prophylaxis and had postoperative colonoscopy were included. Median time to first FC was 217 days (IQR 131-288). 15 (41%) patients had initial FC < 50 ug/g versus 22 (59%) ≥50 ug/g. Median time to first colonoscopy was 234 days (IQR 189-369). Compared to initial FC ≥ 50 ug/g, FC < 50ug/g experienced less endoscopic recurrence (0% vs. 36%, P = .005). Median time to first endoscopic recurrence in FC ≥ 50 ug/g was 145 days. There were 39 matched pairs of FC and colonoscopy. At an FC cutoff of 50 ug/g, calculated sensitivity was 90% and NPV was 93%, whereas specificity and PPV were 48% and 38%, respectively. Conclusions: In this real-world cohort, FC < 50 ug/g is a useful cutoff to exclude endoscopic recurrence in a post-ICR CD population that is at low pretest probability of recurrence.

Nonoperative Management, Repair, or Reconstruction of the Medial Collateral Ligament in Combined Anterior Cruciate and Medial Collateral Ligament Injuries-Which Is Best? A Systematic Review and Meta-analysis.

BACKGROUND: Combined injury of the anterior cruciate ligament (ACL) and the medial collateral ligament (MCL) is a common injury pattern and accounts for 20% of all ligamentous knee injuries. Despite advancements in surgical technique, there is no up-to-date consensus regarding the superiority of nonoperative versus operative management in higher-grade MCL tears of combined ACL-MCL injuries. PURPOSE: To interpret recent literature on treatment options and to provide an updated evidence-based approach for management of combined ACL-MCL knee injuries. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: We performed a systematic review on outcomes following treatment of concomitant ACL and MCL injuries. A computerized search was conducted in PubMed, Embase.com, and Scopus.com. Authors independently assessed eligible studies and screened titles and abstracts. Articles reporting on patients with concomitant ACL and MCL injuries with or without concomitant procedures were included. Data regarding study design, sample size, patient age and sex, length of follow-up, timing of surgery, indications, surgical methods, concomitant procedures, outcomes, and complications were recorded. Patient-reported outcomes (PROs) and functional outcomes, including Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scores, Lysholm and Tegner scores, and range of motion, were estimated via meta-analysis and compared statistically by surgical approach. RESULTS: In total, 18 studies were included in the systematic review with level 1 to level 4 evidence, with a total of 1,534 cases, were included in the systematic review. Of these, 16 studies with sufficient statistical reporting including 997 cases with sufficient follow-up were included in meta-analysis. Three different approaches to combined ACL-MCL injuries were identified: ACL reconstruction with (1) nonoperative MCL, (2) MCL repair, and (3) MCL reconstruction. There was no statistical difference between nonoperative versus surgically managed MCL injuries for PROs, range of motion at final follow up, or quadriceps strength. CONCLUSION: Reconstruction of combined injury in a delayed fashion facilitates return of range of motion and may allow time for low-grade MCL tears to heal. If residual valgus or anteromedial rotatory laxity remains after a period of rehabilitation, then concomitant surgical management of ACL and MCL injuries is warranted. Avulsion MCL injuries and Stener-type lesions may benefit from early repair techniques.

Real-World Surgical and Endoscopic Recurrence Based on Risk Profiles and Prophylaxis Utilization in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Preoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there are limited data exploring and validating proposed clinical risk factors. We aimed to explore the preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence risk in a real-world cohort. METHODS: In this multicenter retrospective analysis, patients with CD who underwent ileocolonic resection (ICR) from 2009 to 2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating disease, and/or perianal disease) and low-risk (nonsmokers and age >50 y) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeert score, ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. RESULTS: A total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, 2 or more ICRs (odds ratio [OR], 1.71; 95% CI, 1.13-2.57), active smoking (OR, 1.73; 95% CI, 1.17-2.53), penetrating disease (OR, 1.41; 95% CI, 1.02-1.94), and history of perianal disease alone (OR, 1.99; 95% CI, 1.42-2.79) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis vs not (10.2% vs 16.7%; P = .02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (high-risk, 28.1% vs 37.4%; P = .03; and low-risk, 21.1% vs 38.3%; P = .002). CONCLUSIONS: Clinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.

Incorporating a polygenic risk score-triaged coronary calcium score into cardiovascular disease examinations to identify subclinical coronary artery disease (ESCALATE): Protocol for a prospective, nonrandomized implementation trial.

