bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of Colon Manometry in Guiding Therapy and Predicting Need for Surgery in Children With Defecation Disorders
Authors: Rodriguez Leonel , Heinz Nicole , Nurko Samuel
Published: September 2019

Objectives:

Colon manometry (CM) has emerged as a tool to evaluate children with defecation problems. Our aim was to evaluate the utility of CM in guiding therapy and predicting surgery in pediatric constipation.

Methods:

Retrospective review of children undergoing CM for 4 indications: constipation, fecal incontinence, postsurgical evaluation and chronic intestinal pseudo‐obstruction. Variables included age, sex, follow‐up, and CM parameters: gastrocolonic response (GC) and quality/quantity of high‐amplitude propagating contractions (HAPCs). Interventions: medical, surgical or no intervention. Outcomes: response to change of therapy guided by CM, response to first intervention guided by CM (CMI) and CM predicting surgery (CMS). Response to therapy was classified according to study indication.

Results:

Five hundred fifty‐five studies (448 patients, 54.4% female; median age 8.9 years) were included, 24% of studies were normal. Change of therapy guided by CM was associated with a high response rate (P = 0.003). Overall response to stimulant laxatives was 48% and was not associated with CM findings. Surgical interventions had a higher response rate than medical or other interventions (P < 0.001). We found no association between the CM interpretation and CMI, but an abnormal CM was predictive of surgery (P < 0.01). GC and presence/number of HAPCs were not associated with CMI or CMS. We also found no association between HAPC quality and CMI but partially propagated HAPCs were predictive of surgery (P < 0.001). Logistic regression analysis showed no factors associated with CMI; however, longer follow up and partially propagated HAPCs were predictive of surgery.

Conclusions:

CM is useful in pediatric defecation disorders, although not predictive of successful medical intervention, an abnormal CM is predictive of surgery. CM should be performed only after medical interventions have failed and surgery is contemplated.
Quantitative Liver Fibrosis Using Collagen Hybridizing Peptide to Predict Native Liver Survival in Biliary Atresia
Authors: Jaramillo Catalina , Guthery Stephen L. , Lowichik Amy , Stoddard Gregory , Kim Taegun , Li Yang , Jensen Michael Kyle
Published: September 2019

Background/Rationale:

Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy (KPE), BA leads to death or liver transplant (LTx). Early‐onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver prognostication.

Results:

We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be girls with a significantly different mean bilirubin (P = 0.002), albumin (P = 0.001), and alanine aminotransferase (P = 0.03) at 3 months post‐KPE. By 1 year post‐KPE, 50% of patients in the high CHP intensity group required LTx versus 27% in the low CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than 3 times the risk of requiring LTx by 4 years of age (hazard ratio 3.6, 95% confidence interval 1.15–10.93, P = 0.03). When controlling for sex and total bilirubin >2 mg/dL and albumin at 3 months post‐KPE, it predicted nearly 7 times the risk of LTx (hazard ratio 6.89, 95% confidence interval 1.38–34.32, P = 0.02).

Conclusion:

Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.
Antibiotic Susceptibility and Therapy in Central Line Infections in Pediatric Home Parenteral Nutrition Patients
Authors: Raphael Bram P. , Fournier Greg , McLaughlin Sarah R. , Puder Mark , Jones Sarah , Flett Kelly B.
Published: September 2019

Background:

Patients receiving home parenteral nutrition (HPN) are at high‐risk for central line‐associated bloodstream infections (CLABSI). There are no published management guidelines, however, for the antibiotic treatment of suspected CLABSI in this population. Historical microbiology data may help inform empiric antimicrobial regimens in this population.

Objective:

The aim of the study was to describe antimicrobial resistance patterns and determine the most appropriate empiric antibiotic therapy in HPN‐dependent children experiencing a community‐acquired CLABSI.

Methods:

Single‐center retrospective cohort study evaluating potential coverage of empiric antibiotic regimens in children on HPN who developed a community‐acquired CLABSI.

Results:

From October 1, 2011 to September 30, 2017, there were 309 CLABSI episodes among 90 HPN‐dependent children with median age 3.8 years old.

Fifty‐nine percent of patients carried the diagnosis of surgical short bowel syndrome. Organisms isolated during these infections included 60% Gram‐positive bacteria, 34% Gram‐negative bacteria, and 6% fungi. Among all staphylococcal isolates, 51% were methicillin sensitive. Among enteric Gram‐negative organisms, sensitivities were piperacillin‐tazobactam 71%, cefepime 97%, and meropenem 99%. Organisms were sensitive to current institutional standard therapy with vancomycin and piperacillin‐tazobactam in 69% of cases compared with vancomycin and cefepime or vancomycin an meropenem in 85% and 96% of cases (both P < 0.01).

