Effect Modification of Selenium Supplementation by Intake and Serum Concentrations of Antioxidants on the Development of Metachronous Colorectal Adenoma.

BACKGROUND: Selenium (Se) is a trace element that has been investigated as a potential chemopreventive agent for colorectal cancer. Dietary intake of other antioxidant nutrients may modify the effect of Se. OBJECTIVE: We examined the association between intake and serum concentrations of retinol, ß-carotene, ß-cryptoxanthin, lycopene, lutein/zeaxanthin, and α- and γ-tocopherol and the development of metachronous colorectal adenoma, and if these nutrients modified the effect of Se. METHODS: We conducted a prospective study of 1874 participants from the Se Trial with data for antioxidant intake, as well as a subcohort of 508 participants with serum biomarker concentrations. RESULTS: Statistically significantly lower odds for the development of metachronous adenoma were observed for those participants in the highest tertile of intake for lutein/zeaxanthin compared to the lowest, with an OR (95% CI) of 0.72 (0.56-0.94). No effect modification for intake of any nutrient was observed. However, circulating concentrations of lycopene exhibited statistically significant effect modification of selenium supplementation (p < 0.06). CONCLUSION: These findings show that intake and circulating concentrations of antioxidant nutrients were not consistently associated with reduced odds for the development of metachronous lesions, although blood concentrations of lycopene may modify the effect of selenium supplementation.

Topical negative pressure wound therapy to prevent wound complications following caesarean delivery in high-risk obstetric patients: A randomised controlled trial.

BACKGROUND AND AIMS: We investigated whether the use of a prophylactic negative pressure wound therapy (NPWT) system in women undergoing caesarean would decrease wound complications in a high-risk population. MATERIALS AND METHODS: A randomised controlled trial was performed. Women with risk factors for wound complications undergoing caesarean delivery were randomised to a standard dressing or NPWT placed over their caesarean wound. We standardised the closure of the subcutaneous fat and skin layers, both with Vicryl. Patients were followed for wound complications for up to 6 weeks after their caesareans. The incidence of wound complications was the primary outcome. The single-use NPWT system, PICO, was provided by Smith and Nephew for use in this trial. The trial was registered on clinicaltrials.gov, # NCT03082664. RESULTS: We report here on 154 women randomised to either a standard dressing or to the NPWT. Wound complication rates were equivalent between groups, with 19.4 and 19.7% (P = 0.43) of women with follow-up information available experiencing wound complications. CONCLUSION: We found no difference in wound complications in women with risk factors treated with a prophylactic NPWT system or standard wound dressing at the time of caesarean birth.

Factors Associated with Cancer Screening Among Hopi Men.

Cancer screening rates remain low among American Indian men, and cancer screening behaviors and barriers to cancer screening among American Indian men are not well understood. This study evaluated cancer screening behaviors in 102 Hopi men who were 50 years of age or older from the Hopi Survey of Cancer and Chronic Disease. Reported cancer screening frequencies were 15.7%, 45.1%, and 35.3% for fecal occult blood test (FOBT), colonoscopy, and prostate-specific antigen (PSA) test, respectively. Among men who reported having had a FOBT, 81.2% had the test more than 1 year ago. Among men who reported a colonoscopy, 60.8% had colonoscopy within the past 3 years. Similarly, among men who reported having had PSA, 72.3% had PSA within the past 3 years. "No one told me" was the most common answer for not undergoing FOBT (33.7%), colonoscopy (48.2%), and PSA (39.4%). Men who reported having had a PSA or digital rectal exam were three times as likely to also report having a FOBT or colonoscopy (odds ratio [OR] 3.19, 95% confidence interval [CI]: 1.21-8.46). Younger age (< 65) was associated with reduced odds of ever having prostate cancer screening (OR 0.28, 95% CI: 0.10-0.77). Ever having colorectal cancer screening and previous diagnosis of cancer increased odds of ever having prostate cancer screening (OR 3.15, 95% CI: 1.13-8.81 and OR 5.28, 95% CI: 1.15-24.18 respectively). This study illustrates the importance of community cancer education for men to improve cancer screening participation.

Subtle differences in autonomic symptoms in people diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

The hypermobile Ehlers-Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease-related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health-related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.

Higher Plasma Selenium Concentrations Are Associated with Increased Odds of Prevalent Type 2 Diabetes.

