Colonoscopy Utilization in Elderly Patients with Dementia: Characteristics, Complications, and Charges in a National Matched-Cohort Analysis.

BACKGROUND: It is projected that the elderly population will continue to increase. Many will develop chronic conditions such as dementia. AIMS: Our aims are to describe the utilization of colonoscopy among patients with dementia and compare outcomes in those with and without dementia. METHODS: This population-based analysis utilized the National Inpatient Sample (NIS) during 2019. Patients with dementia over the age of 60 years receiving colonoscopy were identified utilizing ICD-10 codes. Logistic regression was used for propensity score matching between the comparison groups. A Greedy one-to-one matching algorithm was utilized along with standardized mean differences to assess balance. Mcnemar test, signed rank sum, and paired t-test were used to compare the outcomes. RESULTS: Initially, 50,692 patients without dementia were compared with 4323 patients with dementia. Patients with dementia were more likely to be female, older, less likely White, had lower income, and more likely to be on Medicare. In the matched comparison (4176 in each group), complication analysis showed that patients with dementia did not have higher colonoscopy-related complications. They did have higher rates of other complications including renal/AKI (p = 0.0042), pulmonary/pneumonia (p = 0.003), cerebrovascular accidents (p = 0.0063), and sepsis (< 0.0001). Patients with dementia were also less likely to have routine discharges (< 0.0001), had longer hospital stays (< 0.0001), and higher hospital costs (< 0.0001). CONCLUSIONS: Elderly patients with dementia have similar colonoscopy-related complications as patients without dementia. However, they do have higher complications in general. The decision whether to perform colonoscopy in this patient population is multifactorial. A careful assessment of a dementia patient's history can help with this decision.

Conventional Cytogenetic Analysis of Hematologic Neoplasms: A 20-Year Review of Proficiency Test Results From the College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee.

CONTEXT.­: One goal of the joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee is to ensure the accurate detection and description of chromosomal abnormalities in both constitutional and neoplastic specimens, including hematologic neoplasms. OBJECTIVE.­: To report a 20-year performance summary (1999-2018) of conventional chromosome challenges focusing on hematologic neoplasms. DESIGN.­: A retrospective review was performed from 1999 through 2018 to identify karyotype challenges specifically addressing hematologic neoplasms. The overall performance of participants was examined to identify potential recurring errors of clinical significance. RESULTS.­: Of 288 total conventional chromosome challenges from 1999-2018, 87 (30.2%) were presented in the context of a hematologic neoplasm, based on the provided clinical history, specimen type, and/or chromosomal abnormalities. For these 87 hematologic neoplasm challenges, 91 individual cases were provided and graded on the basis of abnormality recognition and karyotype nomenclature (ISCN, International System for Human Cytogenomic [previously Cytogenetic] Nomenclature). Of the 91 cases, 89 (97.8%) and 87 (95.6%) exceeded the required 80% consensus for grading of abnormality recognition and correct karyotype nomenclature, respectively. The 2 cases (2 of 91; 2.2%) that failed to meet the 80% consensus for abnormality recognition had complex karyotypes. The 4 cases (4 of 91; 4.4%) that failed to meet the 80% consensus for correct karyotype nomenclature were the result of incorrect abnormality recognition (2 cases), missing brackets in the karyotype (1 case), and incorrect breakpoint designation (1 case). CONCLUSIONS.­: This 20-year review demonstrates clinical cytogenetics laboratories have been and continue to be highly proficient in the detection and description of chromosomal abnormalities associated with hematologic neoplasms.

Clinicopathologic features of breast cancer reclassified as HER2-amplified by fluorescence in situ hybridization with alternative chromosome 17 probes.