Conclusions:

Empiric antimicrobial therapy for suspected CLABSI in HPN‐dependent children should include therapy for methicillin‐resistant staphylococci as well as enteric Gram‐negative organisms. Future studies are needed to evaluate clinical outcomes based upon evidence‐based antimicrobial regimens.
Artificial Intelligence Applied to Gastrointestinal Diagnostics
Authors: Patel Vatsal , Khan Marium N. , Shrivastava Aman , Sadiq Kamran , Ali S. Asad , Moore Sean R. , Brown Donald E. , Syed Sana
Published: September 2019

Artificial intelligence (AI), a discipline encompassed by data science, has seen recent rapid growth in its application to healthcare and beyond, and is now an integral part of daily life. Uses of AI in gastroenterology include the automated detection of disease and differentiation of pathology subtypes and disease severity. Although a majority of AI research in gastroenterology focuses on adult applications, there are a number of pediatric pathologies that could benefit from more research. As new and improved diagnostic tools become available and more information is retrieved from them, AI could provide physicians a method to distill enormous amounts of data into enhanced decision‐making and cost saving for children with digestive disorders. This review provides a broad overview of AI and examples of its possible applications in pediatric gastroenterology.
Efficacy of Single‐ Versus Split‐dose Polyethylene Glycol for Colonic Preparation in Children
Authors: Tripathi Parijat Ram , Poddar Ujjal , Yachha Surender Kumar , Sarma Moinak Sen , Srivastava Anshu
Published: September 2019

Objectives:

Polyethylene glycol (PEG) is the most effective colon‐cleansing agent but volume‐related adverse effects are common. Though split‐dose PEG is used in adults, no pediatric study so‐far has compared split‐dose with single‐dose PEG. We aimed at comparing the efficacy and tolerability of split‐dose versus single‐dose PEG for bowel preparation in children.

Methods:

Consecutive children (1–18 years) were randomized into either single‐dose or split‐dose PEG. Single‐dose group received 4000 mL/1.73 m2 PEG solution day before colonoscopy whereas split‐dose group received half dose day before and the remaining half on the day of colonoscopy. Effectiveness of bowel preparation was assessed on Aronchik scale, by the endoscopist who was blinded to the type of preparation. Interobserver variability was analyzed by comparing with independent scoring by the blinded trained endoscopy‐nurse. The trial was registered with Clinical Trials Registry of India (Trail number 2017/08/009303).

Results:

Of the 220 randomized children, 179 completed the study (split‐dose: 93, single‐dose: 86). The mean age of the study population was 11.51 (4.82) years (72.6% boys). The efficacy of bowel preparation was better with split‐dose (satisfactory preparation:76.34% vs 43.02%, P < 0.001) with almost perfect inter‐observer agreement (k = 0.803). Nausea, vomiting, and sleep disturbance were significantly less in split‐dose than single‐dose group (P < 0.05). Split‐dose patients were able to drink PEG solution faster (P = 0.002). Total sleep duration and uninterrupted sleep duration was also better in split‐dose group as compared with single‐dose (P = 0.001).

Conclusions:

Split‐dose PEG is more effective than single‐dose regimen for bowel preparation with better tolerability and improved sleep quality in pediatric population.
Functional Pancreatic Sphincter Dysfunction in Children
Authors: Lin Tom K. , Fishman Douglas S. , Giefer Matthew J. , Liu Quin Y. , Troendle David , Werlin Steven , Lowe Mark E. , Uc Aliye
Published: September 2019

Objective:

Functional pancreatic sphincter dysfunction (FPSD), previously characterized as pancreatic sphincter of Oddi dysfunction, is a rarely described cause of pancreatitis. Most studies are reported in adults with alcohol or smoking as confounders, which are uncommon risk factors in children. There are no tests to reliably diagnose FPSD in pediatrics and it is unclear to what degree this disorder contributes to childhood pancreatitis.

Methods:

We conducted a literature review of the diagnostic and treatment approaches for FPSD, including unique challenges applicable to pediatrics. We identified best practices in the management of children with suspected FPSD and formed a consensus expert opinion.

Results:

In children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), we recommend that other risk factors, specifically obstructive factors, be ruled out before considering FPSD as the underlying etiology. In children with ARP/CP, FPSD may be the etiology behind a persistently dilated pancreatic duct in the absence of an alternative obstructive process. Endoscopic retrograde cholangiopancreatography with sphincterotomy should be considered in a select group of children with ARP/CP when FPSD is highly suspected and other etiologies have been effectively ruled out. The family and patient should be thoroughly counseled regarding the risks and advantages of endoscopic intervention. Endoscopic retrograde cholangiopancreatography for suspected FPSD should be considered with caution in children with ARP/CP when pancreatic ductal dilatation is absent.

Conclusions:

Our consensus expert guidelines provide a uniform approach to the diagnosis and treatment of pediatric FPSD. Further research is necessary to determine the full contribution of FPSD to pediatric pancreatitis.
CD24 and PRAME Are Novel Grading and Prognostic Indicators for Pineal Parenchymal Tumors of Intermediate Differentiation
Authors: Wu Xuehui , Wang Wei , Lai Xiangmeng , Zhou Yangshu , Zhou Xue , Li Jiaoying , Liang Yunshi , Zhu Xiaohui , Ren Xiaoli , Ding Yanqing , Liang Li
Published: September 2019