Background: Selenium, an essential trace element, has been investigated as a potential cancer prevention agent. However, several studies have indicated that selenium supplementation may be associated with an increased risk of type 2 diabetes (T2D), although an equivocal relation of this nature requires confirmation. Objective: We examined the association between baseline plasma concentrations of selenium and the prevalence of T2D, as well as whether participant characteristics or intake of other antioxidant nutrients modified this relation. Methods: We conducted cross-sectional analyses of 1727 participants from the Selenium Trial, a randomized clinical trial of selenium supplementation for colorectal adenoma chemoprevention that had data for baseline selenium plasma concentrations, T2D status, and dietary intake. Logistic regression modeling was used to evaluate the associations between plasma selenium concentrations and prevalent T2D, adjusting for confounding factors. Heterogeneity of effect by participant characteristics was evaluated utilizing likelihood-ratio tests. Results: Mean ± SD plasma selenium concentrations for those with T2D compared with those without T2D were 143.6 ± 28.9 and 138.7 ± 27.2 ng/mL, respectively. After adjustment for confounding, higher plasma selenium concentrations were associated with a higher prevalence of T2D, with ORs (95% CIs) of 1.25 (0.80, 1.95) and 1.77 (1.16, 2.71) for the second and third tertiles of plasma selenium, respectively, compared with the lowest tertile (P-trend = 0.007). No significant effect modification was observed for age, sex, body mass index, smoking, or ethnicity. Increased odds of T2D were seen among those who were in the highest tertile of plasma selenium and the highest category of intake of ß-cryptoxanthin (P-trend = 0.03) and lycopene (P-trend = 0.008); however, interaction terms were not significant. Conclusions: These findings show that higher plasma concentrations of selenium were significantly associated with prevalent T2D among participants in a selenium supplementation trial. Future work is needed to elucidate whether there are individual characteristics, such as blood concentrations of other antioxidants, which may influence this relation.

Topical analgesia treats pain and decreases propofol use during lumbar punctures in a randomized pediatric leukemia trial.

BACKGROUND: Lumbar punctures are frequently performed in pediatric leukemia for central nervous system leukemic prophylaxis. The contribution of local anesthetic with deep sedation is unknown. The objective was to evaluate EMLA (eutectic mixture of local anesthetics) cream as a pain reliever in conjunction with propofol in the setting of routine lumbar punctures. PROCEDURE: We included patients with acute lymphoblastic leukemia aged 3-21 years requiring at least two routine lumbar punctures. Patients were randomly assigned to receive EMLA or placebo cream and the alternate treatment with the second procedure. Patients, personnel and outcome assessors were blinded to allocation. The primary outcome included three indirect measures of pain: total median propofol doses, patient movement and heart rate changes at the time of skin puncture in both treatment groups. RESULTS: Twenty-six patients were enrolled and 25 were analyzed. With EMLA cream, 4 mg/kg (median) of propofol was required (95% CI 3.5-4.4). With placebo, 4.9 mg/kg of propofol was needed (95% CI 4.3-5.6; P = 0.008). When EMLA cream was applied, 8% of patients moved, whereas 84% moved with placebo cream (P < 0.0001). There was a lower average heart rate by seven beats in the EMLA treatment compared to placebo (95% CI -2.3-4.3; 4.1-12.4; P = 0.009). There were no adverse events in either treatment group. CONCLUSIONS: This study demonstrated that the combination of EMLA cream with propofol is beneficial. Topical analgesics are at the discretion of the oncologist, allowing us to advocate for patients by providing safe and efficacious pain management for lumbar punctures.

Cancer Screening on the Hopi Reservation: A Model for Success in a Native American Community.

American Indian women have lower cancer survival rates compared to non-Hispanic White women. Increased cancer screening fostered by culturally sensitive education and community programs may help decrease this disparity. This study assesses the effectiveness of Hopi Cancer Support Services (HCSS) in maintaining high rates of breast and cervical cancer screening among Hopi women and evaluates the impact of participation in HCSS programs on colorectal cancer (CRC) screening. A population-based survey was conducted on the Hopi reservation in 2012 (n = 252 women). Frequency of breast, cervical, and colorectal cancer screenings, participation in HCSS programs and barriers to screening were evaluated. Unconditional multiple logistic regression estimated the independent effect of the HCSS program on CRC screening. Approximately 88 % of Hopi women 40+ reported ever having had a mammogram; 71 % did so within the past 2 years. Approximately 66 % of women 50+ were ever screened for colorectal cancer (FOBT and/or colonoscopy). Women who had their last mammogram through HCSS were 2.81 (95 % CI 1.12, 7.07) times more likely to have been screened for CRC. Breast and cervical cancer screening continues at a high rate among Hopi women and is substantially greater than that reported prior to the inception of HCSS. Furthermore, participation in programs offered by HCSS is strongly associated with increased colorectal cancer screening. This tribal health program (HCSS) has strongly influenced cancer screening among Hopi women and is a model of a tribally run cancer prevention program.

EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons.

Dendritic spines are the postsynaptic compartment of a neuronal synapse and are critical for synaptic connectivity and plasticity. A developmental precursor to dendritic spines, dendritic filopodia (DF), facilitate synapse formation by sampling the environment for suitable axon partners during neurodevelopment and learning. Despite the significance of the actin cytoskeleton in driving these dynamic protrusions, the actin elongation factors involved are not well characterized. We identified the Ena/VASP protein EVL as uniquely required for the morphogenesis and dynamics of DF. Using a combination of genetic and optogenetic manipulations, we demonstrated that EVL promotes protrusive motility through membrane-direct actin polymerization at DF tips. EVL forms a complex at nascent protrusions and DF tips with MIM/MTSS1, an I-BAR protein important for the initiation of DF. We proposed a model in which EVL cooperates with MIM to coalesce and elongate branched actin filaments, establishing the dynamic lamellipodia-like architecture of DF.

Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer.

PURPOSE: Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance. PATIENTS AND METHODS: This multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used. RESULTS: From 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months; P = .04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (P = .03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%; P = .02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (P interaction = .02). CONCLUSION: The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.

Association of low serum albumin with venous thrombosis in pediatric patients.

OBJECTIVES: The incidence of venous thromboembolism (VTE) in children is increasing, attributed in part to increased utilization of central venous catheters (CVCs). Children with protein losing disorders (PLDs) and low serum albumin may have an increased incidence of thrombosis. We sought to determine the prevalence of PLDs and hypoalbuminemia at the time of diagnosis of VTE in pediatric patients and its relationship to central venous catheters. METHODS: We performed a single institution retrospective study of 65 consecutive hospitalized pediatric patients with an acute VTE. Data collected included clinical diagnoses, type of thrombosis, presence or absence of a CVC, and serum albumin level, if available. RESULTS: Of 65 patients with acute VTE, 51 % (33/65) had catheter-related thrombosis (CRT), including 71 % (19/27) of patients <12 years of age and 37 % (14/38) of patients aged 12 to 23 (P = 0.008). Eleven VTEs occurred in patients with a diagnosis of a PLD; of these, ten (91 %) were CRT and one (9 %) was a non-CRT (P = 0.003). Serum albumin levels obtained within four days of diagnosis of VTE were available for 38 patients. An albumin level below the lower limit of the age-adjusted normal reference range was documented in 27/38 (71 %) patients with VTE compared to 1011/3028 (33 %) of all pediatric patients admitted to the hospital during a two-year period (P < 0.0001). Albumin levels were low in 19/22 (86 %) patients with CRT compared with 8/16 (50 %) patients with non-CRT (P = 0.019). CONCLUSION: Low serum albumin levels are highly prevalent among pediatric patients with VTE, especially in those patients with CRT.

p38 MAP kinase plays a functional role in UVB-induced mouse skin carcinogenesis.

UVB irradiation of epidermal keratinocytes results in the activation of the p38 mitogen-activated protein kinase (MAPK) pathway and subsequently activator protein-1 (AP-1) transcription factor activation and cyclooxygenase-2 (COX-2) expression. AP-1 and COX-2 have been shown to play functional roles in UVB-induced mouse skin carcinogenesis. In this study, the experimental approach was to express a dominant negative p38α MAPK (p38DN) in the epidermis of SKH-1 hairless mice and assess UVB-induced AP-1 activation, COX-2 expression, and the skin carcinogenesis response in these mice compared to wild-type littermates. We observed a significant inhibition of UVB-induced AP-1 activation and COX-2 expression in p38DN transgenic mice, leading to a significant reduction of UVB-induced tumor number and growth compared to wild-type littermates in a chronic UVB skin carcinogenesis model. A potential mechanism for this reduction in tumor number and growth rate is an inhibition of chronic epidermal proliferation, observed as reduced Ki-67 staining in p38DN mice compared to wild-type. Although we detected no difference in chronic apoptotic rates between transgenic and nontransgenic mice, analysis of acutely irradiated mice demonstrated that expression of the p38DN transgene significantly inhibited UVB-induced apoptosis of keratinocytes. These results counter the concerns that inhibition of p38 MAPK in a chronic situation could compromise the ability of the skin to eliminate potentially tumorigenic cells. Our data indicate that p38 MAPK is a good target for pharmacological intervention for UV-induced skin cancer in patients with sun damaged skin, and suggest that inhibition of p38 signaling reduces skin carcinogenesis by inhibiting COX-2 expression and proliferation of UVB-irradiated cells.

