Angiotensin II type 1 receptor antibodies and native kidney function in pediatric liver and intestinal transplant recipients.

BACKGROUND: Angiotensin II type-1 receptor antibody (AT1R-Ab) has been associated with vascular injury and kidney dysfunction in pediatric kidney transplant recipients. The role of AT1R-Ab in the development of chronic kidney disease in pediatric liver and intestinal transplant recipients has not been explored. METHODS: Twenty-five pediatric intestinal transplant recipients and 79 pediatric liver transplant recipients had AT1R-Ab levels measured at varying time points in the post-transplant period. Estimated glomerular filtration rate (eGFR) was determined using creatinine based CKiD U25 equation and measured at time of AT1R-Ab measurement, at 1 year post-AT1R-Ab measurement, at 5 years post-AT1R-Ab measurement, and at the most recent routine clinic visit. The prevalence of hypertension and antihypertensive medication use were also evaluated. RESULTS: Younger age at time of AT1R-Ab measurement was associated with AT1R-Ab positivity in liver transplant recipients. There was no association between AT1R-Ab status and change in eGFR, prevalence of hypertension, or use of antihypertensive medications at the described time points. CONCLUSIONS: AT1R-Ab positivity was not associated with a decline in eGFR or hypertension in pediatric liver and intestinal transplant recipients. Further studies are needed using other markers of kidney function, such as cystatin C, to validate this finding. A higher resolution version of the Graphical abstract is available as Supplementary information.

Childhood Cholestatic Liver Diseases that Persist Into Adulthood: Lessons for the Adult Gastroenterologist.

Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases. The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders. The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.

Evidence for reduced BRCA2 functional activity in Homo sapiens after divergence from the chimpanzee-human last common ancestor.

We performed a comparative analysis of human and 12 non-human primates to identify sequence variations in known cancer genes. We identified 395 human-specific fixed non-silent substitutions that emerged during evolution of human. Using bioinformatics analyses for functional consequences, we identified a number of substitutions that are predicted to alter protein function; one of these mutations is located at the most evolutionarily conserved domain of human BRCA2.

Telehealth in surgery: an umbrella review.

BACKGROUND: Telehealth use has increased worldwide during the COVID-19 pandemic. However, hands-on requirements of surgical care may have resulted in slower implementation. This umbrella review (review of systematic reviews) evaluated the perceptions, safety and implementation of telehealth services in surgery, and telehealth usage in Australia between 2020 and 2021. METHODS: PubMed was searched from 2015 to 2021 for systematic reviews evaluating real-time telehealth modalities in surgery. Outcomes of interest were patient and provider satisfaction, safety, and barriers and facilitators associated with its use. Study quality was appraised using the AMSTAR 2 tool. A working group of surgeons provided insights into the clinical relevance to telehealth in surgical practice of the evidence collated. RESULTS: From 2025 identified studies, 17 were included, which were of low to moderate risk of bias. Patient and provider satisfaction with telehealth was high. Time savings, decreased healthcare resource use and lower costs were reported as key advantages of the service. Inability to perform comprehensive examinations was noted as the primary barrier. In Australia, peak telehealth usage coincided with the introduction of temporary telehealth services and increased lockdown measures. CONCLUSIONS: Patients and providers are broadly satisfied with telehealth and its benefits. Barriers may be overcome via multidisciplinary collaboration. Telehealth may benefit surgical care long-term if implemented correctly both during and after the COVID-19 pandemic.

A Rare Case of Steroid-Resistant Neurosarcoidosis of the Cavernous Sinus With Optic Neuropathy: A Case Report.