The pineal parenchymal tumors of intermediate differentiation (PPTIDs) are extremely rare tumor entities. They exhibit low-risk (grade II) and high-risk (grade III) malignancies, which may lead to different therapies and prognosis. However, the histological grading criteria remains elusive, and novel biomarkers may be helpful to differentiate the grade of PPTIDs. Immunohistochemical staining for CD24, PRAME, POU4F2, and HOXD13, and their clinicopathologic analyses were performed in pineal parenchymal tumors and other tumors in the pineal region. CD24 and PRAME were expressed in 9/11 (81.8%) and 8/11(72.7%) cases of PPTIDs grade III, compared with 6/18 (33.3%) and 5/18(27.8%) cases of PPTIDs grade II. The levels of CD24 and PRAME were significantly higher in PPTIDs grade III than grade II. However, there were no differences of HOXD13 and POU4F2 expression levels in PPTIDs grade II and grade III. Interestingly, high expression of CD24 and PRAME were prevalently found in high-grade tumors of the central nervous system. In addition, PPTIDs patients with high expression levels of CD24 and PRAME exhibited a significant shorter survival time. The results of PPTIDs grading by CD24 and PRAME were mostly consistent with WHO criteria, except for two cases. According to the prognostic information of patients, we found that the combination of CD24 and PRAME expression for grading PPTIDs might be more valuable than WHO criteria only. CD24 and PRAME are novel markers for grading and prognostic evaluation of PPTIDs that may be helpful to determine the therapeutic decision for PPTIDs patients.
Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma
Authors: Glass Carolyn , Sholl Lynette M. , Landgraf James R. , Chirieac Lucian , Roggli Victor L.
Published: September 2019

Neurofibromatosis type 2 (NF2), an inherited disorder associated with multiple inherited schwannomas, meningiomas and ependymomas is caused by an autosomal dominant, likely loss of function germline mutation of the NF2 gene. Interestingly, biallelic NF2 gene inactivation is one of the most common mutations associated with the development of malignant mesothelioma (MM), a highly fatal malignancy that arises in the pleura and less frequently in the pericardium, peritoneum, and tunica vaginalis. It has been proposed that NF2 patients could potentially be at increased risk of developing MM. However, patients with inherited NF2 rarely develop MM. To date, only 2 cases describing patients diagnosed with both have been reported in the literature. Here, we describe the third case and for the first time, also provide molecular evidence that a “second hit” involving a somatic mutation is likely required to trigger the development of MM in this rare cohort. In our patient diagnosed with NF2 at age 25 who developed an aggressive peritoneal MM 15 years later, we identified a germline NF2 mutation and somatic mutations including BAP1. Of clinical relevance, our case supports a germline NF2 mutation may not necessarily be more susceptible to develop mesothelioma without a “second hit” mutation.
Pericytoma With t(7;12) and ACTB-GLI1 Fusion
Authors: Kerr Darcy A. , Pinto Andre , Subhawong Ty K. , Wilky Breelyn A. , Schlumbrecht Matthew P. , Antonescu Cristina R. , Nielsen G. Petur , Rosenberg Andrew E.
Published: September 2019

The entity “pericytoma with t(7;12)” was described as a rare, distinct perivascular myoid neoplasm provisionally classified within the family of myopericytic tumors that demonstrates t(7;12)(p22;q13) translocation with resultant ACTB-GLI1 fusion and biologically was felt to behave in an indolent fashion. However, a recent study showed that tumors with this and similar translocations may have variable morphology and immunohistochemical phenotype with inconsistent myopericytic characteristics and a propensity for metastasis, raising questions regarding the most appropriate classification of these neoplasms. Herein, we report 3 additional patients with tumors harboring t(7;12) and ACTB-GLI1 fusion. The tumors arose in adults and involved the proximal tibia and adjacent soft tissues, scapula and adjacent soft tissues, and ovary. All tumors were composed of round-to-ovoid cells with a richly vascularized stroma with many small, delicate, branching blood vessels, where the neoplastic cells were frequently arranged in a perivascular distribution. Both tumors involving bone showed histologic features of malignancy. By immunohistochemistry, all tested tumors were at least focally positive for smooth muscle actin (3/3) and CD99 (patchy) (2/2), with variable staining for muscle-specific actin (2/3), S100 protein (1/3), epithelial membrane antigen (2/3), and pan-keratin (1/3); all were negative for desmin and WT1 (0/3). The 2 patients with bone tumors developed metastases (27 and 84 mo after diagnosis). Whether these tumors are best classified as malignant myopericytoma variants or an emerging translocation-associated sarcoma of uncertain differentiation remains to be fully clarified; however, our study further documents the potential for these tumors to behave in an aggressive fashion, sometimes over a prolonged clinical course.
Mucin Pools Following Neoadjuvant Chemoradiotherapy for Rectal Cancer
Authors: Reynolds Ian S. , O’Connell Emer , Fichtner Michael , Kay Elaine W. , McNamara Deborah A. , Prehn Jochen H.M. , Burke John P.
Published: September 2019