Prone Positioning With Deep Inspiration Breath Hold for Left Breast Radiotherapy.

BACKGROUND: With advances in treatment, outcomes for early-stage breast cancer are improving. We investigated the combination of prone position and deep inspiration breath hold to decrease cardiac doses for left-sided breast radiotherapy. MATERIAL AND METHODS: Fifteen patients with left-sided breast cancer were enrolled on a single-institution prospective study. Each patient underwent 2 prone positioned computed tomography simulation scans utilizing free breathing and breath-hold. Separate treatment plans for each computed tomography simulation scan were created using tangential fields, and heart and left lung doses were compared between free breathing and breath-hold plans. The technique with the lower mean dose for the heart was used for treatment. All patients were treated with a hypofractionated regimen of 40 to 42 Gy in 15 to 16 fractions, followed by a lumpectomy cavity boost of 10 Gy in 5 fractions when indicated. Wilcoxon paired signed rank tests and paired t tests were performed for statistical analysis of dosimetric endpoints. RESULTS: The median age of our patients was 58 years (range, 40-72 years). One patient was not able to tolerate prone positioning at simulation, leaving 14 patients with evaluable paired scans. The average mean heart dose with free breathing and with breath-hold was 0.93 Gy and 0.72 Gy, respectively (P = .0063). The average max heart dose with free breathing and with breath-hold was 15.70 Gy and 7.19 Gy, respectively (P = .001). The average mean left lung dose with free breathing and with breath-hold was 0.65 Gy and 0.88 Gy, respectively (P = .011). CONCLUSIONS: Our results indicate that breath-hold using the real-time position management system may provide additional cardiac dose reduction in patients receiving prone left-breast radiotherapy treated with tangential fields.

Feasibility and Acceptability of a Type 2 Diabetes Prevention Intervention for Mothers and Children at a Federally Qualified Healthcare Center.

BACKGROUND: Maternal obesity and gestational diabetes mellitus (GDM) contribute to increased risk for type 2 diabetes mellitus (T2DM) among both mothers and their offspring. Randomized trials demonstrated T2DM risk reduction in adults following lifestyle behavior change and modest weight loss; the evidence base for at-risk children remains limited. PURPOSE: Evaluate the feasibility, acceptability, and preliminary efficacy of a T2DM prevention intervention for mother-child dyads delivered by Federally Qualified Health Center staff. METHODS: A group randomized design tested the effects of a behavioral lifestyle intervention on T2DM risk factors in women with a history of GDM and their 8- to 12-year-old children. Mother-child dyads were recruited and randomized to intervention or wait-listed control conditions. Intervention participants completed the 13-week intervention; control participants received standard of care. Baseline and 13-week measures assessed program acceptability and feasibility, and explored effects on body weight, waist circumference, hemoglobin A1c, and lifestyle behaviors. RESULTS: Forty-two dyads were randomized and 35 (83%) completed pre-/post-measurements. Participants and program leaders positively rated content and engagement. Nearly all strongly agreed that activities were enjoyable (97%), applicable (96%), useful (97%), and motivational (96%). Attendance averaged 65% across 2 cohorts; delivery costs were approximately $225/dyad. There were no significant differences in body weight, BMI (or BMI z-score), waist circumference, hemoglobin A1c, diet quality, physical activity, sleep, or home environment changes between intervention and control groups. CONCLUSIONS: A family T2DM prevention program was feasibly delivered by FQHC staff, and acceptable to mothers and children. Program efficacy will be evaluated in an adequately powered clinical trial.

A Protective Role for Arachidonic Acid Metabolites against Advanced Colorectal Adenoma in a Phase III Trial of Selenium.

Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E2 (PGE2), with an OR (95% CI) of 0.55 (0.33-0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33-0.94)); and of a large adenoma with higher PGE2 ((0.52 (0.31-0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.

In Vivo Reflectance Confocal Microscopy as a Response Monitoring Tool for Actinic Keratoses Undergoing Cryotherapy and Photodynamic Therapy.