BACKGROUND: Identifying and targeting established modifiable risk factors has been a successful strategy for reducing the burden of coronary artery disease (CAD) at the population-level. However, up to 1-in-4 patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. Polygenic risk scores (PRS) have demonstrated an ability to improve risk prediction models independent of traditional risk factors and self-reported family history, but a pathway for implementation has yet to be clearly identified. The aim of this study is to examine the utility of a CAD PRS to identify individuals with subclinical CAD via a novel clinical pathway, triaging low or intermediate absolute risk individuals for noninvasive coronary imaging, and examining the impact on shared treatment decisions and participant experience. TRIAL DESIGN: The ESCALATE study is a 12-month, prospective, multicenter implementation study incorporating PRS into otherwise standard primary care CVD risk assessments, to identify patients at increased lifetime CAD risk for noninvasive coronary imaging. One-thousand eligible participants aged 45 to 65 years old will enter the study, which applies PRS to those considered low or moderate 5-year absolute CVD risk and triages those with CAD PRS ≥80% for a coronary calcium scan. The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) >0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sex-matched percentile, the use and intensity of lipid- and blood pressure-lowering therapeutics, cholesterol and blood pressure levels, and health-related quality of life (HRQOL). CONCLUSION: This novel trial will generate evidence on the ability of a PRS-triaged CACS to identify subclinical CAD, as well as subsequent differences in traditional risk factor medical management, pharmacotherapy utilization, and participant experience. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12622000436774. Trial was prospectively registered on March 18, 2022. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383134.

A Case of Opsoclonus-Myoclonus-Ataxia With Neuronal Intermediate Filament IgG Detected in Cerebrospinal Fluid.

ABSTRACT: A 62-year-old man presented with headache, fever, and malaise. He was diagnosed with Anaplasma phagocytophilum, confirmed by serum polymerase chain reaction, and started on oral doxycycline. After 5 days of treatment, the patient began to experience gait imbalance with frequent falls, as well as myoclonus, and confusion. Examination was notable for opsoclonus-myoclonus-ataxia (OMA) and hypometric saccades. Cerebrospinal fluid (CSF) autoimmune encephalitis panel demonstrated a markedly elevated neuronal intermediate filament (NIF) immunoglobulin G antibody titer of 1:16, with positive neurofilament light- and heavy-chain antibodies. These antibodies were suspected to have been triggered by the Anaplasma infection. Repeat CSF examination 8 days later still showed a positive immunofluorescence assay for NIF antibodies, but the CSF titer was now less than 1:2. Body computed tomography imaging was unrevealing for an underlying cancer. Our patient illustrates a postinfectious mechanism for OMA and saccadic hypometria after Anaplasma infection.

Neuropeptides Modulate Local Astrocytes to Regulate Adult Hippocampal Neural Stem Cells.

Neural stem cells (NSCs) in the dentate gyrus (DG) reside in a specialized local niche that supports their neurogenic proliferation to produce adult-born neurons throughout life. How local niche cells interact at the circuit level to ensure continuous neurogenesis from NSCs remains unknown. Here we report the role of endogenous neuropeptide cholecystokinin (CCK), released from dentate CCK interneurons, in regulating neurogenic niche cells and NSCs. Specifically, stimulating CCK release supports neurogenic proliferation of NSCs through a dominant astrocyte-mediated glutamatergic signaling cascade. In contrast, reducing dentate CCK induces reactive astrocytes, which correlates with decreased neurogenic proliferation of NSCs and upregulation of genes involved in immune processes. Our findings provide novel circuit-based information on how CCK acts on local astrocytes to regulate the key behavior of adult NSCs.

Transphyseal Anterior Cruciate Ligament Reconstruction Using Hybrid Transtibial Femoral Drilling and a Quadriceps Tendon Autograft.

