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TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan–Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression.

Background The Elders Mentoring Program (EMP) is part of a strengths-based community-based participatory research partnership with the Cree communities of Maskwacîs, Alberta, Canada. The EMP objective is to promote maternal and child health through traditional Cree teachings and support from community Elders to pregnant women and their partners. During the COVID-19 pandemic, the Elders decided to shift the program to an online format in early 2021. The Elders continued to offer mentorship to program participants virtually by Zoom and telephone, and online workshops. The objective of this study was to qualitatively explore the experiences of women that took part in the virtual EMP. Methods We utilized qualitative description as our method, informed by our overarching community-led research partnership. Semi-structured phone interviews were conducted by Maskwacîs research assistants (RAs) with 11 women who participated in the virtual program. Interviews were conducted between December 2021 and June 2022. The participants were asked about their perceptions of the program and its benefits. The interviews were recorded, transcribed, and coded by four RAs using thematic analysis. Results Although cultural teachings are traditionally offered in person, the shift to the virtual platform was greatly appreciated by all the women. Technology can be a useful tool for cultural teachings and language to be shared among community members when they cannot be physically together. Four main themes emerged from the data, representing the participants’ experiences, and learning through their interactions with the Elders from the EMP. The themes are: Ohpikihâwasowin (grounding and guiding on the path to be a healthy parent); Indigenous ways of healing; On the path of cultural learning; and Identity for self and baby. Conclusion The virtual adaptation of the EMP allowed a space for Elders to offer support to women living in and out of the community to provide guidance with their pregnancies and into motherhood. The workshops and one-on-one calls allowed for cultural revitalization which is critical for Indigenous well-being. All the participants found that the teachings and interactions positively impacted their pregnancy and parenthood. Overall, the virtual program demonstrated a venue for intergenerational healing and resilience.

In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs ( N  = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes ( RAD51, RAD54L, RAD54B ), which are potentially targetable, as well as PMS2 and BRCA1 , are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients. DNA damage repair genes have been linked with increased aggressiveness of prostate cancer, however, the extent of mutation of these genes has not been analyzed within a cohort of African American patients. Here, the authors identify increased mutation rates in specific DNA repair genes, compared with prostate cancer patients with European Ancestry.

Aminoacyl-tRNA synthetases (ARSs) are crucial enzymes for protein translation. Mutations in genes encoding ARSs are associated with human disease. Tyrosyl-tRNA synthetase is encoded by YARS which is ubiquitously expressed and implicated in an autosomal dominant form of Charcot-Marie-Tooth and autosomal recessive YARS-related multisystem disease. We report on a former 34-week gestational age male who presented at 2 months of age with failure to thrive (FTT) and cholestatic hepatitis. He was subsequently diagnosed with hyperinsulinemic hypoglycemia with a negative congenital hyperinsulinism gene panel and F-DOPA positron-emission tomography (PET) scan that did not demonstrate a focal lesion. Autopsy findings were notable for overall normal pancreatic islet size and morphology. Trio whole exome sequencing identified a novel homozygous variant of uncertain significance in YARS (c.611A > C, p.Tyr204Cys) with each parent a carrier for the YARS variant. Euglycemia was maintained with diazoxide (max dose, 18 mg/kg/day), and enteral dextrose via gastrostomy tube (G-Tube). During his prolonged hospitalization, the patient developed progressive liver disease, exocrine pancreatic insufficiency, acute renal failure, recurrent infections, ichthyosis, hematologic concerns, hypotonia, and global developmental delay. Such multisystem features have been previously reported in association with pathogenic YARS mutations. Although hypoglycemia has been associated with pathogenic YARS mutations, this report provides more conclusive data that a YARS variant can cause hyperinsulinemic hypoglycemia. This case expands the allelic and clinical heterogeneity of YARS-related disease. In addition, YARS-related disease should be considered in the differential of hyperinsulinemic hypoglycemia associated with multisystem disease.

Mechanistic studies of deregulated ERG in prostate cancer and other cancers continue to enhance its role in cancer biology and its utility as a biomarker and therapeutic target. Here, we show that ERG, through its physical interaction with androgen receptor, induces AR aggregation and endoplasmic reticulum stress in the prostate glands of ERG transgenic mice. Histomorphological alterations and the expression of ER stress sensors Atf6, Ire1α, Perk, their downstream effectors Grp78/BiP and eIF2α in ERG transgenic mouse prostate glands indicate the presence of chronic ER stress. Transient activation of apoptotic cell death during early age correlated well with the differential regulation of ER stress sensors, in particular Perk. Epithelial cells derived from ERG transgenic mouse prostates have increased prostasphere formation with resistance to radiation induced cell death. Continued activation of cell survival factors, Atf6 and Ire1α during chronic ER stress due to presence of ERG in prostate epithelium induces survival pathways and provides a selection pressure in the continuum of ERG dependent neoplastic process. These novel insights will enhance the understanding of the mechanistic functions of ERG in prostate tumor biology and towards development of early targeted therapeutic strategies for prostate cancer.