Reflectance confocal microscopy (RCM) presents a non-invasive method to image actinic keratosis (AK) at a cellular level. However, RCM criteria for AK response monitoring vary across studies and a universal, standardized approach is lacking. We aimed to identify reliable AK response criteria and to compare the clinical and RCM evaluation of responses across AK severity grades. Twenty patients were included and randomized to receive either cryotherapy (n = 10) or PDT (n = 10). Clinical assessment and RCM evaluation of 12 criteria were performed in AK lesions and photodamaged skin at baseline, 3 and 6 months. We identified the RCM criteria that reliably characterize AK at baseline and display significant reduction following treatment. Those with the highest baseline odds ratio (OR), good interobserver agreement, and most significant change over time were atypical honeycomb pattern (OR: 12.7, CI: 5.7-28.1), hyperkeratosis (OR: 13.6, CI: 5.3-34.9), stratum corneum disruption (OR: 7.8, CI: 3.5-17.3), and disarranged epidermal pattern (OR: 6.5, CI: 2.9-14.8). Clinical evaluation demonstrated a significant treatment response without relapse. However, in grade 2 AK, 10/12 RCM parameters increased from 3 to 6 months, which suggested early subclinical recurrence detection by RCM. Incorporating standardized RCM protocols for the assessment of AK may enable a more meaningful comparison across clinical trials, while allowing for the early detection of relapses and evaluation of biological responses to therapy over time.

Increased PD-L1 Expression in Human Skin Acutely and Chronically Exposed to UV Irradiation.

Overexpression of PD-L1 (CD274) on tumor cells may represent a hallmark of immune evasion, and overexpression has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). While PD-L1/PD-1 activity in the skin has been primarily described in inflammatory models, our goal was to examine PD-L1 expression in human keratinocytes exposed to UV irradiation. We assessed PD-L1 expression in human sun-protected (SP) and sun-damaged (SD) skin, actinic keratosis (AK), and cSCC using IHC and protein microarray. Both methods found low baseline levels of PD-L1 in SP and SD skin and significantly increased expression in cSCC. Next, we examined PD-L1 expression in acute models of UV exposure. In human SP skin exposed to 2-3 MED of UV (n = 20), epidermal PD-L1 was induced in 70% of subjects after 24 h (P = 0.0001). SKH-1 mice exposed to acute UV also showed significant epidermal PD-L1 induction at 16, 24 and 48 h. A time- and dose-dependent induction of PD-L1 was confirmed in cultured human keratinocytes after UV, which was markedly reduced in the presence of MEK/ERK, JNK or STAT3 inhibitors. These findings suggest that UV induces upregulation of PD-L1 through established, pharmacologically targetable stress-signaling pathways in keratinocytes.

Analyzing outcomes of neoadjuvant and adjuvant treatment for borderline-resectable pancreatic adenocarcinoma in the perioperative period at an academic institution.

BACKGROUND: Only 15-20% of pancreatic ductal adenocarcinoma (PDAC) patients are upfront surgical candidates at presentation, and for this cohort of patients, the 5-year survival is a mere 20% despite adjuvant therapy. Previous data indicate that in clinical practice most of these cases are "borderline-resectable," and there is currently no mature data on perioperative treatment. METHODS: We performed a retrospective electronic chart review of patients with "borderline-resectable"PDAC treated at an academic comprehensive cancer center, dividing them into groups based on surgery alone, surgery plus neoadjuvant, adjuvant, or neoadjuvant plus adjuvant perioperative treatment groups. The objectives were to determine the median overall survival (mOS), progression-free survival (PFS) and disease-free survival (DFS). Statistical analysis was performed to assess the association of demographic, tumor traits, and interventions with OS, PFS and DFS. RESULTS: Only surgery followed by adjuvant therapy showed an increase in mOS [hazard ratio (HR) 0.22; 95% CI, 0.09-0.51; P<0.001), after adjustment for radiation (yes vs. no), resection margins (R0 vs. R1 or R2), and tumor location (head vs. body or tail). Patients who received adjuvant therapy after surgery had 2.1 times greater odds to be alive at 24 months after diagnosis than those who had surgery alone (P=0.015). PFS and DFS were not statistically significantly different among treatment groups after adjustment. Those whose disease was located in the head of the pancreas had a significantly improved OS (HR =0.27; 95% CI, 0.11-0.64; P=0.003), PFS (HR =0.40; 95% CI, 0.17-0.94; P=0.035), and DFS (HR =0.30; 95% CI, 0.13-0.67; P=0.004). Negative margins led to a significant improvement in PFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001) and DFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001). Those who received radiation had a non-significantly improved OS, PFS, and DFS (P>0.05). CONCLUSIONS: Our study corroborated that patients treated with adjuvant therapy after surgical resection had an mOS benefit as reported on prior phase III clinical trials. Patients with "borderline-resectable" pancreatic cancer are encouraged to participate in a clinical trial or clinically be treated with adjuvant therapy until more mature results from the ongoing perioperative prospective study are available.