OBJECTIVE: Dual probe fluorescence in situ hybridization (FISH) assays for determination of human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer provide a ratio of HER2 to chromosome 17. The ratio may be skewed by copy number alterations (CNA) in the control locus for chromosome 17 (CEP17). We analyzed the impact of alternative chromosome 17 control probes on HER2 status in a series of breast cancers with an emphasis on patients reclassified as amplified. METHODS: Breast cancer patients with equivocal HER2 immunohistochemistry (2+) and equivocal FISH with CEP17 were included. Reclassification of HER2 status was assessed with alternative chromosome 17 control probes (LIS1 and RARA). RESULTS: A total of 40 unique patients with 46 specimens reflexed to alternative chromosome 17 probe testing were identified. The majority (>80%) of patients had pT1-2, hormone receptor-positive tumors with an intermediate or high combined histologic grade. There were 34/46 (73.9%) specimens reclassified as amplified with alternative probes, corresponding to 29/40 (72.5%) patients. Of the patients reclassified as amplified with alternative probes, 34.5% (10/29) received HER2-targeted therapy. CONCLUSION: In this series, the majority of breast cancers tested with alternative chromosome 17 control probes under the 2013 ASCO/CAP Guidelines were converted to HER2-amplified. The treatment data and the clinicopathologic profile of the tumors suggest that most of these patients will neither receive nor benefit from HER2-targeted therapy. The findings support the recommendation in the 2018 ASCO/CAP HER2 Guidelines to discontinue the use of alternative chromosome 17 probes.

Increasing the diagnostic yield of exome sequencing by copy number variant analysis.

As whole exome sequencing (WES) becomes more widely used in the clinical realm, a wealth of unanalyzed information will be routinely generated. Using WES read depth data to predict copy number variation (CNV) could extend the diagnostic utility of this previously underutilized data by providing clinically important information such as previously unsuspected deletions or duplications. We evaluated ExomeDepth, a free R package, in addition to an aneuploidy prediction method, to detect CNVs in WES data. First, in a blinded pilot study, five out of five genomic alterations were correctly identified from clinical samples with previously defined chromosomal gains or losses, including submicroscopic deletions, duplications, and chromosomal trisomy. We then examined CNV calls among 53 patients participating in the NCGENES research study and undergoing WES, who had existing clinical chromosomal microarray (CMA) data that could be used for validation. For unique CNVs that overlap well with WES coverage regions, sensitivity was 89% for deletions and 65% for duplications. While specificity of the algorithm calls remains a concern, this is less of an issue at high threshold filtering levels. When applied to all 672 patients from the exome sequencing study, ExomeDepth identified eleven diagnostically relevant CNVs ranging in size from a two exon deletion to whole chromosome duplications, as well as numerous other CNVs with varying clinical significance. This opportunistic analysis of WES data yields an additional 1.6% of patients in this study with pathogenic or likely pathogenic CNVs that are clinically relevant to their phenotype as well as clinically relevant secondary findings. Finally, we demonstrate the potential value of copy number analysis in cases where a single heterozygous likely or known pathogenic single nucleotide alteration is identified in a gene associated with an autosomal recessive condition.

Lymphomas with pseudo-double-hit BCL6-MYC translocations due to t(3;8)(q27;q24) are associated with a germinal center immunophenotype, extranodal involvement, and frequent BCL2 translocations.

High-grade B-cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements, "double-hit" or "triple-hit" lymphomas (DTHL), are aggressive neoplasms associated with a poor prognosis. A t(3;8)(q27;q24) rarely occurs in B-cell lymphomas that results in a unique "pseudo-double-hit" BCL6-MYC fusion, indistinguishable by interphase fluorescence in situ hybridization (FISH) from more conventional DTHL with independent MYC and BCL6 translocations. Reports of t(3;8)(q27;q24) lymphomas are sparse, and to better characterize their pathologic, cytogenetic, and clinical features, 6 new cases from 2 institutions and 19 previously published cases were reviewed. All new cases displayed aggressive morphologic features, and most previously published cases were classified as aggressive lymphomas. Collectively, all t(3;8)(q27;q24) cases had a germinal center (GC) phenotype, and most had complex karyotypes (22/24, 92%), including frequent concomitant BCL2 rearrangements (17/24, 71%). When compared to two large published DTHL cohorts, t(3;8)(q27;q24) lymphomas less often expressed BCL2 (P < .01), had a greater likelihood of extranodal involvement (P < .01), and more frequently appeared triple-hit by FISH analysis (P < .01). Despite presenting with aggressive clinicopathologic features, 100% (6/6) of t(3;8;)(q27;q24) patients achieved complete remission after intensive induction regimens, and 2- and 3-year overall survival rates were 63% (10/16) and 57% (8/14), respectively. These findings suggest that lymphomas with t(3;8)(q27;q24) may represent a subset of GC B-cell lymphomas distinct from conventional DTHL. Our results further highlight the value of routine karyotype assessment in aggressive B-cell lymphomas, and the importance of recognizing the t(3;8)(q27;q24) so that its clinical significance can be more fully explored.

Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.

Association between body mass index and pain following transobturator sling.

We aimed to prospectively evaluate the association between body mass index (BMI) and development of postoperative-onset pain in women undergoing transobturator midurethral sling procedures. We conducted a prospective, observational cohort study of women undergoing inside-to-out transobturator midurethral sling. At preoperative visit, height, weight, self-reported activity level and baseline pain were documented. At postoperative visits, patients indicated pain location and severity, procedure success, and satisfaction. We used log binomial regression to calculate risk ratios, controlling for potential confounders. For the 129 women included, median age was 50.0 years and BMI was 27.2 kg/m2. Adjusting for age and activity level, overweight and obese women had significantly increased risk of postoperative-onset pain compared to normal BMI women. Overweight women were at 1.70 (95%CI 1.05-2.75) times the risk compared to leaner counterparts, whereas obese women were at 1.76 times the risk (95%CI 1.04-2.89). Neither success nor satisfaction was associated with BMI. Impact statement Over three million midurethral slings have been placed worldwide for the treatment or prevention of stress urinary incontinence. The procedure has been studied in lean, overweight and obese populations, and found to have similar efficacy regardless of BMI. Similarly, the risks of midurethral sling have been well-documented, including the risk of pain after transobturator sling. Little attention has been given to whether this risk of postoperative pain varies based on patient BMI. Our previous work suggesting that leaner patients might be at increased risk of postoperative pain following transobturator sling was limited by the shortcomings of a retrospective study design. In this prospective study, we were able to adjust for age and activity level, finding that higher BMI women were at increased risk of postoperative pain, while reporting similar levels of satisfaction with the procedure. Future research is needed to find what differences in anatomy or physiology can explain this finding. From a clinical standpoint, thorough counselling of all patients but particularly those with elevated BMI, is required so that appropriate expectations regarding recovery can be set preoperatively.

The Use of Mechanical Bowel Preparation in Pelvic Reconstructive Surgery: A Randomized Controlled Trial.

OBJECTIVE: To compare mechanical bowel preparation (MBP) using oral magnesium citrate with sodium phosphate enema to sodium phosphate (NaP) enema alone during minimally invasive pelvic reconstructive surgery. METHODS: We conducted a single-blind, randomized controlled trial of MBP versus NaP in women undergoing minimally invasive pelvic reconstructive surgery. The primary outcome was intraoperative quality of the surgical field. Secondary outcomes included surgeon assessment of bowel handling and patient-reported tolerability symptoms. RESULTS: One hundred fifty-three participants were enrolled; 148 completed the study (71 MBP and 77 NaP). Patient demographics, clinical and intraoperative characteristics were similar. Completion of assigned bowel preparation was similar between MBP (97.2%) and NaP (97.4%). The MBP group found the preparation more difficult (P<0.01) and reported more overall discomfort and negative preoperative side effects (all P≤0.01). Quality of surgical field at initial port placement was excellent/good in 80.0% of the MBP group compared with 62.3% in the NaP group (P=0.02). This difference was not maintained by the conclusion of surgery (P=0.18). Similar results were seen in the intent-to-treat population. Surgeons accurately guessed preparation 65.7% of the time for MBP versus 41.6% for NaP (P=0.36). At 2 weeks postoperatively, both reported a median time for return of bowel function of 3.0 (2.0-4.0) days. CONCLUSIONS: Mechanical bowel preparation with oral magnesium citrate before minimally invasive pelvic reconstructive surgery offered initial improvement in the quality of surgical field, but this benefit was not sustained. It was associated with an increase in patient discomfort preoperatively, but did not seem to impact postoperative return of bowel function. LEVEL OF EVIDENCE: I.

