Cost-Effectiveness of Radar Localisation Versus Wire Localisation for Wide Local Excision of Non-palpable Breast Cancer.

BACKGROUND: Wire localisation (WL) is the "gold standard" localisation technique for wide local excision (WLE) of non-palpable breast lesions but has disadvantages that have led to the development of wireless techniques. This study compared the cost-effectiveness of radar localisation (RL) to WL. METHODS: This was a single-institution study of 110 prospective patients with early-stage breast cancer undergoing WLE using RL with the SCOUT® Surgical Guidance System (2021-2023) compared with a cohort of 110 patients using WL. Margin status, re-excision rates, and surgery delays associated with preoperative localisation were compared. Costs from a third-party payer perspective in Australian dollars (AUD$) calculated by using microcosting, break-even point, and cost-utility analyses. RESULTS: A total of 110 WLEs using RL cost a total of AUD$402,281, in addition to the device cost of AUD$77,150. The average additional cost of a surgery delay was AUD$2318. Use of RL reduced the surgery delay rate by 10% (p = 0.029), preventing 11 delays with cost savings of AUD$25,496. No differences were identified in positive margin rates (RL: 11.8% vs. WL: 17.3%, p = 0.25) or re-excision rates (RL: 14.5% vs. WL: 21.8%, p = 0.221). In total, 290 RL cases are needed to break even. The cost of WLE using RL was greater than WL by AUD$567. There was a greater clinical benefit of 1.15 quality-adjusted life-years (QALYs) and an incremental cost-utility ratio of AUD$493 per QALY favouring RL. CONCLUSIONS: Routine use of RL was a more cost-effective intervention than WL. Close to 300 RL cases are likely needed to be performed to recover costs of the medical device. CLINICAL TRIAL REGISTRATION: ACTRN12624000068561.

Impact of lower level trauma center proliferation on patient outcomes.

Background: In attempt to increase trauma system coverage, our state added 21 level 3 (L3TC) and level 4 trauma centers (L4TC) to the existing 7 level 1 trauma centers from 2008 to 2012. This study examined the impact of adding these lower-level trauma centers (LLTC) on patient outcomes. Methods: Patients in the state trauma registry age ≥ 15 from 2007 to 2012 were queried for demographic, injury, and outcome variables. These were compared between 2007 (PRE) and 2008-2012 (POST) cohorts. Multivariate logistic regression was performed to assess independent predictors of mortality. Subgroup analyses were performed for Injury Severity Score (ISS) ≥15, age ≥ 65, and trauma mechanisms. Results: 143,919 adults were evaluated. POST had significantly more female, geriatric, and blunt traumas (all p < 0.001). ISS was similar. Interfacility transfers increased by 10.2 %. Overall mortality decreased by 0.6 % (p < 0.001). Multivariate logistic regression analysis showed that being in POST was not associated with survival (OR: 1.07, CI: 0.96-1.18, p = 0.227). Subgroup analyses showed small reductions in mortality, except for geriatric patients. After adjusting for covariates, POST was not associated with survival in any subgroup, and trended toward being a predictor for death in penetrating traumas (OR: 1.23; 1.00-1.53, p = 0.059). Conclusions: Unregulated proliferation of LLTCs was associated with increased interfacility transfers without significant increase in trauma patients treated. LLTC proliferation was not an independent protector against mortality in the overall cohort and may worsen mortality for penetrating trauma patients. Rather than simply increasing the number of LLTCs within a region, perhaps more planned approaches are needed. Key message: This is, to our knowledge, the first work to study the effect of rapid lower level trauma center proliferation on patient outcomes. The findings of our analysis have implications for strategic planning of future trauma systems.

Durability of radiofrequency ablation for long-segment and ultralong-segment Barrett's esophagus over 10 years.