Neoadjuvant chemoradiotherapy (CRT) is the standard of care for locally advanced rectal cancer. Morphologic changes such as fibrosis, inflammatory infiltrates, and the formation of extracellular mucin pools can be identified in the resection specimen after neoadjuvant CRT. The association of mucin pool formation with clinicopathologic variables and outcomes is unclear. The aim of this study was to meta-analyze all available evidence with regard to mucin pool formation and clinicopathologic outcomes following neoadjuvant CRT for rectal cancer. A comprehensive search for published studies analyzing outcomes between patients who formed mucin pools and patients who did not following neoadjuvant CRT for rectal cancer was performed. A random-effects model was used to combine the data. This study adhered to the recommendations of the MOOSE (Meta-analyses of Observational Studies in Epidemiology) guidelines. Data from 11 studies describing 1947 patients were included. Mucin pool formation was not associated with sex, T stage, N stage, tumor regression, pathologic complete response rate, lymphovascular invasion, perineural invasion, differentiation, margin status, local or distant recurrence, and disease-free or overall survival. Mucin pool formation is not associated with tumor response or downstaging; furthermore, on the basis of these data, it is not associated with local or systemic recurrence rate or survival.
Pathology of Echinococcosis
Authors: Reinehr Michael , Micheloud Charlotte , Grimm Felix , Kronenberg Philipp A. , Grimm Johannes , Beck Annika , Nell Juliane , Meyer zu Schwabedissen Cordula , Furrer Eva , Müllhaupt Beat , Barth Thomas F.E. , Deplazes Peter , Weber Achim
Published: September 2019

Infection of humans by the larval stage of the tapeworms Echinococcus granulosus sensu lato or Echinococcus multilocularis causes the life-threatening zoonoses cystic echinococcosis (CE) and alveolar echinococcosis (AE). Although cystic liver lesions are a hallmark of both diseases, course, prognosis, and patients’ management decisively differ between the two. The wide and overlapping spectrum of morphologies and the limited availability of ancillary tools are challenges for pathologists to reliably diagnose and subtype echinococcosis. Here, we systematically and quantitatively recorded the pathologic spectrum in a clinically and molecularly defined echinococcosis cohort (138 specimens from 112 patients). Immunohistochemistry using a novel monoclonal antibody (mAbEmG3) was implemented, including its combined application with the mAbEm2G11. Six morphologic criteria sufficiently discriminated between CE and AE: size of smallest (CE/AE: >2/≤2 mm) and largest cyst (CE/AE: >25/≤25 mm), thickness of laminated layer (CE/AE: >0.15/≤0.15 mm) and pericystic fibrosis (CE/AE: >0.6/≤0.6 mm), striation of laminated layer (CE/AE: moderate-strong/weak), and number of cysts (CE/AE: ≤9/>9). Combined immunohistochemistry with mAbEm2G11 (E. multilocularis specific) and mAbEmG3 (reactive in AE and CE) was equally specific as and occasionally more sensitive than polymerase chain reaction. On the basis of these findings, we developed a diagnostic algorithm for the differential diagnosis of echinococcosis. In summary, we have not only identified the means to diagnose echinococcosis with greater certainty, but also defined morphologic criteria, which robustly discriminate between CE and AE. We expect our findings to improve echinococcosis diagnostics, especially of challenging cases, beneficially impacting the management of echinococcosis patients.
SMARCA4-deficient Uterine Sarcoma and Undifferentiated Endometrial Carcinoma Are Distinct Clinicopathologic Entities
Authors: Kolin David L. , Quick Charles M. , Dong Fei , Fletcher Christopher D.M. , Stewart Colin J.R. , Soma Anita , Hornick Jason L. , Nucci Marisa R. , Howitt Brooke E.
Published: September 2019

Undifferentiated and dedifferentiated endometrial carcinomas (UDEC) are aggressive uterine tumors which may show loss of expression of SMARCA4 (BRG1) or SMARCB1 (INI-1). The recently described SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) has a morphology which overlaps with UDEC. In this study, we compared clinical, morphologic, immunohistochemical, and molecular characteristics to identify features which differentiate SDUS from UDEC. Cases of SDUS (n=12) were compared with cases of UDEC (n=84, 55 of which were previously published). Immunohistochemistry was performed for p53, mismatch repair proteins, claudin-4, SMARCA4, and SMARCB1. Targeted molecular profiling was performed on 15 cases. Patients with SDUS were significantly younger than those with UDEC (mean 35.8 vs. 61.2 y, P=0.0001). UDEC and SDUS showed morphologic overlap; however, phyllodiform architecture favored a diagnosis of SDUS (36% vs. 0%, P=0.005), while prominent nuclear pleomorphism was only seen in some cases of UDEC (0% vs. 24%, P=0.15). Compared with SDUS, UDEC more frequently showed TP53 mutations (0% vs. 34%, P=0.03), microsatellite instability (0% vs. 44%, P=0.006), and intact SMARCA4 and SMARCB1 (0% vs. 80%); a panel combining these immunohistochemical markers had a sensitivity of 100% and specificity of 92% in distinguishing SDUS and UDEC. Cases of UDEC had mutations in genes associated with endometrial adenocarcinomas (eg, TP53, PTEN, PIK3CA) and occasionally SMARCA4, while SDUS was characterized solely by inactivating mutations in SMARCA4. Disease-specific survival was shorter in SDUS than UDEC (median survival 9 and 36 mo, P=0.01). In conclusion, SDUS occurs in younger patients than UDEC, has a worse prognosis, and in most cases has a distinct molecular and immunohistochemical profile.
Indolent T-Cell Lymphoproliferative Disorder of the Uterine Corpus: A Case Report
Authors: Thomas Sally J. , Morley Nicholas , Lashen Hany , Naresh Kikkeri N. , Fernando Malee
Published: September 2019