Karyotypic abnormalities associated with Epstein-Barr virus status in classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (CHL) is morphologically characterized by scattered malignant Hodgkin/Reed-Sternberg (HRS) cells that are far outnumbered by surrounding reactive hematolymphoid cells. Approximately half of all cases of CHL are associated with infection by Epstein-Barr virus (EBV), an oncogenic herpesvirus that expresses a number of proteins thought to contribute to transformation. While a small number of published studies have attempted to identify recurrent cytogenetic abnormalities in CHL, no large case series have explored karyotypic differences between EBV-positive and EBV-negative tumors. Here, we report a two-institution retrospective investigation of cytogenetic features characterizing CHL. In our cohort, cases of EBV-negative CHL were characterized by more complex routine karyotypes than their EBV-positive counterparts (24.6 versus 15.6 independent aberrations per case, P = 0.009). The increased complexity of EBV-negative cases was driven by a number of features suggestive of genomic instability, including a larger number of independent chromosomal breakpoints (P = 0.03) and apparently aneuploid autosomes (P = 0.008). Compelling but nonsignificant trends also suggest a larger modal number and increased marker chromosomes in EBV-negative cases (P = 0.13 and 0.06, respectively). While some of these differences are related to histologic subtype, others appear independent of histology. Finally, a significant subset of EBV-positive tumors has a surprisingly simple karyotype relative to what is normally seen in CHL, an observation suggesting considerable biological and genetic diversity in this disease.

Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome.

Hemiconvulsion-hemiplegia-epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient's complex genetic background.

Cell-free DNA testing in a trisomy 21 pregnancy with confined placental mosaicism for a cell line with trisomy for both chromosomes 18 and 21.

NIPT (noninvasive prenatal testing) detected trisomy for two chromosomes. One trisomy reflected the fetal karyotype, and the other resulted from CPM (confined placental mosaicism). This case illustrates that extensive cytogenetic analysis can be required to identify CPM, and that patients should be counseled regarding the possibility of discordant NIPT results.

Systematic review of medical home models to promote transitions to primary adult health care for adolescents living with autism spectrum disorder.

BACKGROUND: There is a growing number of children diagnosed and living with autism spectrum disorders (ASDs) in the United States. This increasing incidence and prevalence of ASDs require care coordination within a medical home model, which needs to continue into adulthood. AIM: This paper is an evidence review of medical home models for transitioning adolescents living with ASDs from pediatric primary healthcare practices to adult primary care practices. METHOD: Databases were reviewed and articles selected based on inclusion and exclusion criteria. RESULTS: Nine articles were reviewed and four met criteria. None of the articles addressed medical home models to transition adolescents living with ASDs into adult primary healthcare services. LINKING EVIDENCE TO ACTION: There is a need for nursing to work within an interdisciplinary framework to educate adult healthcare providers on the needs of adolescents living with ASDs and to evaluate medical home transition models for this vulnerable population.

Trends in cancer diagnoses and survival among persons with AIDS in a high HIV prevalence urban area.