Significant controversy exists regarding the optimal surgical technique for anterior cruciate ligament (ACL) reconstruction in adolescents with 1 to 3 years of skeletal growth remaining. Graft choice and physeal injury remain primary concerns given significantly elevated rates of failure of hamstring autograft reconstructions in this population, as well as risks of leg-length discrepancy and growth axis deviation. Traditional (more vertical) transtibial drilling of the femoral tunnel can reduce risks of physeal injury but has been shown to have less accuracy restoring the native femoral ACL footprint and associated incomplete knee stabilization. On the other hand, anteromedial and outside-in drilling yields improvements in the tunnel location and biomechanics but at the cost of a more oblique trajectory and greater risk of physeal injury. A hybrid transtibial pin technique using a Pathfinder guide facilitates femoral drilling with the "best of both worlds," allowing for reproduction of the native ACL footprint and a more physeal-respecting femoral tunnel. When combined with an all-soft tissue quadriceps tendon autograft and suspensory fixation, the hybrid transtibial method yields a reliable, safe, and robust construct with promising results for the young athlete. We describe our preferred graft harvest, tunnel drilling, and fixation techniques to minimize physeal risks and optimize outcomes.

Effectiveness of Lifestyle Interventions for Prevention of Harmful Weight Gain among Adolescents from Ethnic Minorities: A Systematic Review.

The escalating obesity among adolescents is of major concern, especially among those from an ethnic minority background. The adolescent period offers a key opportunity for the implementation of positive lifestyle behaviours as children transition to adulthood. The objective of this review was to examine the effectiveness of lifestyle interventions for adolescents and their impact in ethnic and racial minorities for the prevention of overweight and obesity. Seven electronic databases were searched from 2005 until March 2019 for randomized controlled trials of lifestyle programs conducted in this population. The main outcome was change in Body Mass Index (BMI) z-score (kg/m2) or change in BMI and secondary outcomes were changes in physical activity and diet. Thirty studies met the inclusion criteria. Seven studies reported and/or conducted subgroup analysis to determine if ethnic/racial group affected weight change. None demonstrated an overall decrease in BMI z-score. However, six of the seven demonstrated changes in secondary measures such as fruit and vegetable intake and screen time. Results did not differ by ethnic/racial group for primary and secondary outcomes. Overweight and obesity prevention among adolescents from ethnic minorities is an area that needs further research. There is a lack of interventions that include analyses of effectiveness in ethnic minorities.

Physeal-Sparing Medial Patellofemoral Ligament Reconstruction With Suture Anchor for Femoral Graft Fixation.

Patellar instability is a common problem in the active pediatric population. When nonoperative treatment of the instability fails, growth-respecting surgical stabilization techniques are required. As the incidence of medial patellofemoral ligament (MPFL) reconstruction has increased, techniques have improved to avoid physeal injury to the distal femur. These techniques are technically demanding because of the small size of the distal femoral epiphysis in children, as well as the relatively large socket size (7-8 mm in diameter, >20 mm in length) required for sound fixation with a tenodesis screw as originally described. The size of the femoral tunnel for interference fixation puts the surrounding structures at risk of damage. We present a modification of the epiphyseal socket technique for anatomic growth-sparing MPFL reconstruction using a small soft anchor for femoral graft fixation. This has the proposed advantages of diminishing volumetric bony removal from the epiphysis; increasing the margin of safety with respect to notch, trochlear, and/or physeal damage; and reducing the risk of thermal damage to the physis during socket reaming. This technique is technically simple and can be easily learned by surgeons familiar with adult MPFL reconstruction techniques.

Outcomes After Revision Anterior Shoulder Stabilization: A Systematic Review.