Background The relationship between race, prostate tumor location, and BCR‐free survival is inconclusive. This study examined the independent and joint roles of patient race and tumor location on biochemical recurrence‐free (BCR) survival. Methods A retrospective cohort study was conducted among men with newly diagnosed, biopsy‐confirmed, NCCN‐defined low risk CaP who underwent radical prostatectomy (RP) at the Walter Reed National Military Medical Center from 1996 to 2008. BCR‐free survival was modeled using Kaplan‐Meier estimation curves and multivariable Cox proportional hazards (PH) analyses. Results There were 539 eligible patients with low‐risk CaP (25% African American, AA; 75% Caucasian American, CA). Median age at CaP diagnosis and post‐RP follow‐up time was 59.2 and 8.1 years, respectively. Kaplan‐Meier analyses showed no significant association between race (P = .52) or predominant tumor location (P = .98) on BCR‐free survival. In Cox PH multivariable analysis, neither race (HR = 1.18; 95% CI = 0.68‐2.02; P = .56) nor predominant tumor location (HR = 1.13; 95% CI = 0.59‐2.15; P = .71) was an independent predictor of BCR‐free survival. Conclusions Neither race nor predominant tumor location was associated with adverse oncologic outcome. Neither race nor predominant tumor location was associated with decreased biochemical recurrence (BCR)‐free survival, either independently or jointly.

Abstract BACKGROUND Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system. Approximately 20% of new diagnoses are pediatric patients. Treatment for pediatric IBD has changed in recent years, focusing on decreased steroid use, and shifting to early initiation of biologics, especially in those at risk for complicated disease. Infliximab (IFX) is used for induction and maintenance. Clinical trials have shown that IFX improves clinical remission rates, and decreases hospitalizations and surgery rates. However, there is conflicting long-term data on whether infliximab has changed the natural course of IBD and decreased surgical risk. OBJECTIVE The objective of our study was to evaluate factors associated with increased risk of surgery in pediatric CD and UC patients using a large national health claims network database. METHODS We used TriNetX database and identified patients up to age 18 years, with a diagnosis of CD or UC (using ICD 9 and 10 codes) and treated with infliximab from January 1, 2006 to October 1, 2020. For each patient, we collected data on demographics profile, medication use, IBD related surgeries, and complications. Patients were then categorized into “early treatment” and “late treatment” groups, with early treatment being those who initiated infliximab therapy within 90 days of IBD diagnosis. The primary outcome was the need for surgery (partial or total colectomy, small intestinal resection and stricturoplasty). Secondary outcome was any IBD related complications (intraabdominal abscess, fistula formation, perianal abscess, fistuloectomy and fistulotomy). RESULTS A total of 7,954 IBD patients met inclusion criteria, of which 5,756 patients had CD, and 2,198 patients had UC. There were 2366 patients who were started on infliximab therapy within 90 days of initial diagnosis and the remaining 5,558 patients were in the late treatment group. A total of 169 (2.1%) patients underwent a major surgery and 560 (7%) patients experienced an IBD-related complication. Multivariate regression analysis did not reveal any significant association between timing of initiation of infliximab therapy and risk of surgery for both CD (OR: 1.12; 95% CI: 0.72 to 1.69, P=0.60) and UC (OR:1.57 ;95% CI: 0.91, 2.67, P=0.09). However, among CD patients, TPN use (OR: 5.45; 95% CI: 1.15 to 18.76, P = 0.014), fistulizing CD (OR: 4.59; 95% CI: 2.73 to 7.49; P <0.0001) and malnutrition (OR: 1.62; 95% CI: 1.02 to 2.47, P = 0.03), were more likely to develop IBD-related complications. There were no significant risk factors associated with greater odds of surgery or IBD-related complications in UC patients. CONCLUSION Late initiation of infliximab therapy was not associated with increased risk of surgery or IBD-related complication compared to early therapy. Prospective studies are needed to further evaluate these findings.