BACKGROUND: Long-term durability data for radiofrequency ablation (RFA) to prevent esophageal adenocarcinoma in long-segment (LSBE) and ultralong-segment Barrett's esophagus (ULSBE) is lacking. This study aimed to determine 10-year cancer progression, eradication, and complication rates in LSBE and ULSBE patients treated with RFA. METHODS: Single-surgeon prospective database of patients with LSBE (≥ 3 to < 8 cm) and ULSBE (≥ 8 cm) who underwent RFA (2001-2021) were retrospectively analyzed. Ten-year cancer progression calculated with Kaplan-Meier analysis. Eradication rates, including complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM), and rates of recurrence and complications, compared between LSBE and ULSBE groups. RESULTS: Ten years after starting treatment, the cancer rate was 14.3% in 56 patients. CR-D and CR-IM rates were 87.5% and 67.9%, respectively. Relapse rates from CR-D were 1.8% and 3.6% from CR-IM. Eradication rates for dysplasia in LSBE and ULSBE patients (90.6% versus 83.3%) and IM (71.9% versus 62.5%) were not significantly different. ULSBE patients required higher mean number of ablation sessions for IM eradication (4.7 versus 3.7, p = 0.032), while complication rates including strictures (4.2% versus 6.2%), perforation (0 versus 0), and bleeding (4.2% versus 3.1%), were similar between ULSBE and LSBE patients, respectively. On multivariate analysis, shorter Barrett's segment and baseline low-grade dysplasia were associated with increased likelihood for eradication of IM and dysplasia. A total number of ablation sessions or endoscopic resections ≥ 3 was associated with reduced likelihood for eradication. CONCLUSION: RFA was durable in maintaining dysplasia and IM eradication in both LSBE and ULSBE over 10 years, and with low complication rates. IM eradication was more difficult to achieve in ULSBE. Late development of cancer occurred in 14.3%.

Recurrence in Paraesophageal Hernia: Patient Factors and Composite Surgical Repair in 862 Cases.

BACKGROUND: Repair of giant paraesophageal hernia (PEH) is associated with a considerable hernia recurrence rate by objective measures. This study analyzed a large series of laparoscopic giant PEH repair to determine factors associated with anatomical recurrence. METHOD: Data was extracted from a single-surgeon prospective database of laparoscopic repair of giant PEH from 1991 to 2021. Upper endoscopy was performed within 12 months postoperatively and selectively thereafter. Any supra-diaphragmatic stomach was defined as anatomical recurrence. Patient and hernia characteristics and technical operative factors, including "composite repair" (360° fundoplication with esophagopexy and cardiopexy to right crus), were evaluated with univariate and multivariate analysis. RESULTS: Laparoscopic primary repair was performed in 862 patients. The anatomical recurrence rate was 27.3% with median follow-up of 33 months (IQR 16, 68). Recurrence was symptomatic in 45% of cases and 29% of these underwent a revision operation. Hernia recurrence was associated with younger age, adversely affected quality of life, and were associated with non-composite repair. Multivariate analysis identified age < 70 years, presence of Barrett's esophagus, absence of "composite repair", and hiatus closure under tension as independent factors associated with recurrence (HR 1.27, 95%CI 0.88-1.82, p = 0.01; HR 1.58, 95%CI 1.12-2.23, p = 0.009; HR 1.72, 95%CI 1.2-2.44, p = 0.002; HR 2.05, 95%CI 1.33-3.17, p = 0.001, respectively). CONCLUSION: Repair of giant PEH is associated with substantial anatomical recurrence associated with patient and technique factors. Patient factors included age < 70 years, Barrett's esophagus, and hiatus tension. "Composite repair" was associated with lower recurrence rate.

Novel Dual Tracer Indocyanine Green and Radioisotope Versus Gold Standard Sentinel Lymph Node Biopsy in Breast Cancer: The GREENORBLUE Trial.

BACKGROUND: The methods for sentinel lymph node (SLN) biopsy in breast cancer have been variable in type and number of tracers. Some units have abandoned the use of blue dye (BD) due to adverse reactions. Fluorescence-guided biopsy with indocyanine green (ICG) is a relatively novel technique. This study compared the clinical efficacy and costs between novel dual tracer ICG and radioisotope (ICG-RI) with "gold standard" BD and radioisotope (BD-RI). METHODS: Single-surgeon study of 150 prospective patients with early breast cancer undergoing SLN biopsy (2021-2022) using ICG-RI compared with a retrospective cohort of 150 consecutive previous patients using BD-RI. Number of SLNs identified, rate of failed mapping, identification of metastatic SLNs, and adverse reactions were compared between techniques. Cost-minimisation analysis performed by using Medicare item numbers and micro-costing analysis. RESULTS: Total number of SLNs identified with ICG-RI and BD-RI was 351 and 315, respectively. Mean number of SLNs identified with ICG-RI and BD-RI was 2.3 (standard deviation [SD] 1.4) and 2.1 (SD 1.1), respectively (p = 0.156). There were no cases of failed mapping with either dual technique. Metastatic SLNs were identified in 38 (25.3%) ICG-RI patients compared with 30 (20%) BD-RI patients (p = 0.641). There were no adverse reactions to ICG, whereas four cases of skin tattooing and anaphylaxis were associated with BD (p = 0.131). ICG-RI cost an additional AU$197.38 per case in addition to the initial cost for the imaging system. CLINICAL TRIAL REGISTRATION:  ACTRN12621001033831. CONCLUSIONS: Novel tracer combination, ICG-RI, provided an effective and safe alternative to "gold standard" dual tracer. The caveat was the significantly greater costs associated with ICG.