Sarcoidosis is an inflammatory disease that presents with nervous system involvement in 5-10% of cases, commonly known as neurosarcoidosis.1 While there are no randomized controlled trials for the treatment of neurosarcoidosis, expert opinion supports initial treatment with corticosteroids and the use of steroid-sparing or anti-TNF agents in refractory or severe cases. We report a case of a 48-year-old African American male with a past medical history of biopsy-proven hepatic and renal sarcoidosis and progressive headache, dizziness, and blurry vision for 5 months, presenting with an acute exacerbation of right-sided vision loss over one day. MRI of the brain revealed a dural-based mass extending into the right cavernous sinus and compressing the right optic nerve. Given the pathological confirmation of systemic granulomatous disease consistent with sarcoidosis, clinical manifestations, bilateral hilar and mediastinal lymphadenopathy, MRI findings typical of central nervous system inflammation, and exclusion of other possible etiologies, the patient was diagnosed with probable neurosarcoidosis. Corticosteroids initially resolved his symptoms; however, he suffered an acute relapse. Combination therapy with corticosteroids plus mycophenolate mofetil (MMF) led to the eventual resolution of his symptoms. Only 8 cases of neurosarcoidosis involving the cavernous sinus have been reported. Our patient represents the only reported case of probable neurosarcoidosis of the cavernous sinus with optic neuropathy successfully treated with corticosteroid plus MMF combination therapy. We highlight the need to consider early, aggressive treatment in cases of neurosarcoidosis with optic neuropathy and to develop criteria to guide treatment strategy based on neurolocalization and the degree of neurological disability.

15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration.

The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis; however, practical strategies to enhance splenic support of transplanted HSPCs have proved elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases BM prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution after BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages, megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced nonpathologic splenic extramedullary hematopoiesis at steady state, and pretransplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to macrophages, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches, promote hematopoietic regeneration, and improve clinical outcomes of BMT.

The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas.

PURPOSE: Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes. EXPERIMENTAL DESIGN: Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression. RESULTS: For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance. CONCLUSIONS: In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFß signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.

Inhibition of 15-PGDH Protects Mice from Immune-Mediated Bone Marrow Failure.

Aplastic anemia (AA) is a human immune-mediated bone marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor and by immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies are needed to accelerate hematologic recovery in patients receiving front-line IST. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low-dose IST enhanced total white blood cell, neutrophil, and platelet recovery, achieving responses similar to those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.

The Evolutionary Origins of Recurrent Pancreatic Cancer.

Surgery is the only curative option for stage I/II pancreatic cancer; nonetheless, most patients will experience a recurrence after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer, we performed whole-exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease after adjuvant or first-line platinum therapy corresponds to an increased mutational burden. Recurrent disease is enriched for genetic alterations predicted to activate MAPK/ERK and PI3K-AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment-induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In 1 patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings suggest routine post-treatment sampling may have value in the management of recurrent pancreatic cancer. SIGNIFICANCE: The biological features or clinical vulnerabilities of recurrent pancreatic cancer after pancreaticoduodenectomy are unknown. Using whole-exome sequencing we find that recurrent disease has a distinct genomic landscape, intermetastatic genetic heterogeneity, diverse clonal origins, and higher mutational burden than found for treatment-naïve disease.See related commentary by Bednar and Pasca di Magliano, p. 762.This article is highlighted in the In This Issue feature, p. 747.

A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma.

Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.

An analysis of genetic heterogeneity in untreated cancers.

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.

Central venous catheter repair is highly successful in children with intestinal failure.

PURPOSE: Damaged central venous catheters (CVCs) are commonly repaired to avoid line replacement and preserve vascular access. However, limited data suggest an increased risk for central line-associated bloodstream infections (CLABSIs) associated with the repair procedure. The purpose of this study was to describe outcomes of CVC repairs among parenteral nutrition (PN) dependent children with intestinal failure (IF). METHODS: A 2-year retrospective review was performed on children with IF on home PN > 6 months. Outcomes of interest were repair success and postrepair CLABSI incidence. Descriptive statistics included medians and frequencies. RESULTS: A total of 36 pediatric IF patients underwent 96 CVC repairs during the study period. The median CVC repair count was 1.5 repairs/patient (range, 1 to 16 repairs/patient) with >1 repair in half the patients. Ninety-four broken catheters (98%) were successfully repaired with restoration of function. Of the unsuccessful repairs (2%), the two catheters eventually required surgical removal and replacement. One repair (1%) was followed by a CLABSI with Enterococcus faecalis in an immunocompromised patient. CONCLUSION: CVC repair is a highly successful procedure with a low risk for infection. Catheter repair should be considered whenever possible as it may extend the lifetime of the catheter and decrease the risk for vascular access loss. LEVEL OF EVIDENCE: Treatment study; level IV.