Primary lymphoproliferative disorders of the uterus are rare, with the majority being B-cell diseases or aggressive T-cell disease. We present the case of a 31-yr old in whom an Indolent T-cell lymphoproliferative disorder (iTCLPD) was identified in resection chippings for a suspected fibroid, following presentation with menorrhagia. Laboratory investigations revealed an oligoclonal T-cell infiltrate with the immunophenotype of nonactivated cytotoxic T cells, and a proliferative fraction of 10% to 15%. There was no clinical or radiologic evidence of systemic disease, and the patient remained well with no indication of relapse 1 yr from resection and diagnosis. iTCLPD of the uterine corpus has features in common with the recently described iTCLPD of the gastrointestinal tract and primary cutaneous acral CD8+T-cell lymphoma. Recognition of these parallels is important as few other cases of iTCLPD have been described, and it suggests local resection rather than systemic treatment as the best therapeutic strategy.
Sarcomatous Transformation in Undifferentiated/Dedifferentiated Endometrial Carcinoma: An Underrecognized Phenomenon and Diagnostic Pitfall
Authors: Vroobel Katherine M. , Attygalle Ayoma D.
Published: September 2019

Undifferentiated/dedifferentiated carcinoma is an aggressive endometrial carcinoma which remains underrecognized but may account for up to 9% of all endometrial malignancies. We describe 3 cases in which the undifferentiated component was associated with sarcomatous differentiation, characterized by spindled cells in 2 cases and heterologous malignant cartilage in 1 case. Two of the 3 cases demonstrated mismatch repair deficiency by immunohistochemistry. This phenomenon has not previously been formally reported and increases the likelihood of misdiagnosis, especially within biopsy samples; differential diagnoses may include endometrial stromal sarcoma and grade 3 endometrioid adenocarcinoma with spindled morphology. We review the current literature and provide strategies for resolving the differential diagnoses, with a suggested panel of antibodies which includes EMA, E-cadherin, and mismatch repair proteins as approximately 50% of cases show loss of mismatch repair expression.
Mutational Profile in Vulvar, Vaginal, and Urethral Melanomas: Review of 37 Cases With Focus on Primary Tumor Site
Authors: Zarei Shabnam , Voss Jesse S. , Jin Long , Jenkins Sarah M. , Bryce Alan H. , Erickson Lori A. , Bell Debra A. , Kipp Benjamin R. , Flotte Thomas J.
Published: September 2019

Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.
High Rates of Biomarker-Confirmed Alcohol Use Among Pregnant Women Living With HIV in South Africa and Uganda
Authors: Raggio Greer A. , Psaros Christina , Fatch Robin , Goodman Georgia , Matthews Lynn T. , Magidson Jessica F. , Amanyire Gideon , Cross Anna , Asiimwe Stephen , Hahn Judith A. , Haberer Jessica E. ,   on behalf of the META team
Published: September 2019

Background:

Alcohol use is common among people living with HIV and particularly harmful during pregnancy. However, objective data on alcohol use in pregnant women living with HIV (WLWH) are lacking. In areas with high levels of alcohol use generally, such as South Africa and Uganda, these data are needed to inform interventions.

Methods:

Pregnant and nonpregnant, antiretroviral therapy-naive WLWH were recruited from outpatient clinics in South Africa and Uganda. Women provided self-report data on previous three-month alcohol use and potential mental health correlates of alcohol use (depression and stigma). Blood samples were used to measure phosphatidylethanol (PEth), an objective biomarker of recent alcohol intake. We analyzed any alcohol use (ie, any self-reported use or PEth-positive [≥8 ng/mL]) and under-reporting of alcohol use (ie, no self-reported use with concurrent PEth-positive).

Results:

Among pregnant WLWH (n = 163, median age was 26 [interquartile range: 23–29], median gestational age was 20 weeks [interquartile range: 16–26]), 40% were using alcohol and 16% under-reported alcohol use. Neither any alcohol use nor under-reporting of alcohol use differed significantly between pregnant and nonpregnant women or by country (P > 0.05). Greater depression (but not greater stigma) was significantly associated with any alcohol use (adjusted odds ratio = 1.41, 95% confidence interval: [1.01 to 1.99]; P = 0.045).

Conclusions:

Alcohol use was prevalent and under-reported among pregnant WLWH in South Africa and Uganda, similar to nonpregnant participants, and associated with depression. General health care and antenatal clinic settings present opportunities to provide integrated alcohol-based counseling and depression treatment.
Human herpesvirus 6 in transplant recipients: an update on diagnostic and treatment strategies
Authors: Hill Joshua A.
Published: September 2019

Purpose of review

The current review article focuses on recent advances in the approach to the diagnosis and treatment of human herpesvirus 6B (HHV-6B) in hematopoietic cell and solid organ transplant recipients.

