Citations

AbstractObjectivesEosinophilic esophagitis (EoE) is often diagnosed in school‐age children between 6‐ and 9‐year‐old. There is less known about those who are diagnosed with EoE that are younger than 6 years old. The objective of this study is to compare clinical presentation, comorbidities, and outcomes based on age at diagnosis of EoE.MethodsSingle‐center retrospective chart review of children (<18 years) diagnosed with EoE between 2005 and 2020. We recorded demographics, clinical presentation, family history, past medical history, treatment, and endoscopic findings. Children in this cohort were classified based on age into three age groups: <2 years, 2−<6 years, and 6−<18 years.ResultsWe identified 256 children with EoE, the mean age (SD) at the time of diagnosis was 9 (5.2) years and 184 (72%) were male. We had 164 (64%) patients with available follow‐up esophagogastroduodenoscopies (EGDs) data (495 EGDs in total) of those 99/164 (60%) reached mucosal remission. In the very young children (<2 years) vomiting was the most common presentation, while poor weight gain was seen more in the 2−<6‐year group in comparison to the >6‐years. Food impaction and abdominal pain were most likely to present in older children 6−18 years. Combination therapy, as opposed to a single therapy, induced remission at a higher frequency in the <6‐year group in comparison to the 6−<18‐year group (85% vs. 66%).ConclusionEoE should be considered in younger children presenting with feeding difficulty and poor weight gain. Combination therapy seems to be more effective in younger children with EoE, but further studies with bigger sample size are needed to study the efficacy of the different combination therapies.

Purpose Identifying actionable oncogenic mutations have changed the therapeutic landscape in different types of tumors. This study investigated the utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) assay, in clinical practice in a developing country. Methods In this retrospective cohort study, CGP was performed on clinical samples from patients with different solid tumors recruited between December 2016 and November 2020, using hybrid capture-based genomic profiling, at the individual treating physicians’ request in the clinical care for therapy decisions. Kaplan–Meier survival curves were estimated to characterize the time-to-event variables. Results Patients median age was 61 years (range: 14–87 years), and 64.7% were female. The most common histological diagnosis was lung primary tumors, with 90 patients corresponding to 52.9% of the samples (95% CI 45.4-60.4%). Actionable mutations with FDA-approved medications for specific alterations correspondent to tumoral histology were identified in 58 cases (46.4%), whereas other alterations were detected in 47 different samples (37.6%). The median overall survival was 15.5 months (95% CI 11.7 months-NR). Patients who were subjected to genomic evaluation at diagnosis reached a median overall survival of 18.3 months (95% CI 14.9 months-NR) compared to 14.1 months (95% CI 11.1 months-NR) in patients who obtained genomic evaluation after tumor progression and during standard treatment ( P = .7). Conclusion CGP of different types of tumors identifies clinically relevant genomic alterations that have benefited from targeted therapy and improve cancer care in a developing country to guide personalized treatment to beneficial outcomes of cancer patients.

INTRODUCTION: To describe the clinical, endoscopic, and histopathology features of esophageal graft-vs-host disease (GVHD). Methods: Patients with biopsy-proven esophageal GVHD diagnosed at Mayo Clinic between 2000 and 2021 were included. Results: In 43 esophageal patients, other organ GVHD was present in 58% before and 86% at esophageal GVHD diagnosis. Esophageal specific symptoms were uncommon (dysphagia 26% and odynophagia/heartburn 5%). Esophagogastroduodenoscopy was abnormal in 72% patients demonstrating erosive esophagitis, ulceration, desquamation, or rings/furrows in a diffuse or focal pattern. DISCUSSION: There should be a low threshold for esophageal biopsies for GVHD because esophageal symptoms and endoscopic findings may be nonspecific or absent.

Abstract Background: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer (NSCLC). Methods: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial NGS panel in liquid biopsy.Results: There were ten males (66.7%), and the median patient’s age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival (OS) of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate (ORR) was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.Conclusions: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Significance Statement A higher percentage of the kidney cortex area that exhibits interstitial fibrosis/tubular atrophy (IF/TA) is a feature of poor prognosis on biopsy. This study describes IF/TA density (the number of IF/TA foci per area of cortex) and shows it predicts progressive CKD, independent of both percentage IF/TA and clinical characteristics among patients who have undergone nephrectomy. Other patterns of IF/TA and inflammation were not predictive for progressive CKD and mortality beyond percentage IF/TA and clinical characteristics. At the same percentage IF/TA, a higher IF/TA density suggests more scattered and widespread damage to the nephrons, with a worse kidney prognosis. This information may be helpful for accurate interpretation of the severity of “chronic changes” observed on a kidney biopsy. Background Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. Methods We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000–2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm 2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6–12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. Results Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m 2 ), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. Conclusions Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

PURPOSE BIM activation is essential for epidermal growth factor receptor ( EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions ( BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