The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells.

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins (BMPs). The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B (KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen's pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

Association of Short-Term Patient-Reported Outcomes With Long-Term Oncologic Outcomes in Localized Prostate Cancer Patients Treated With Radiation Therapy and Androgen Deprivation Therapy in a Randomized Controlled Trial.

PURPOSE: Both oncologic outcomes and patient-reported outcomes are pivotal in prostate cancer (PCa). However, it remains unknown if there is any association between these 2 outcomes. In this secondary analysis of a randomized controlled trial, we investigated the association of short-term changes in patient-reported outcome with long-term event-free survival (EFS) and metastasis-free survival (MFS) in localized PCa. METHODS AND MATERIALS: Localized PCa patients with a Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen (PSA) <30 ng/mL were randomized to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiation therapy or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy. Patient-reported symptom burden was evaluated using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ)-PR.25. Clinically meaningful deterioration (CMD) was defined as a ≥10-point worsening at any time within 10 months postrandomization regardless of subsequent improvement. Landmark analyses were performed to determine the association of CMD of urinary and bowel symptoms separately with EFS and MFS in patients who responded to the baseline questionnaire, were alive, and were event free at 10 months. RESULTS: Overall, 393 patients had responded to the baseline QLQ. One patient died, and 1 patient had failure within 10 months. Therefore, 391 patients were eligible for the landmark analyses. After adjusting for age, Gleason score, PSA, performance status, and treatment group, CMD of urinary symptoms was associated with worse EFS (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.21-2.65) and MFS (HR, 1.69; 95% CI, 1.11-2.57). Considering deaths as competing events, CMD of urinary symptoms was associated with a significant increase in the relative incidence of progression (subdistribution HR, 2.42; 95% CI, 1.12-5.20). However, no association was found between CMD of bowel symptoms and EFS or MFS. CONCLUSIONS: In this study, short-term CMD of urinary symptoms was associated with significantly inferior EFS and MFS and an increase in the relative incidence of progression. Further investigations are needed to explore the biological rationale of such association in the context of ADT and radiation therapy.

HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer.

PURPOSE: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. EXPERIMENTAL DESIGN: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. RESULTS: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. CONCLUSIONS: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.

HIV Screening and Early Referral in the Trauma Population: The Experience of a Large Safety Net Hospital.

BACKGROUND: While the prevalence of HIV infection in the population is 0.5%, it is higher among trauma patients as are rates of unknown seropositivity. Routine HIV screening for all trauma evaluations was implemented at our urban level I center in 2009. We aimed to evaluate use and results of the program in our trauma population. METHODS: This was a retrospective analysis of all trauma evaluations between July 2015 and February 2018. After passage of legislation rescinding the requirement for consent to perform HIV testing, our trauma service instituted an order set which automatically tested for HIV unless the ordering physician opted out. Patients found to be infected with HIV were to be counseled and referred to specialty care. RESULTS: Of 6175 consecutive trauma evaluations during the study period, 449 (7.3%) patients had been screened within the prior year and were excluded. Of the remaining cohort, 2024 (35.3%) patients were screened with 27 (1.3%) testing positive. Among those testing positive for infection, 100% were male, 77% white, 63% non-Hispanic, and 70% lacked insurance. Twenty-five (92.6%) patients received counseling and 19 were referred to specialty care. Age, gender, race, ethnicity, Injury Severity Score, trauma activation level, and payor type were not significant predictors for positive HIV screen on logistic regression analysis. CONCLUSIONS: Despite a significantly higher rate of HIV in the trauma population, only a third of patients are screened. Such high infection rates justify the existence of this screening program but steps must be taken to increase screening rate. LEVEL OF EVIDENCE: Level 3.

One-year mortality in geriatric trauma patients: Improving upon the geriatric trauma outcomes score utilizing the social security death index.