Precancerous neoplastic cells can move through the pancreatic ductal system.

Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.

Minimal functional driver gene heterogeneity among untreated metastases.

Metastases are responsible for the majority of cancer-related deaths. Although genomic heterogeneity within primary tumors is associated with relapse, heterogeneity among treatment-naïve metastases has not been comprehensively assessed. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. We found that within individual patients, a large majority of driver gene mutations are common to all metastases. Further analysis revealed that the driver gene mutations that were not shared by all metastases are unlikely to have functional consequences. A mathematical model of tumor evolution and metastasis formation provides an explanation for the observed driver gene homogeneity. Thus, single biopsies capture most of the functionally important mutations in metastases and therefore provide essential information for therapeutic decision-making.

Local recurrences at the anastomotic area are clonally related to the primary tumor in sporadic colorectal carcinoma.

PURPOSE: Anastomotic recurrences (AR) occur in 2-10% of colorectal carcinoma cases after resection of primary tumor (PT). Currently, there are no molecular data investigating their genetic profile and multiple theories exist about their pathogenesis. The aim of our study was to compare the genomic profile of AR to that of the patients' corresponding matched PT and, when available, to a distant metastasis (DM). EXPERIMENTAL DESIGN: Thirty-six tumors from 14 patients were genotyped using a capture-based, next-generation assay to define the mutational status of 341 cancer-associated genes. All patients had R0 resection of their PT and AR occurred 1.1-7.0 years following PT resection. A DM or a second AR was analyzed in 8 patients. All tumors were microsatellite stable except in one patient with Lynch syndrome. RESULTS: A total of 254 somatic mutations were detected including 138 mutations in the microsatellite stable (MSS) cases. The most commonly mutated genes were APC, KRAS, TP53, PIK3CA, ATM and PIK3R1. In all patients with MSS tumors the AR and PT shared between 50-100% of mutations, including mutations in key driver genes, consistent with these tumors being clonally related. Genetic events private to DM were not detected in AR and phylogenetic analysis showed that ARs were more closely related to PT than DM. In the Lynch syndrome patient the PT and AR showed distinct somatic mutations consistent with independent primaries. CONCLUSIONS: ARs are clonally related to PT in sporadic colorectal carcinomas and do not appear to represent seeding of the anastomotic site by distant metastases.

Reconstructing metastatic seeding patterns of human cancers.

Reconstructing the evolutionary history of metastases is critical for understanding their basic biological principles and has profound clinical implications. Genome-wide sequencing data has enabled modern phylogenomic methods to accurately dissect subclones and their phylogenies from noisy and impure bulk tumour samples at unprecedented depth. However, existing methods are not designed to infer metastatic seeding patterns. Here we develop a tool, called Treeomics, to reconstruct the phylogeny of metastases and map subclones to their anatomic locations. Treeomics infers comprehensive seeding patterns for pancreatic, ovarian, and prostate cancers. Moreover, Treeomics correctly disambiguates true seeding patterns from sequencing artifacts; 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumour heterogeneity among distinct samples. In silico benchmarking on simulated tumour phylogenies across a wide range of sample purities (15-95%) and sequencing depths (25-800 × ) demonstrates the accuracy of Treeomics compared with existing methods.

Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer.

The extent of heterogeneity among driver gene mutations present in naturally occurring metastases-that is, treatment-naive metastatic disease-is largely unknown. To address this issue, we carried out 60× whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity. Even with respect to these passenger mutations, our analysis suggests that the genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of known driver gene mutations among metastases in the same patient has critical and encouraging implications for the success of future targeted therapies in advanced-stage disease.