Significance Statement Predicting outcomes on the basis of renal histology after a radical nephrectomy has been limited to studies with small sample sizes, short follow-ups, and only a descriptive characterization of histology. In this study of 936 patients followed up for a median of 6.4 years after establishing a new baseline kidney function following radical nephrectomy, the authors used morphometric methods to quantitatively characterize microstructural features on large renal wedge sections. Findings of larger nephrons and more extensive glomerulosclerosis and interstitial fibrosis predicted progressive CKD; interstitial fibrosis also predicted mortality from causes other than cancer. These findings provide insight into the important microstructural features of “generic” CKD in patients without a specific kidney disease and support the use of quantitative methods to evaluate renal histology after a radical nephrectomy to determine patients’ long-term risks. Background Nephron hypertrophy and nephrosclerosis may be important determinants of CKD and mortality. However, studies of outcomes associated with these microstructural features have been limited to small tissue specimens from patients selected for either good kidney health or known kidney disease. Methods To determine whether microstructural features are predictive of progressive CKD and mortality outcomes, we studied patients who underwent a radical nephrectomy for a tumor. Large wedge sections of renal parenchyma distal to the tumor were stained and scanned into high-resolution images; we annotated the cortex and all glomeruli to calculate glomerular volume, cortex volume per glomerulus, and percentage of globally sclerotic glomeruli. Morphometric measurements also included percentages of artery luminal stenosis and interstitial fibrosis/tubular atrophy (IF/TA) of the cortex. At follow-up visits every 6–12 months, we determined which patients experienced progressive CKD (defined as dialysis, kidney transplantation, or a 40% decline from postnephrectomy eGFR). Cox models for these outcomes were adjusted for age, sex, body mass index, hypertension, diabetes, smoking, eGFR, and proteinuria. Results Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73 m 2 ), 117 progressive CKD events, 183 noncancer deaths, and 116 cancer deaths occurred during a median follow-up of 6.4 years. Larger glomerular volume, larger cortex per glomerulus, and higher percentage of globally sclerotic glomeruli or IF/TA predicted progressive CKD. Higher percentage IF/TA also predicted noncancer mortality. Microstructural features did not predict cancer mortality or recurrence. Conclusions After a radical nephrectomy, larger nephrons and nephrosclerosis predicted progressive CKD, and IF/TA predicted noncancer mortality. Morphometric analysis of renal parenchyma can predict noncancer clinical events in patients long after their radical nephrectomy.

Precision oncology is the field that places emphasis on the diagnosis and treatment of tumors that harbor specific genomic alterations susceptible to inhibition or modulation. Although most alterations are only present in a minority of patients, a substantial effect on survival can be observed in this subgroup. Mass genome sequencing has led to the identification of a specific driver in the translocations of the tropomyosin receptor kinase family (NTRK) in a subset of rare tumors both in children and in adults, and to the development and investigation of Larotrectinib. This medication was granted approval by the US Food and Drug Administration for NTRK-positive tumors, regardless of histology or age group, as such, larotrectinib was the first in its kind to be approved under the premise that molecular pattern is more important than histology in terms of therapeutic approach. It yielded significant results in disease control with good tolerability across a wide range of diseases including rare pediatric tumors, salivary gland tumors, gliomas, soft-tissue sarcomas, and thyroid carcinomas. In addition, and by taking different approaches in clinical trial design and conducting allocation based on biomarkers, the effects of target therapies can be isolated and quantified. Moreover, and considering developing nations and resource-limited settings, precision oncology could offer a tool to reduce cancer-related disability and hospital costs. In addition, developing nations also present patients with rare tumors that lack a chance of treatment, outside of clinical trials. This, in turn, offers the possibility for international collaboration, and contributes to employment, education, and health service provisions. The reviews of this paper are available via the supplemental material section.

Significance Statement The quality of a kidney obtained from a living donor is often inferred from the donor’s age, risk factors, and kidney function. Little is known about the influence of a donated kidney’s structural features on the risk of death-censored graft failure in the recipient. In an analysis of 2293 kidney donor-recipient pairs, the authors identified subclinical nephrosclerosis, larger nephron size (but not nephron number), and smaller medullary volume as structural predictors of death-censored graft failure that were independent of both donor and recipient clinical characteristics. These findings provide important insights into the factors that define the “intrinsic quality” of the living kidney donor graft at the time of donation, and support use of intraoperative biopsies to identify donor kidneys that are at higher risk for failure. Background Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. Methods Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. Results The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. Conclusions Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft’s “intrinsic quality” at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

Significance Statement Research investigating glomerular morphology in different cortical regions has been limited to animal models and a small number of human autopsy kidneys. In this study, the authors used tissue from living patients who underwent a radical nephrectomy (for a renal tumor) to characterize glomerular morphology and glomerulosclerosis by cortical depth. They found that glomerular volume and glomerulosclerosis differed by depth across three cortical regions (superficial, middle, and deep). Although most clinical associations with glomerulosclerosis and glomerulomegaly did not differ by cortical depth, there were important exceptions. Age-related glomerulosclerosis appeared to be an ischemic process and was more evident in the superficial (subcapsular) region. Diabetes-related glomerulosclerosis was more evident in the deep (juxtamedullary) region. Obesity more strongly associated with larger glomeruli in the superficial region. Background Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited. Methods To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions. Results The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µ m 3 , respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex. Conclusions Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.