Citations

PURPOSE This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

Abstract Introduction Transnasal access to the anterior skull base provides a minimally invasive approach for sellar and parasellar masses compared with its open counterparts. The unique microbiome of the sinonasal mucosa provides distinct challenges not encountered with other cranial approaches. The use of antibiotics in these cases has not been standardized, and data remain scarce regarding infectious outcomes. Methods We conducted a multicenter retrospective analysis of shared quality data points for the endoscopic endonasal approach (EEA) for pituitary adenomas, along with other sellar and parasellar region masses that were included by participating institutions. Patient and operative characteristics, perioperative and postoperative antibiotic regimens and their durations, intraoperative and postoperative cerebrospinal fluid leak, and onset of postoperative meningitis and sinusitis were compared. Results Fifteen institutions participated and provided 6 consecutive months' worth of case data. Five hundred ninety-three cases were included in the study, of which 564 were pituitary adenomectomies. The incidences of postoperative meningitis and sinusitis were low (0.67 and 2.87% for all pathologies, respectively; 0.35% meningitis for pituitary adenomas) and did not correlate with any specific antibiotic regimen. Immunocompromised status posed an increased odds of meningitis in pituitary adenomectomies (28.6, 95% confidence interval [1.72–474.4]). Conclusions The results show no clear benefit to postoperative antimicrobial use in EEA, with further larger studies needed.

Abstract Introduction Cognitive behavior therapy for insomnia (CBT-I), a first-line therapy for patients with chronic insomnia disorder (ChID), is underutilized due to reduced access to trained providers and other barriers. We developed an interactive care plan (ICP) combining individual aspects of CBT-I. This ICP, which integrates with the electronic health record (EHR), is designed to deliver personalized and scalable CBT-I to patients with ChID. We report data from initial implementation and evaluation of a ChID ICP deployed at a tertiary sleep medicine clinic. Methods The ICP was developed following patient and provider interviews and focus groups. Patients diagnosed with ChID were offered enrollment and engaged in the ICP through an app. The ICP has embedded logic that may escalate care or offer an exit from the program, depending upon the patient’s response to questions. Key variables ascertained from the patient included sleep efficiency (SE), sleep timing and the Insomnia Severity Index (ISI), and how satisfied they were with their progress (Likert scale). We also measured In Basket messaging related to use of the ICP. Results A total of 222 patients [57% female, age=56.4±15.9 years (average ±SD), 92.7% white] were enrolled in the initial 120 days of ICP implementation. Most referrals were initiated by physicians or advanced practitioners (77.9%). ISI at initiation was 15±5.18 and SE was 74.55±16.65%. Patients spent 35.9±26.25 days engaging with the ICP. The ISI score at 28 days was 12.89±4.98 and SE was 78.9±13.4% with both showing significant improvement from baseline (p=0.013; p=0.002; respectively). Self-rated satisfaction with progress did not significantly correlate with actual improvement in ISI or SE (p>0.05). The ICP generated 3.89±2.3 In Basket messages per patient. Conclusion Patients who actively engaged with the ICP showed significant improvements in insomnia severity and sleep efficiency. While a majority of the patients were neutral towards the ICP and only a small minority expressed dissatisfaction, these data indicate that the ICP will have clinical utility in busy sleep medicine practices with reduced access to behavioral sleep specialists. Support (If Any)

Objective This qualitative study sought to learn from patients with cancer -- in their own words -- about anxiety associated with medical testing. Methods Patients with cancer or a history of cancer were recruited from an oncology clinic. After oral consent, each was interviewed in person. A semi-structured interview guide was used to help focus the interviews. Interviews were then recorded, transcribed, and analyzed with rigorous qualitative methods. Results Twenty patients are the focus of this report, which highlights 2 main themes from the data. The first is that anxiety related to medical testing is a real entity. Although not all patients experienced it, those who did described it as such (“I was a little apprehensive.” “It’s the anticipation.” “I don’t think it bothers me until I get near the time for testing.”). The second theme focused on coping. Patients offered insight on how to cope (“So I just deal with it and work.” “And don’t let myself sink into a pity pot ….” “See your scan as a tool instead of … instead of um … a death sentence, I suppose.”) Conclusion In patients with cancer, the anxiety from medical testing is real, could perhaps be mitigated by sharing coping methods from patient to patient, and merits further study.