Recent findings

Over the past few years, key studies have broadened our understanding of best practices for the prevention and treatment of HHV-6B encephalitis after transplantation. Moreover, important data have been reported that support a potential role of HHV-6B reactivation in the development of acute graft-versus-host disease and lower respiratory tract disease in transplant recipients. Finally, increasing recognition of inherited chromosomally integrated HHV-6 (iciHHV-6) and an expanding array of diagnostic tools have increased our understanding of the potential for complications related to viral reactivation originating from iciHHV-6 in donors or recipients.

Recent advances in diagnostic tools, disease associations, and potential treatments for HHV-6B present abundant opportunities for improving our understanding and management of this complex virus in transplant recipients.
Primary immunodeficiencies and invasive fungal infection: when to suspect and how to diagnose and manage
Authors: Lionakis Michail S.
Published: September 2019

Purpose of review

Invasive fungal infections (IFIs) most often occur secondary to acquired immunodeficiency states such as transplantation, AIDS or immune-modulatory treatment for neoplastic and autoimmune disorders. Apart from these acquired conditions, several primary immunodeficiency disorders (PIDs) can present with IFIs in the absence of iatrogenic immunosuppression. This review highlights recent advances in our understanding of PIDs that cause IFIs, which may help clinicians in the diagnosis and management of such infections.

Recent findings

A growing number of PIDs that cause varying combinations of invasive infections by commensal Candida, inhaled molds (primarily Aspergillus), Cryptococcus, Pneumocystis, endemic dimorphic fungi, dermatophytes, and/or agents of phaeohyphomycosis has uncovered the organ- and fungus-specific requirements for effective antifungal host defense in humans. Employing certain diagnostic algorithms tailored to the infecting fungus can facilitate the genetic diagnosis of the underlying PID, which has implications for the optimal management of affected patients.

Heightened clinical suspicion is required for the diagnosis of underlying genetic defects in patients who develop IFIs in the absence of acquired immunodeficiency. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is typically needed to achieve remission, but hematopoietic stem-cell transplantation may sometimes be necessary to promote immune restoration and infection control.
Anaerobic resistance: should we be worried?
Authors: Cooley Louise , Teng Jasmine
Published: September 2019

Purpose of review

Anaerobic bacteria are implicated in a broad range of infections and can cause significant morbidity and mortality. As such, development of antimicrobial resistance (AMR) increases the risk of worse clinical outcomes and death.

Recent findings

Anaerobe AMR is highly variable according to region and species included in the survey. The overall trend is to increasing resistance, particularly in Europe and Asia, and in the Bacteroides fragilis group and Clostridium sp. Conversely, with the decline in RT027, resistance in Clostridiodes difficile is decreasing. Resistance to moxifloxacin and clindamycin has reached 30–50%, whereas prevalence of metronidazole and carbapenem resistance is generally low. Infections due to multidrug anaerobes have been increasingly reported, with clinical studies demonstrating adverse clinical outcomes, including higher mortality, with anaerobic resistance or inappropriate therapy. The role of antimicrobial stewardship in the setting of increasing anaerobe resistance is yet to be fully elucidated.

These findings highlight the importance of continuous surveillance in monitoring emerging trends in anaerobe AMR. Mean inhibitory concentrations should be reported due to variable susceptibility breakpoints and for detection of isolates with reduced susceptibility. At a local level, the clinical microbiology laboratory has a key role in identifying and undertaking susceptibility testing to inform individual patient management, develop local antibiograms and liaise with antimicrobial stewardship teams. A greater understanding of the clinical impact of anaerobic resistance and the role of antimicrobial stewardship in preventing resistance is required.
An overview of guidelines for the management of hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria
Authors: Cillóniz Catia , Dominedò Cristina , Torres Antoni
Published: September 2019

Purpose of review

Multidrug-resistant (MDR) Gram-negative pathogens in hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are associated with poor clinical outcomes. These pathogens represent a global threat with few therapeutic options. In this review, we discuss current guidelines for the empiric management of HAP/VAP caused by MDR Gram-negative pathogens.

Recent findings

The incidence of MDR Gram-negative bacteria is rising among cases of nosocomial pneumonia, such that it is now becoming a significant challenge for clinicians. Adherence to international guidelines may ensure early and adequate antimicrobial therapy, guided by local microbiological data and awareness of the risk factors for MDR bacteria.

Due to the increasing prevalence of HAP/VAP caused by MDR Gram-negative pathogens, management should be guided by the local ecology and the patient's risk factors for MDR pathogens. The main risk factors are prior hospitalization for at least 5 days, prior use of broad-spectrum antibiotics, prior colonization with resistant pathogens, admission to hospital settings with high rates of MDR pathogens, and septic shock at the time of diagnosis with nosocomial pneumonia.
The role of fosfomycin for multidrug-resistant gram-negative infections
Authors: Bassetti Matteo , Graziano Elena , Berruti Marco , Giacobbe Daniele Roberto
Published: September 2019

Purpose of review

In the last decade, an increasing interest in using fosfomycin for the treatment of multidrug-resistant gram-negative (MDR-GNB) infections have been registered, especially when none or only a few other active alternatives remained available.