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3.

Prostate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared with patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases.

Evaluation of the Number-Needed-to-Biopsy Metric for the Diagnosis of Cutaneous Melanoma: A Systematic Review and Meta-analysis.

IMPORTANCE: To date, no concerted effort has been made to date to evaluate the literature on number-needed-to-biopsy (NNB) metrics, particularly to account for the differences in clinician type and melanoma prevalence in certain geographic locations. OBJECTIVE: To review and synthesize worldwide data for NNB for the diagnosis of cutaneous melanoma. DATA SOURCE: MEDLINE, Embase, and PubMed databases were searched for English-language articles published worldwide from January 1, 2000, to November 28, 2018. STUDY SELECTION: A total of 46 studies were included that addressed NNB for at least 3681 clinicians worldwide and included 455 496 biopsied tumors and 29 257 melanomas; primary care practitioner (PCP) data were only available from Australia. DATA EXTRACTION AND SYNTHESIS: Articles were screened for eligibility, and possible overlapping data sets were resolved. Data extracted included clinician specialization, use of dermoscopy, geographic region and location-specific health care system, study design, number of benign tumors, number of melanomas, and NNB. The review followed the PRISMA guidelines. MAIN OUTCOME AND MEASURES: The NNB for the diagnosis of cutaneous melanoma. RESULTS: A total of 46 studies were included that addressed NNB for at least 3681 clinicians worldwide and included 455 496 biopsied tumors and 29 257 melanomas; primary care practitioner (PCP) data were only available from Australia. The reported NNB ranged from 2.2 to 287, and the weighted mean NNB for all included publications was 15.6. The exclusion of publications structured as all biopsied tumors, owing to variable data characterization, resulted in reported NNB ranging from 2.2 to 30.5, with a global weighted mean NNB of 14.8 for all clinicians, 7.5 for all dermatologists, 14.6 for Australian PCPs, and 13.2 for all US-based dermatological practitioners, including dermatologists and advanced practice professionals. The summary effect size (ES) demonstrates that a mean 4% of biopsies demonstrated melanoma for study stratum A (all biopsied skin tumors, ES, 0.04; 95% CI, 0.03-0.05), and a mean 12% of biopsies demonstrated melanoma for study strata B (melanocytic tumors on pathology review, ES, 0.12; 95% CI, 0.10-0.14) and C (clinical concern for melanoma, ES; 0.12; 95% CI, 0.09-0.14). CONCLUSIONS AND RELEVANCE: The existing NNB for cutaneous melanoma appeared to vary widely worldwide, lacking standardization in the metric and its reporting, and according to clinician characteristics as well; the NNB of US-based clinicians may warrant further exploration.

Feasibility of a family-focused YMCA-based diabetes prevention program in youth: The E.P.I.C. Kids (Encourage, Practice, and Inspire Change) Study.

Efficacious lifestyle modification programs for children at risk of type 2 diabetes (T2D) have not been well established outside of clinical settings. In this study, the feasibility of a family-focused, YMCA-based prevention program for children at risk of T2D was evaluated between September 2015 and July 2016 in Tucson, Arizona. A 12-week YMCA-led lifestyle intervention was adapted for 9-12-year-old children and their families to encourage healthy eating, physical activity, and supportive home environments. Two YMCA locations were randomized to offer either a face-to-face lifestyle coach-led intervention or an alternating face-to-face and digitally-delivered intervention. Program feasibility and preliminary effects on child anthropometric and behavioral outcomes were assessed at baseline and post-intervention. Changes were assessed using linear regression combining delivery formats, with adjustment for clustering of participants within site/format. Forty-eight children (10.9 ±â€¯1.2 years old; 45% female; 40% Hispanic; 43% White; 87% obese) and their parents enrolled, and 36 (75%) completed 12-week measures. Weekly program attendance averaged 61%. Participants and coaches highly rated program content and engagement strategies. Statistically significant changes in child BMI-z score (-0.05, p = 0.03) and family food and physical activity environment (+5.5% family nutrition and physical activity score, p = 0.01) were observed. A YMCA-led family-focused T2D intervention was feasible for the YMCA and participants and effects on child weight, behavior, and the home environment warranted further investigation.