BACKGROUND: Primary shoulder stabilization is successful, but there continues to be a risk of recurrence after operative repair, particularly in the young athlete. It is important for surgeons to understand the outcomes after various revision stabilization techniques to best counsel patients and manage expectations. PURPOSE: To analyze recurrent instability and revision surgery rates in patients who underwent revision anterior glenohumeral stabilization procedures with either arthroscopic repair, open repair, coracoid transfer, free bone block, or capsular reconstruction. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We performed a systematic review of level 2 to 4 evidence studies using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical studies of revision anterior glenohumeral stabilization (arthroscopic repair, open repair, coracoid transfer, free bone block, or capsular reconstruction) with a minimum 2-year follow-up were analyzed. The rate of recurrent instability, rate of revision surgery, patient-reported outcomes, and range of motion were extracted and reported. Study methodological quality was evaluated using the Downs and Black quality assessment score. RESULTS: A total of 37 studies met inclusion criteria and were available for analysis: 20 studies evaluated arthroscopic repair, 8 evaluated open repair, 5 evaluated Latarjet procedure, 3 evaluated bone block, and 2 evaluated capsular reconstruction. There was 1 study included in both arthroscopic and Latarjet procedures, for a total of 1110 revision cases. There was 1 level 2 study, and the remainder were level 3 or 4 with poor Downs and Black scores. Participants analyzed were most commonly young (weighted mean age, 26.1 years) and male (78.4%). The weighted mean clinical follow-up after revision surgery was 47.8 months. The weighted mean rate of recurrent instability was 3.8% (n = 245) after the Latarjet procedure, 13.4% (n = 260) after open repair, 16.0% (n = 531) after arthroscopic repair, 20.8% (n = 72) after bone block, and 31.0% (n = 35) after capsular reconstruction. The weighted mean rate of additional revision surgery was 0.0% after bone block, 0.02% after the Latarjet procedure, 9.0% after arthroscopic repair, 9.3% after open repair, and 22.8% after capsular reconstruction. Patient-reported outcomes and objective measures of range of motion and strength improved with all revision techniques. CONCLUSION: The current review identifies a deficiency in the literature pertaining to consistent meaningful outcomes and the effect of bone loss after revision shoulder stabilization. Published studies demonstrate, however, that revision shoulder stabilization using arthroscopic, open, coracoid transfer, or bone block techniques yielded satisfactory objective and patient-reported outcomes. The Latarjet procedure exhibited the lowest recurrent instability rate. This study confirms that recurrent instability remains a common problem, despite revision shoulder stabilization. The quality of research in revision shoulder stabilization remains poor, and higher quality studies are needed to establish best practices for treatment of this complex problem.

Comorbidity landscape of the Danish patient population affected by chromosome abnormalities.

PURPOSE: Most chromosome abnormality patients require long-term clinical care. Awareness of mosaicism and comorbidities can potentially guide such health care. Here we present a population-wide analysis of direct and inverse comorbidities affecting patients with chromosome abnormalities. METHODS: We extracted direct and inverse comorbidities for the 11 most prevalent chromosome abnormalities from the Danish National Patient Registry (covering 6.9 million patients hospitalized between 1994 and 2015): trisomy 13, 18, and 21, Klinefelter (47,XXY), triple X, XYY, Turner (45,X), Wolf-Hirschhorn, Cri-du-chat, Angelman, and Fragile X syndromes (FXS). We also performed four sub-analyses for male/female Down syndrome (DS) and FXS and non-mosaic/mosaic DS and Turner syndrome. RESULTS: Our data cover 9,003 patients diagnosed with at least one chromosome abnormality. Each abnormality showed a unique comorbidity signature, but clustering of their profiles underlined common risk profiles for chromosome abnormalities with similar genetic backgrounds. We found that DS had a decreased risk for three inverse cancer comorbidities (lung, breast, and skin) and that male FXS and non-mosaic patients have a much more severe phenotype than female FXS and mosaic patients, respectively. CONCLUSION: Our study underlines the importance of considering mosaicism, sex, and the associated comorbidity profiles of chromosome abnormalities to guide long-term health care of affected patients.

Combing the Hairball: Improving Visualization of miRNA-Target Interaction Networks.

The visualization of regulatory networks is becoming increasingly important in order to understand molecular mechanisms and diseases. MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) responsible of the post-transcriptional regulation of messenger RNAs (mRNAs) and other ncRNAs. MiRNAs are involved in numerous biological processes including development, cell proliferation, and apoptosis. They are also key molecules in major complex diseases such as cancer and cardiovascular diseases. A single miRNA can regulate many targets, making the analysis and visualization of these complex networks challenging. Here, we present standard and advanced visualization approaches to represent networks with a special focus on miRNA-target interactions.

A Large-Cohort, Longitudinal Study Determines Precancer Disease Routes across Different Cancer Types.

Although many diseases are associated with cancer, the full spectrum of temporal disease correlations across cancer types has not yet been characterized. A population-wide study of longitudinal disease trajectories is needed to interrogate the general medical histories of patients with cancer. Here we performed a retrospective study covering a 20-year period, using 6.9 million patients from the Danish National Patient Registry linked to 0.7 million patients with cancer from the Danish Cancer Registry. Statistical analysis identified all significant disease associations occurring prior to cancer diagnoses. These associations were used to build frequently occurring, longitudinal disease trajectories. Across 17 cancer types, a total of 648 significant diagnoses correlated directly with a cancer, while 168 diagnosis trajectories of time-ordered steps were identified for seven cancer types. The most common diseases across cancer types involved cardiovascular, obesity, and genitourinary diseases. A comprehensive, publicly available web tool of interactive illustrations for all cancer disease associations is provided. By exploring the precancer landscape using this large dataset, we identify disease associations that can be used to derive mechanistic hypotheses for future cancer research. SIGNIFICANCE: This study offers an innovative approach to examine prediagnostic disease and cancer development in a large national population-based setting and provides a publicly available tool to foster additional cancer surveillance research.