Recent findings

Fosfomycin may remain active against a considerable proportion of MDR-GNB. In observational studies, a possible curative effect of oral fosfomycin monotherapy has been described for uncomplicated urinary tract infections (UTI) and bacterial prostatitis caused by MDR-GNB, whereas intravenous fosfomycin has been mostly used in combination with other agents for various type of severe MDR-GNB infections. The ZEUS randomized controlled trial (RCT) has started to provide high-level evidence about the possible use of fosfomycin for complicated UTI caused by extended-spectrum β-lactamase-producing GNB, but no results of large RCT are currently available to firmly guide the use of fosfomycin for carbapenem-resistant GNB.

Fosfomycin is an important therapeutic option for MDR-GNB infections. Further pharmacokinetic/pharmacodynamic and clinical research is needed to optimize its use.
Pharmacologic optimization of antibiotics for Gram-negative infections
Authors: Gill Christian M. , Nicolau David P.
Published: September 2019

Purpose of review

Antimicrobial resistance among Gram-negative organisms is a rapidly escalating global challenge. Pharmacologic dose optimization based on pharmacokinetic/pharmacodynamic principles is essential for managing Gram-negative infections. High-risk patient populations may receive nonoptimized antimicrobial dosing because pf physiologic changes in acute illness and/or medical interventions. The purpose of this review is to discuss opportunities for pharmacologic optimization of new agents and highlight patient populations that are often associated with poor drug exposure profiles.

Recent findings

Dose optimization of the novel β-lactam-β-lactamase inhibitor combinations has been evaluated through optimizing exposure at the site of infection, evaluating target attainment of both the β-lactam and the β-lactamase-inhibitor in critically ill patients, and evaluating drug exposure to prevent the development of resistance. Plazomicin, a novel aminoglycoside, has pharmacodynamic optimization potential via therapeutic drug monitoring and nomogram-based dosing. Recent studies have evaluated the adequacy of dosing in varying degrees of renal function specifically acute kidney injury, continuous renal replacement therapy (CRRT), and augmented renal clearance (ARC).

The application of fundamental pharmacokinetic/pharmacodynamic principles is required to optimize new antimicrobials in the treatment of serious Gram-negative infections. Exposure at the site of infection, pharmacokinetics in critically ill patients, and exposures to prevent resistance are all considerations to improve microbiologic and clinical outcomes. Therapeutic drug monitoring may be needed for high-risk patients.
BK polyomavirus-specific antibody and T-cell responses in kidney transplantation: update
Authors: Kaur Amandeep , Wilhelm Maud , Wilk Sabrina , Hirsch Hans H.
Published: September 2019

Purpose of review

BK polyomavirus (BKPyV) has emerged as a significant cause of premature graft failure after kidney transplantation. Without effective antiviral drugs, treatment is based on reducing immunosuppression to regain immune control over BKPyV replication. The paradigm of high-level viruria/decoy cells, BKPyV-DNAemia, and proven nephropathy permits early interventions. Here, we review recent findings about BKPyV-specific antibody and T-cell responses and their potential role in risk stratification, immune monitoring, and therapy.

Recent finding

Kidney transplant recipients having low or undetectable BKPyV-specific IgG immunoglobulin G (IgG) are higher risk for developing BKPyV-DNAemia if the donor has high BKPyV-specific IgG. This observation has been extended to neutralizing antibodies. Immunosuppression, impaired activation, proliferation, and exhaustion of BKPyV-specific T cells may increase the risk of developing BKPyV-DNAemia and nephropathy. Clearance of BKPyV-DNAemia was correlated with high CD8 T cell responses to human leukocyte antigen (HLA)-types presenting BKPyV-encoded immunodominant 9mers. For clinical translation, these data need to be assessed in appropriately designed clinical studies, as outlined in recent guidelines on BKPyV in kidney transplantation.

Evaluation of BKPyV-specific immune responses in recipient and donor may help to stratify the risk of BKPyV-DNAemia, nephropathy, and graft loss. Future efforts need to evaluate clinical translation, vaccines, and immunotherapy to control BKPyV replication.
Povidone-iodine Irrigation for Pediatric Perforated Appendicitis May Be Protective
Authors: Anderson Kathryn Tinsley , Putnam Luke Randall , Bartz-Kurycki Marisa Angeline , Hamilton Emma Catherine , Yafi Michael , Pedroza Claudia , Austin Mary Thomas , Kawaguchi Akemi Lorraine , Kao Lillian Shiow-Yu , Lally Kevin Patrick , Tsao KuoJen
Published: September 2019

Objectives:

A randomized controlled trial was conducted to test the hypothesis that povidone-iodine (PVI) irrigation versus no irrigation (NI) reduces postoperative intra-abdominal abscess (IAA) in children with perforated appendicitis.

Methods:

A 100 patient pilot randomized controlled trial was conducted. Consecutive patients with acute perforated appendicitis were randomized (1:1) to PVI or NI from April 2016 to March 2017 and followed for 1 year. Patients and postoperative providers were blinded to allocation. The primary endpoint was 30-day image-confirmed IAA. Secondary outcomes included initial and total 30-day length of stay (LOS), emergency department (ED) visits, and readmissions. Intention-to-treat analyses were performed to estimate the probability of clinical benefit using Bayesian regression models (an optimistic prior for the primary outcome and neutral priors for secondary outcomes). Frequentist statistics were also used.

