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Abstract Although the prevalence of eosinophilic gastrointestinal disorders (EGIDs) is increasing, there is evidence that eosinophilic gastritis and/or duodenitis (EG/EoD) are underdiagnosed. Patients with EG/EoD often present with chronic, non-specific gastrointestinal (GI) symptoms, similar to patients with functional GI disorders. We hypothesized that systematic evaluation, including multiple esophageal, gastric and duodenal biopsies, of patients with chronic GI symptoms might reveal a high rate of gastroduodenal eosinophila, with or without eosinophilic esophagitis (EoE). Methods We performed a prospective multi-center study of patients with non-specific GI symptoms for ≥6 months, from 20 sites. Patients completed a questionnaire assessing abdominal pain, abdominal cramping, early satiety, bloating, nausea, vomiting, diarrhea, and loss of appetite. Those with daily average symptom severity scores ≥3/10 for any single symptom underwent esophagogastroduodenoscopy (EGD) with collection of 4 esophageal (EoE), 8 gastric, and 4 duodenal biopsies, analyzed by central pathologists. Histologic criteria for EoE was ≥15eos/hpf in ≥1 esophageal site and for EG/EoD was peak eosinophil counts ≥30/hpf in ≥5 gastric hpfs and/or 3 duodenal hpfs—criteria used in randomized trials. Results Of 556 patients screened, 405 (73%) met symptom criteria and underwent EGD; 181 patients (45%, mean age 45, 73% female) who underwent EGD met the histologic criteria for EG/EoD, and of these, 7% also had EoE diagnosed. Overall 2% met histologic criteria for EoE alone. Of patients who met the histologic criteria for EG/EoD, 93% were previously diagnosed with gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), or functional dyspepsia (FD) (Figure 1). The average duration of GI symptoms in the screened population as well as those that met histologic criteria for EG/EoD was 11 years. Conclusion Forty-five percent of patients with moderate-to-severe GI symptoms who underwent EGD met histologic criteria for EG/EoD. Over 90% of these patients had previously been diagnosed with GERD, IBS, and/or FD, and had minimal overlap with EoE. EGD with systematic gastroduodenal biopsies, and intentional evaluation for tissue eosinophilia, should be performed in patients with chronic GI symptoms. Accurate diagnosis of EG/EoD is required for appropriate, targeted treatment and improved outcomes of patients with moderate-to-severe GI symptoms.

AbstractObjectiveThis study was undertaken to determine whether the vertical parasagittal approach or the lateral peri‐insular/peri‐Sylvian approach to hemispheric surgery is the superior technique in achieving long‐term seizure freedom.MethodsWe conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri‐insular/peri‐Sylvian, or lateral trans‐Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time‐to‐event method and calculated using the Kaplan–Meier survival method.ResultsData for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri‐insular/peri‐Sylvian or trans‐Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%–70.2%) of the entire cohort at 10‐year follow‐up. Seizure freedom was 88.8% (95% CI = 78.9%–94.3%) at 1‐year follow‐up and persisted at 85.5% (95% CI = 74.7%–92.0%) across 5‐ and 10‐year follow‐up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%–91.5%) at 1‐year to 72.1% (95% CI = 66.9%–76.7%) at 5‐year to 57.2% (95% CI = 46.6%–66.4%) at 10‐year follow‐up for the lateral subgroup. Log‐rank test found that vertical hemispherotomy was associated with durable seizure‐free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time‐to‐seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08–6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05–12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique.SignificanceThis pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise‐based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long‐term seizure outcomes.

Abstract The basis for acquired resistance to JAK inhibition in patients with JAK2-driven hematologic malignancies is not well understood. We report a patient with a myeloproliferative neoplasm (MPN) with a BCR activator of RhoGEF and GTPase (BCR)–JAK2 fusion with initial hematologic response to ruxolitinib who rapidly developed B-lymphoid blast transformation. We analyzed pre-ruxolitinib and blast transformation samples using genome sequencing, DNA mate-pair sequencing (MPseq), RNA sequencing (RNA-seq), and chromosomal microarray to characterize possible mechanisms of resistance. No resistance mutations in the BCR-JAK2 fusion gene or transcript were identified, and fusion transcript expression levels remained stable. However, at the time of blast transformation, MPseq detected a new IKZF1 copy-number loss, which is predicted to result in loss of normal IKZF1 protein translation. RNA-seq revealed significant upregulation of genes negatively regulated by IKZF1, including IL7R and CRLF2. Disease progression was also characterized by adaptation to an activated B-cell receptor (BCR)–like signaling phenotype, with marked upregulation of genes such as CD79A, CD79B, IGLL1, VPREB1, BLNK, ZAP70, RAG1, and RAG2. In summary, IKZF1 deletion and a switch from cytokine dependence to activated BCR-like signaling phenotype represent putative mechanisms of ruxolitinib resistance in this case, recapitulating preclinical data on resistance to JAK inhibition in CRLF2-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia.

Abstract BACKGROUND Trials of lumbar spondylolisthesis are difficult to compare because of the heterogeneity in the populations studied. OBJECTIVE To define patterns of clinical presentation. METHODS This is a study of the prospective Quality Outcomes Database spondylolisthesis registry, including patients who underwent single-segment surgery for grade 1 degenerative lumbar spondylolisthesis. Twenty-four-month patient-reported outcomes (PROs) were collected. A k-means clustering analysis—an unsupervised machine learning algorithm—was used to identify clinical presentation phenotypes. RESULTS Overall, 608 patients were identified, of which 507 (83.4%) had 24-mo follow-up. Clustering revealed 2 distinct cohorts. Cluster 1 (high disease burden) was younger, had higher body mass index (BMI) and American Society of Anesthesiologist (ASA) grades, and globally worse baseline PROs. Cluster 2 (intermediate disease burden) was older and had lower BMI and ASA grades, and intermediate baseline PROs. Baseline radiographic parameters were similar ( P > .05). Both clusters improved clinically ( P < .001 all 24-mo PROs). In multivariable adjusted analyses, mean 24-mo Oswestry Disability Index (ODI), Numeric Rating Scale Back Pain (NRS-BP), Numeric Rating Scale Leg Pain, and EuroQol-5D (EQ-5D) were markedly worse for the high-disease-burden cluster (adjusted- P < .001). However, the high-disease-burden cluster demonstrated greater 24-mo improvements for ODI, NRS-BP, and EQ-5D (adjusted- P < .05) and a higher proportion reaching ODI minimal clinically important difference (MCID) (adjusted- P = .001). High-disease-burden cluster had lower satisfaction (adjusted- P = .02). CONCLUSION We define 2 distinct phenotypes—those with high vs intermediate disease burden—operated for lumbar spondylolisthesis. Those with high disease burden were less satisfied, had a lower quality of life, and more disability, more back pain, and more leg pain than those with intermediate disease burden, but had greater magnitudes of improvement in disability, back pain, quality of life, and more often reached ODI MCID.