Washington, DC (DC), has among the highest AIDS prevalence and cancer incidence in the USA. This study compared cancer diagnoses and survival among AIDS cases with AIDS-defining cancers (ADCs) to those with non-AIDS-defining cancers (NADCs) in DC from 1996 to 2006. Survival by cancer type and time period was also examined for 300 individuals diagnosed with AIDS who developed cancer; 49% of AIDS cases developed an ADC. ADC cases were younger at both AIDS and cancer diagnosis and had significantly lower median CD4 counts at AIDS diagnosis than NADC cases. The most frequent cancers were non-Hodgkin lymphoma (NHL; 44% of ADC), Kaposi's sarcoma (40% of ADC), and lung cancer (20% of NADC). There was no significant difference in distribution of cancers when comparing ADCs to NADCs, or over time (1996-2001 vs. 2002-2006). Survival among NHL, oral cavity, and lung cancer cases was 0.4, 0.8, and 0.3 years, respectively; the risk of death was approximately two times higher for each of these cancers when compared to other cancers. Given the high burden of cancer and HIV in DC, early highly active antiretroviral therapy initiation, routine cancer screening, and risk reduction through behavioral modification should be emphasized to prevent cancer among HIV-infected persons.

Aortopathy in the 7q11.23 microduplication syndrome.

The 7q11.23 microduplication syndrome, caused by the reciprocal duplication of the Williams-Beuren syndrome deletion region, is a genomic disorder with an emerging clinical phenotype. Dysmorphic features, congenital anomalies, hypotonia, developmental delay highlighted by variable speech delay, and autistic features are characteristic findings. Congenital heart defects, most commonly patent ductus arteriosus, have been reported in a minority of cases. Included in the duplicated region is elastin (ELN), implicated as the cause of supravalvar aortic stenosis in patients with Williams-Beuren syndrome. Here we present a series of eight pediatric patients and one adult with 7q11.23 microduplication syndrome, all of whom had aortic dilation, the opposite vascular phenotype of the typical supravalvar aortic stenosis found in Williams-Beuren syndrome. The ascending aorta was most commonly involved, while dilation was less frequently identified at the aortic root and sinotubular junction. The findings in these patients support a recommendation for cardiovascular surveillance in patients with 7q11.23 microduplication syndrome.

Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.

Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein. Using a bioluminescence resonance energy transfer-based assay (CAMYEL, cAMP sensor using YFP-Epac-Rluc), we assessed the predicted compounds for their ability to bind Epac and modulate its activity. We identified a thiobarbituric acid derivative, 5376753, that allosterically inhibits Epac activity and used Swiss 3T3 and HEK293 cells to test the ability of this compound to modulate the activity of Epac and PKA, as determined by Rap1 activity and vasodilator-stimulated phosphoprotein phosphorylation, respectively. Compound 5376753 selectively inhibited Epac in biochemical and cell migration studies. These results document the utility of a computational approach to identify a domain for allosteric regulation of Epac and a novel compound that prevents the activation of Epac1 by cAMP.

PTEN deficiency mediates a reciprocal response to IGFI and mTOR inhibition.

UNLABELLED: Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies. IMPLICATIONS: PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials.

Characterization of pain after inside-out transobturator midurethral sling.

OBJECTIVES: This study aimed to evaluate the prevalence, severity, duration, and location of pain after transobturator midurethral sling. METHODS: We evaluated patients who underwent inside-out transobturator sling from March 2011 through February 2013. Presence of pelvic girdle pain, its severity, and location were documented preoperatively and at 2- and 6-week postoperative visits. Pain severity was measured on a scale of 1 to 10, with 10 being the "worst imaginable" pain. RESULTS: Of the 130 women analyzed, the median age was 50.0 years (interquartile range, 44.0-62.0). Thirty-nine percent of women reported preoperative pain, mostly mild with a median score of 1.0 (1.0-5.0). The most common sites of postoperative-onset pain were the lateral leg, medial leg, groin, and low back. Women reporting preoperative pain were not more likely to report postoperative-onset pain than women without preoperative pain (P = 0.42). Twelve percent of women at 2 weeks and 0.8% at 6 weeks reported severe postoperative-onset pain. Women reporting postoperative-onset pain were equally likely to be satisfied with the procedure as those without pain at 2 (P = 0.76) and 6 (P = 0.74) weeks. CONCLUSIONS: Women undergoing transobturator sling commonly report preoperative pain. An expected postoperative increase in pain generally resolved by the sixth postoperative week. The lateral leg was the most common site of pain. Postoperative-onset pain was not associated with decreased patient satisfaction.