Results:

Baseline characteristics were similar between treatment arms. The PVI arm had 12% postoperative IAA versus 16% in the NI arm (relative risk 0.72, 95% credible interval 0.38–1.23). Bayesian analysis estimates 89% probability that PVI reduces IAA. High probability of benefit was seen in all secondary outcomes for the PVI arm: fewer ED visits and readmissions, and shorter initial and total 30-day LOS. The probability of benefit in reduction of total 30-day LOS in PVI patients was 96% and was significant (P = 0.05) on frequentist analysis.

Conclusions:

PVI irrigation for perforated appendicitis in children demonstrated a strong probability of reduction in postoperative IAA with a high probability of decreased LOS. With the favorable probability of benefit in all outcomes, this pilot study serves as evidence to continue a definitive trial.
Live Confocal Tissue Assessment With SYTO16/PI and WGA Staining Visualizes Acute Organ Damage and Predicts Delayed Graft Function in Kidney Transplantation
Authors: Weissenbacher Annemarie , Oberhuber Rupert , Hermann Martin , Soleiman Afshin , Ulmer Hanno , Mayer Gert , Margreiter Christian , Maglione Manuel , Bösmüller Claudia , Messner Franka , Resch Thomas , Cardini Benno , Troppmair Jakob , Margreiter Raimund , Öfner Dietmar , Schneeberger Stefan
Published: September 2019

Objective:

The aim of our prospective clinical trial was to test a tissue staining technique (real-time confocal analysis [RTCA]) as a rapid assessment tool for donor kidney quality and function in human kidney transplantation.

Summary Background Data:

Tools for objective graft tissue viability assessment before kidney transplantation are lacking. RTCA has recently been established and tested in a pilot study using rodent kidneys.

Methods:

RTCA was performed in kidney biopsies stained with SYTO16/PI and WGA. A score between −3 (100% nonviable) and +3 (100% viable) describes the sum of viable cells divided by the number of nonviable cells per examined area (glomerulus, proximal, and distal tubules). The primary study endpoint was the delayed graft function (DGF).

Results:

Seventy-one kidney transplant recipients were transplanted. The median recipient and donor age were 58.5 and 57 years, respectively. Cold ischemia time was 13.6 ± 4.7 hours; anastomosis time was 30.8 ± 8.7 minutes (mean ± SD). Overall, 23 (33.8%) patients developed DGF. The RTCA score was significantly lower in kidneys developing DGF −0.43 ± 1.78 versus no DGF 0.91 ± 2.17, P = 0.01. The Remuzzi score did not differ between DGF and no DGF, P = 0.13. Remuzzi score and RTCA score correlate inversely significantly; P = 0.004. In the multivariate analysis, solely RTCA score was revealed as a significant independent factor predicting DGF; P = 0.015, Wald = 5.95, odds ratio = 0.72, 95% confidence interval = 0.55 to 0.94.

Conclusions:

Our data demonstrate that RTCA is feasible and clinically meaningful. The RTCA score predicts DGF and is a valid option to be applied in renal transplantation.
The Neglectable Impact of Delayed Graft Function on Long-term Graft Survival in Kidneys Donated After Circulatory Death Associates With Superior Organ Resilience
Authors: de Kok Michèle J. , McGuinness Dagmara , Shiels Paul G. , de Vries Dorottya K. , Nolthenius Joanne B. Tutein , Wijermars Leonie G. , Rabelink Ton J. , Verschuren Lars , Stevenson Karen S. , Kingsmore David B. , McBride Martin , Ploeg Rutger J. , Bastiaannet Esther , Schaapherder Alexander F. , Lindeman Jan H.
Published: September 2019

Objective:

To explore putative different impacts of delayed graft function (DGF) on long-term graft survival in kidneys donated after brain death (DBD) and circulatory death (DCD).

Background:

Despite a 3-fold higher incidence of DGF in DCD grafts, large studies show equivalent long-term graft survival for DBD and DCD grafts. This observation implies a differential impact of DGF on DBD and DCD graft survival. The contrasting impact is remarkable and yet unexplained.

Methods:

The impact of DGF on DBD and DCD graft survival was evaluated in 6635 kidney transplants performed in The Netherlands. DGF severity and functional recovery dynamics were assessed for 599 kidney transplants performed at the Leiden Transplant Center. Immunohistochemical staining, gene expression profiling, and Ingenuity Pathway Analysis were used to identify differentially activated pathways in DBD and DCD grafts.

Results:

While DGF severely impacted 10-year graft survival in DBD grafts (HR 1.67; P < 0.001), DGF did not impact graft survival in DCD grafts (HR 1.08; P = 0.63). Shorter dialysis periods and superior posttransplant eGFRs in DBD grafts show that the differential impact was not caused by a more severe DGF phenotype in DBD grafts. Immunohistochemical evaluation indicates that pathways associated with tissue resilience are present in kidney grafts. Molecular evaluation showed selective activation of resilience-associated pathways in DCD grafts.

Conclusions:

This study shows an absent impact of DGF on long-term graft survival in DCD kidneys. Molecular evaluation suggests that the differential impact of DGF between DBD and DCD grafts relates to donor-type specific activation of resilience pathways in DCD grafts.