Effect of lapatinib on meningioma growth in adults with neurofibromatosis type 2.

INTRODUCTION: Epidermal growth factor receptors EGFR and ErbB2 are overexpressed in schwannomas and meningiomas. Preclinical and clinical data indicate that lapatinib, an EGFR/ErbB2 inhibitor, has antitumor activity against vestibular schwannomas in neurofibromatosis type 2 (NF2) patients. Its antitumor activity against meningiomas, however, is unknown. METHODS: We conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated on a phase 2 clinical trial with lapatinib (NCT00973739). We included patients with at least one volumetrically measurable meningioma (> 0.5 cm3) who received at least five 28-day courses of treatment. Patients received lapatinib 1500 mg daily. Meningioma response was assessed using 3-dimensional MRI volumetrics. Progressive meningioma growth and response were defined as + 20 and - 20% change in tumor volume from baseline, respectively. Off-treatment was defined as any period > 5 months without lapatinib. RESULTS: Eight patients (ages: 20-58 years) who met criteria had 17 evaluable meningiomas with a combined volume of 61.35 cc at baseline, 61.17 cc during treatment, and 108.86 cc (+ 77.44% change) off-treatment, p = 0.0033. Median time on-treatment and off-treatment was 15.5 and 16.7 months, respectively. On-treatment mean and median annualized growth rates were 10.67 and 1.32%, respectively. Off-treatment mean and median annualized growth rates were 20.05 and 10.42%, respectively. The best volumetric response was - 26.1% after 23 months on lapatinib. Two tumors increased > 20% volumetrically on-treatment, compared to eight tumors off-treatment. CONCLUSIONS: These data suggest that lapatinib may have growth-inhibitory effects on meningiomas in NF2 patients, and support prospective studies of lapatinib for NF2 patients with progressive meningiomas.

Diagnosing Ring-Enhancing Lesions in the Brain of a Patient With AIDS Without Brain Biopsy: A Case of Central Nervous System Histoplasmoma.

We report a case of a Puerto Rican male with advanced AIDS who presented with multiple falls and pancytopenia. Magnetic resonance imaging (MRI) of the brain, as initial workup, revealed 2 ring-enhancing brain lesions. Initial cerebrospinal fluid analysis revealed minimal cells, mildly elevated protein, and no organism seen on gram stain. Due to prohibitive thrombocytopenia, brain biopsy was deferred. He had neither clinical nor radiographic improvement despite empiric therapy for both toxoplasmosis and bacterial abscesses. Indicated by pancytopenia, bone marrow (BM) aspiration was performed. Culture of BM aspirate grew Histoplasma capsulatum. Urine histoplasma antigen was markedly elevated. He was treated with liposomal amphotericin B (LamB) for progressive disseminated histoplasmosis with probable central nervous system involvement. Cerebrospinal fluid histoplasma antigen obtained after 2 months of LamB was detected. After prolonged course of LamB, he took itraconazole. Brain MRI at 7-month follow-up revealed significant improvement from baseline study.

An Adeno-Associated Virus-Based Toolkit for Preferential Targeting and Manipulating Quiescent Neural Stem Cells in the Adult Hippocampus.

Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need. Here, we report a recombinant adeno-associated virus serotype 4 (rAAV4)-based toolkit that preferentially targets hippocampal qNSCs and allows for lineage tracing, functional analyses, and activity manipulation of adult qNSCs. Importantly, targeting qNSCs in a non-Cre-dependent fashion opens the possibility for studying qNSCs in less genetically tractable animal species and may have translational impact in gene therapy by preferentially targeting qNSCs.

NetSig: network-based discovery from cancer genomes.