BACKGROUND: Geriatric Trauma Outcomes Score (GTOS) predicts in-patient mortality in geriatric trauma patients and has been validated in a prospective multicenter trial and expanded to predict adverse discharge (GTOS II). We hypothesized that these formulations actually underestimate the downstream sequelae of injury and sought to predict longer-term mortality in geriatric trauma patients. METHODS: The Parkland Memorial Hospital Trauma registry was queried for patients 65 years or older from 2001 to 2013. Patients were then matched to the Social Security Death Index. The primary outcome was 1-year mortality. The original GTOS formula (variables of age, Injury Severity Score [ISS], 24-hour transfusion) was tested to predict 1-year mortality using receiver operator curves. Significant variables on univariate analysis were used to build an optimal multivariate model to predict 1-year mortality (GTOS III). RESULTS: There were 3,262 patients who met inclusion. Inpatient mortality was 10.0% (324) and increased each year: 15.8%, 1 year; 17.8%, 2 years; and 22.6%, 5 years. The original GTOS equation had an area under the curve of 0.742 for 1-year mortality. Univariate analysis showed that patients with 1-year mortality had on average increased age (75.7 years vs. 79.5 years), ISS (11.1 vs. 19.1), lower GCS score (14.3 vs. 10.5), more likely to require transfusion within 24 hours (11.5% vs. 31.3%), and adverse discharge (19.5% vs. 78.2%; p < 0.0001 for all). Multivariate logistic regression was used to create the optimal equation to predict 1-year mortality: (GTOSIII = age + [0.806 × ISS] + 5.55 [if transfusion in first 24 hours] + 21.69 [if low GCS] + 34.36 [if adverse discharge]); area under the curve of 0.878. CONCLUSION: Traumatic injury in geriatric patients is associated with high mortality rates at 1 year to 5 years. GTOS III has robust test characteristics to predict death at 1 year and can be used to guide patient centered goals discussions with objective data. LEVEL OF EVIDENCE: Prognostic, level III.

Metabolomic Markers of Phthalate Exposure in Plasma and Urine of Pregnant Women.

Phthalates are known endocrine disruptors and found in almost all people with several associated adverse health outcomes reported in humans and animal models. Limited data are available on the relationship between exposure to endocrine disrupting chemicals and the human metabolome. We examined the relationship of metabolomic profiles in plasma and urine of 115 pregnant women with eleven urine phthalate metabolites measured at 26 weeks of gestation to identify potential biomarkers and relevant pathways. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 415 metabolites in plasma and 151 metabolites in urine samples. We have chosen metabolites with the best defined peaks for more detailed analysis (138 in plasma and 40 in urine). Relationship between urine phthalate metabolites and concurrent metabolomic markers in plasma and urine suggested potential involvement of diverse pathways including lipid, steroid, and nucleic acid metabolism and enhanced inflammatory response. Most of the correlations were positive for both urine and plasma, and further confirmed by regression and PCA analysis. However, after the FDR adjustment for multiple comparisons, only 9 urine associations remained statistically significant (q-values 0.0001-0.0451), including Nicotinamide mononucleotide, Cysteine T2, Cystine, and L-Aspartic acid. Additionally, we found negative associations of maternal pre-pregnancy body mass index (BMI) with more than 20 metabolomic markers related to lipid and amino-acid metabolism and inflammation pathways in plasma (p = 0.01-0.0004), while Mevalonic acid was positively associated (p = 0.009). Nicotinic acid, the only significant metabolite in urine, had a positive association with maternal BMI (p = 0.002). In summary, when evaluated in the context of metabolic pathways, the findings suggest enhanced lipid biogenesis, inflammation and altered nucleic acid metabolism in association with higher phthalate levels. These results provide new insights into the relationship between phthalates, common in most human populations, and metabolomics, a novel approach to exposure and health biomonitoring.

DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias.

DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

Moving Beyond Screening: How Emergency Departments Can Help Extinguish the HIV/AIDS Epidemic.

While great strides have been made in diagnostic and treatment strategies, human immunodeficiency virus (HIV) remains a major public health epidemic. The Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report article, "Vital Signs: HIV Diagnosis, Care, and Treatment Among Persons Living with HIV - United States, 2011," highlights current areas of concern regarding HIV diagnosis and care. The CDC estimates that 1.2 million people in the U.S. are living with HIV. Of them, 86% have received a diagnosis (14% remain undiagnosed and unaware), but only 40% are engaged in care and a mere 30% are virally suppressed. Emergency departments (EDs) can play a major role in combatting the HIV epidemic through regular screening and facilitating linkage to chronic HIV care. Universal opt-out screening as recommended by the CDC in 2006 has been shown to be effective but expensive, and has not been widely implemented in EDs nationwide. Cost-effective models and a renewed commitment from ED providers are needed to enhance ED-based HIV containment strategies.

Pain perception in sequential cataract surgery: comparison of first and second procedures.