Background: Automated insulin delivery (AID) systems have proven effective in increasing time-in-range during both clinical trials and real-world use. Further improvements in outcomes for single-hormone (insulin only) AID may be limited by suboptimal insulin delivery settings. Methods: Adults (≥18 years of age) with type 1 diabetes were randomized to either sensor-augmented pump (SAP) (inclusive of predictive low-glucose suspend) or adaptive zone model predictive control AID for 13 weeks, then crossed over to the other arm. Each week, the AID insulin delivery settings were sequentially and automatically updated by an adaptation system running on the study phone. Primary outcome was sensor glucose time-in-range 70–180 mg/dL, with noninferiority in percent time below 54 mg/dL as a hierarchical outcome. Results: Thirty-five participants completed the trial (mean age 39 ± 16 years, HbA1c at enrollment 6.9% ± 1.0%). Mean time-in-range 70–180 mg/dL was 66% with SAP versus 69% with AID (mean adjusted difference +2% [95% confidence interval: −1% to +6%], P = 0.22). Median time <70 mg/dL improved from 3.0% with SAP to 1.6% with AID (−1.5% [−2.4% to −0.5%], P = 0.002). The adaptation system decreased initial basal rates by a median of 4% (−8%, 16%) and increased initial carbohydrate ratios by a median of 45% (32%, 59%) after 13 weeks. Conclusions: Automated adaptation of insulin delivery settings with AID use did not significantly improve time-in-range in this very well-controlled population. Additional study and further refinement of the adaptation system are needed, especially in populations with differing degrees of baseline glycemic control, who may show larger benefits from adaptation.

Abstract The pre‐mRNA‐processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss‐of‐function variants in PRPF8 . These individuals have clinical features that may represent a new neurodevelopmental syndrome.

Apolipoprotein E (APOE) is a lipid transporter involved in neural cholesterol metabolism. Highly expressed in astrocytes and microglia, APOE4, one of the three isoforms of the transporter, is a strong genetic risk factor for Alzheimer’s disease, while APOE3 is considered moderate risk and APOE2 protective. Despite recent advances in Alzheimer’s disease research, the exact mechanism by which APOE4 influences the progression of the disease has yet to be determined. One hallmark pathological feature of Alzheimer’s disease is the accumulation of hyperphosphorylated tau protein in the brain. To investigate the role of APOE isoform expression in the accumulation of hyperphosphorylated tau protein, a microglia‐specific cre‐ recombinase‐mediated APOE inducible mouse model was used. Phosphorylated‐tau accumulation, microglia activation, and neurodegeneration of the hippocampus and piriform cortex upon specific expression of APOE3 were quantified. APOE3 expressing mice had exacerbated neurodegeneration and tau accumulation in the hippocampus. Additionally, it appeared that APOE3 expressing mice had increased microglial activation. Thus, APOE expression may be involved in the activation of microglia in Alzheimer’s disease, eliciting an overactive immune response that accelerates disease progression.

Introduction: Atrial arrhythmias are common in patients with D-TGA and atrial switch. We sought to analyze the arrhythmia substrate and catheter ablation approaches and outcomes. Methods: We performed a retrospective review of all clinical and procedural data in patients with D-TGA followed at a large tertiary care center. Results: In a cohort of 152 patients (mean age 30±11 years), atrial tachycardia was present in 69(45%) patients. Ablations were performed in 39(26%) patients: macro-reentrant atrial flutter (N=37), atrial fibrillation (N=4), and focal automatic atrial tachycardia (N=3). Detailed electrophysiology study data was available for 34 patients. At first ablation (N=28), cavo-tricuspid isthmus dependent flutter (CTI, 23(82%)) was most common, followed by right atriotomy-related flutter (IART, 16(57%)) and focal atrial tachycardia (FAT, 1(3.5%)). Bidirectional CTI block often required ablation on both sides of the baffle to complete the isthmus line. Access to the pulmonary venous atrium was obtained in 82% of first-time ablations (via retrograde aortic access, 74%, baffle puncture, 6%, or baffle fenestration, 12%) and in 100% of redo procedures. The first ablation was acutely successful in 25 (89%) patients; the other 3 patients had either partial procedural success (1), failed ablation (1), or underwent an empirical ablation (1). Long-term arrhythmia recurrence occurred in 13(46%) after the first ablation and class III antiarrhythmic medications were utilized in 12 patients. At least one long-term recurrence occurred in 11(44%) patients. Importantly, clinical arrhythmia burden was significantly reduced post-ablation, with rare and short-limited episodes amenable to antiarrhythmic drugs or cardioversion. Repeat ablation was required in 3 cases. Long-term arrhythmia recurrence after a previously completed CTI line involved different arrhythmia mechanisms: scar-related reentry (80%) and automatic atrial tachycardia (40%). Conclusions: Atrial arrhythmia in patients with D-TGA often involves the CTI and atriotomy scars. Ablation of the CTI typically requires access to the pulmonary venous atrium to achieve bidirectional block. Despite late recurrence, the clinical arrhythmic burden is substantially improved.

Abstract Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

Antibiotic resistance, particularly to carbapenems, is of increasing concern in Bacteroides fragilis . Carbapenem resistance in B. fragilis is most often mediated by the activation of chromosomally encoded metallo-β-lactamase cfiA by the presence of an upstream insertion sequence (IS).