Abstract INTRODUCTION Biologics are effective medications used for induction and maintenance of remission in pediatric patients with inflammatory bowel disease (IBD). Insurance companies often require clinicians to obtain prior authorization (PA) prior to administration of biologics. Recent data determined that PA was associated with delays in care in pediatric IBD patients and an increased risk of subsequent healthcare utilization. Our study aim was to assess the effect of the PA process and its impact on care delivery for pediatric patients with IBD. METHODS A retrospective chart review of pediatric patients with IBD was conducted, including those with the diagnosis of ulcerative colitis or Crohn’s disease prescribed a biologic medication. Data obtained from medical records included demographics, IBD characteristics, insurance PAs, and clinical outcomes from 2015 to 2023. Outcome measures included time from initial PA submission to completion of the PA process, time from initial PA submission to first outpatient dose, frequency of insurance mandated medication changes, and number of hospitalizations for an inpatient dose. Analyses examined differences between those with PAs that were approved versus those who were initially denied. RESULTS We analyzed 134 patients who received a new biologic during our study period, of which 100 were newly diagnosed patients. Of the total sample, mean age was 12.5 years, 53.7% were male, with 96.2% non-Hispanic, 77.6% white, and 69.4% patients had Crohn’s disease. The most common medication prescribed was infliximab (81.3%). Of the patients in the approved group, 72.9% of patients had commercial insurance compared to 52.1% in the denied group (p=0.0152). Median time from initial PA submission to completion of PA process was 13 days for those denied vs. 3 days for those approved (p<0.0001). Of the patients denied, median time from initial PA submission to denial was 4 days (0-27) and median time from denial to subsequent approval was 7 days (0-75). Median time from initial PA submission to first outpatient dose was 30 days in the denied group vs. 13 days for the approved group (p<0.0001). 51% of patients in the denied group required hospitalization for their first biologic dose after PA initiation compared to 20% in the approved group (p=0.0002). CONCLUSION We found a significant delay in care for patients who received a prior authorization denial from insurance. Time from initial authorization submission to first dose was significantly different between the approved and denied groups. Prior authorization denials were also associated with significantly higher rate of hospitalizations for an infusion, potentially driving up overall cost of care.

The growth of complementary and alternative medicine (CAM) has led some family medicine practices to include CAM. Acupuncture or herbal medicine, for example, may be offered at such practices. When a practice incorporates both CAM and conventional treatments, its goals and values may differ from those found in traditional primary care. Little is known about the development of these integrated practices, which may be expected to become more widespread. To identify some of the concepts and challenges shaping family medicine practices that incorporate CAM. Comparative case study. Multi-method assessment process including participant observation, key informant interviews, semi-structured depth interviews, and observation of patient-provider encounters. Four family medicine/CAM practices in the mid-Atlantic region of the United States. Key themes that influence these practices' organization include dimensions of health, the selection of therapies used, the practices' approach to evidence, their perspective on the amount of time spent with patients, and their adaptations to financial concerns. Each practice emphasized long patient visits. In each, physicians had expertise that enabled them to draw on both conventional medicine and CAM. Successful incorporation of CAM modalities within a family medicine framework requires adaptation not only at the practice level but also by individual physicians.

Abstract OBJECTIVES Achieving endoscopic remission has become the preferred clinical endpoint in the care of inflammatory bowel disease (IBD) patients. This requires repeat colonoscopy in patients with ulcerative colitis (UC) after initiation of therapy. Recent adult data suggests findings in the left colon on flexible sigmoidoscopy can be highly predictive of the findings if a full colonoscopy was performed; however, pediatric data is lacking for this association. The primary aim our study to assess the accuracy of findings on the left colon with the right colon for repeat endoscopy in pediatric patients with UC. METHODS This was a retrospective chart review of pediatric patients with UC seen at a single, academic center between 2010-2021. Patient demographics, clinical disease activity, laboratory values and endoscopic findings were collected. The Mayo Endoscopy Score (MES) was used to assess the findings in the right and left colon by a single reader (JM). Histologic findings were assessed using the Geobes index by a pathology resident (AKA) and over-read by an attending pathologist (SS). Weighted kappa correlation was used to assess concordance between left and right colon endoscopic and histologic findings. Receiver operator curve (ROC) analysis was used to assess the accuracy of left-sided findings predicting right-sided findings. RESULTS We analyzed repeat endoscopies from 57 patients, of which 31 (54.4%) were male, mean age at UC diagnosis was 13.5 ± 4.1 years, 53 (93%) were Caucasian. Most common medication was oral mesalamine (67.2%) and most common distribution was pancolitis (53.4%). Mean time between index and repeat colonoscopy was 11.3 months. On repeat colonoscopy, endoscopic findings on the left colon moderately correlated with findings on the right colon [(κ = 0.53 (0.30-0.75)], similarly histologic findings for the left and right colon had a moderate correlation [(κ = 0.41 (0.17-0.64)]. Area under the ROC (AUC) was 0.89 for endoscopic remission anywhere in the colon and 0.98 for complete endoscopic healing anywhere in the colon. Longer interval between the index and follow-up colonoscopy did not affect odds of concordance. CONCLUSIONS We found that endoscopic and histologic severity correlated between the right and left colon for repeat assessment after initiation of biologic therapy. Left sided findings were highly accurate for endoscopic remission and complete endoscopic healing anywhere in the colon. This data suggest a flexible sigmoidoscopy could be feasible in lieu of full colonoscopy when assessing for endoscopic remission in pediatric patients with UC, to reduce the burden to the family and healthcare system. Further, prospective studies with a central reading component for histology and endoscopy are needed to validate these findings.