PURPOSE: To compare pain and anxiety between first and second cataract extractions under topical anesthesia with monitored anesthesia care. SETTING: University ophthalmology clinic. DESIGN: Cohort study. METHODS: Consecutive adults having bilateral sequential clear corneal cataract extraction using phacoemulsification under topical anesthesia with monitored anesthesia care were recruited. Exclusion criteria included baseline eye pain, poor comprehension, and complicated cataract extraction. Patients completed 4 short perioperative surveys with each cataract extraction as follows: the Amsterdam Preoperative Anxiety and Information Scale (APAIS) and the State-Trait Anxiety Scale (STAI) preoperatively and a 0-to-10 visual analog scale pain survey twice after surgery. Pain and difference in pain were the primary outcomes. RESULTS: Of the 65 patients who completed the study, 26 (40%) reported higher visual analog scale pain scores for the second cataract extraction. Overall, the median pain score was 0 (range 0 to 6) for the first cataract extraction and 1 (range 0 to 9) for the second (P = .004). By 1 day postoperatively, the pain scores were similar (median 0; range 0 to 9; P = .58). Both APAIS and STAI anxiety scores decreased between surgeries (P = .003 and P < .001, respectively). CONCLUSIONS: Although cataract extraction remained relatively painless under topical anesthesia with monitored anesthesia care, there was a subtle increase in pain in the second surgery relative to the first. This appears to be associated with decreased preoperative anxiety and may be related to the amnestic effects of intravenous sedation. These data may explain a common operative observation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Determination of eniluracil and 5-fluorouracil in human plasma by LC-MS/MS.

BACKGROUND: 5-fluorouracil (5-FU) has been one of the most widely used chemotherapeutic agents to treat various tumors, and eniluracil (5-ethynyluracil or EU) is being developed as a novel modulator of 5-FU. RESULTS: A simple and sensitive LC-MS/MS method was developed for reliably quantifying both EU and 5-FU in human plasma. The method was validated for EU over a dynamic concentration range from 4.13 ng/ml (LOQ) to 1030 ng/ml and for 5-FU over a dynamic concentration range from 8.61 ng/ml (LOQ) to 1080 ng/ml. The analog, 5-bromouracil, was used as the internal standard for calibration curves and quantitation. Method validation has covered the scope of precision, accuracy, specificity, LOQ, linearity/range, freeze-thaw cycles, benchtop integrity/stability, storage stability, matrix effect, recoveries and so on, in accordance with US FDA bioanalytical method validation guidelines. CONCLUSIONS: The validated method has shown good applicability for clinical studies and may be used for other clinical trials that involve measuring the concentration of EU and 5-FU simultaneously in human plasma and potentially in other similar biological matrices.

Systems biology analysis of Sjögren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands.

OBJECTIVE: To identify key target genes and activated signaling pathways associated with the pathogenesis of Sjögren's syndrome (SS) by conducting a systems analysis of parotid glands manifesting primary SS or primary SS/mucosa-associated lymphoid tissue (MALT) lymphoma phenotypes. METHODS: A systems biology approach was used to analyze parotid gland tissue samples obtained from patients with primary SS, patients with primary SS/MALT lymphoma, and subjects without primary SS (non-primary SS controls). The tissue samples were assessed concurrently by gene-expression microarray profiling and proteomics analysis, followed by weighted gene-coexpression network analysis. RESULTS: Gene-coexpression modules related to primary SS and primary SS/MALT lymphoma were significantly enriched with genes known to be involved in the immune/defense response, apoptosis, cell signaling, gene regulation, and oxidative stress. Detailed functional pathway analyses indicated that primary SS-associated modules were enriched with genes involved in proteasome degradation, apoptosis, signal peptides of the class I major histocompatibility complex (MHC), complement activation, cell growth and death, and integrin-mediated cell adhesion, while primary SS/MALT lymphoma-associated modules were enriched with genes involved in translation, ribosome biogenesis and assembly, proteasome degradation, class I MHC signal peptides, the G13 signaling pathway, complement activation, and integrin-mediated cell adhesion. Combined analyses of gene expression and proteomics data implicated 6 highly connected "hub" genes for distinguishing primary SS from non-primary SS, and 8 hub genes for distinguishing primary SS/MALT lymphoma from primary SS. CONCLUSION: Systems biology analyses of the parotid glands from patients with primary SS and those with primary SS/MALT lymphoma revealed pathways and molecular targets associated with disease pathogenesis. The identified gene modules/pathways provide further insights into the molecular mechanisms of primary SS and primary SS/MALT lymphoma. The identified disease-hub genes represent promising targets for therapeutic intervention, diagnosis, and prognosis.