Methods that integrate molecular network information and tumor genome data could complement gene-based statistical tests to identify likely new cancer genes; but such approaches are challenging to validate at scale, and their predictive value remains unclear. We developed a robust statistic (NetSig) that integrates protein interaction networks with data from 4,742 tumor exomes. NetSig can accurately classify known driver genes in 60% of tested tumor types and predicts 62 new driver candidates. Using a quantitative experimental framework to determine in vivo tumorigenic potential in mice, we found that NetSig candidates induce tumors at rates that are comparable to those of known oncogenes and are ten-fold higher than those of random genes. By reanalyzing nine tumor-inducing NetSig candidates in 242 patients with oncogene-negative lung adenocarcinomas, we find that two (AKT2 and TFDP2) are significantly amplified. Our study presents a scalable integrated computational and experimental workflow to expand discovery from cancer genomes.

Network biology concepts in complex disease comorbidities.

The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being collected electronically, disease co-occurrences are starting to be quantitatively characterized. Linking network dynamics to the real-life, non-ideal patient in whom diseases co-occur and interact provides a valuable basis for generating hypotheses on molecular disease mechanisms, and provides knowledge that can facilitate drug repurposing and the development of targeted therapeutic strategies.

Adjuvant radiation therapy in stage III node-positive uterine cancer.

OBJECTIVES: To determine the association of adjuvant radiotherapy and outcomes of women with stage III node-positive uterine cancer. METHODS: All patients with surgically-staged stage III node-positive uterine cancer from the Surveillance Epidemiology and End Results database of the US National Cancer Institute from 1988 to 2001 were identified. Data were analyzed using Kaplan-Meier and logistic regression methods. RESULTS: Of 943 women, the median age was 64 years (range: 28-93). 82.1%, 8.6%, and 6.8% were White, Black, and Asian respectively. The median number of removed nodes was 11. 54.9% had a single positive node and 45.1% had 2-5 positive nodes. Endometrioid, papillary serous, sarcomas, and clear cell carcinomas comprised of 69.7%, 16.3%, 9.9%, and 4.1% of histologies, respectively. 67.3% of the women underwent adjuvant radiotherapy with a 5-year disease-specific survival of 67.9% compared to 53.4% in those without radiotherapy (p<0.001). Adjuvant radiotherapy improved the survival from 54.4% to 74.3% (p<0.001) in those with a single positive node and from 52.4% to 59.7% (p=0.089) in those with 2-5 positive nodes. On multivariate analysis, older age, non-endometrioid histology, and lack of adjuvant radiotherapy remained as significant independent prognostic factors for worsened survival. CONCLUSIONS: Our data suggest that adjuvant radiotherapy is associated with a significant survival benefit in women with single-positive node endometrioid uterine cancers. Prospective clinical trials are warranted to confirm these findings.

Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers.

OBJECTIVE: To compare the clinico-pathologic characteristics and survival of women with clear cell versus other epithelial ovarian cancers. METHODS: Data were obtained from the Surveillance, Epidemiology and End Results Program between 1988 and 2001 and analyzed using Kaplan-Meier and Cox proportional hazards models. RESULTS: Of 28,082 women with epithelial ovarian cancer, 1411 (5%) had clear cell, 13,835 (49.3%) papillary serous, 3655 (13%) endometrioid, 2711 (9.7%) mucinous, and 6470 (23%) had unspecified histologies. The median age of overall patients was 64 years; with clear cell patients presenting at younger age (55 years). The proportion of clear cell histology was significantly higher in Asians versus Whites, Blacks, and others (11.1% versus 4.8%, 3.1%, and 5.5%; p<0.001). Clear cell carcinoma is more likely to be diagnosed at early-stage (67.3%) compared to 19.2% in serous, 61.6% endometrioid, and 61.3% in mucinous carcinomas (p<0.005). Retroperitoneal lymph node metastases were found in 13.6% of serous carcinomas, 7.9% clear cell, 7.3% endometrioid, and 3.8% of mucinous (p<0.001). Adjusted for stage, the 5-year disease-specific survival of patients with clear cell carcinoma is worse compared to serous: 85.3% vs. 86.4% for stage I, 60.3% vs. 66.4% stage II, 31.5% vs. 35.0% stage III, and 17.5% vs. 22.2% for stage IV, respectively (p<0.001). On multivariate analysis, age, stage, grade, histology, and surgical treatment were independent predictors of disease-specific survival. CONCLUSIONS: Our data suggest that women with clear cell ovarian cancer present at a younger age, are more likely to be Asian, and have a poorer prognosis compared to serous cancers.