Citations

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration–approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include ( 1 ) an irreversible loss of kidney function as a surrogate for progression to kidney failure, ( 2 ) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, ( 3 ) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and ( 4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

AbstractObjectiveThe objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis.MethodsAn international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM.ResultsThere was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic–clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug‐resistant epilepsy.SignificanceThis international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

AbstractObjectiveThere are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome).MethodsAn international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM.ResultsThere was a strong consensus for valproic acid as the first‐line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel‐blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome.SignificanceThis international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

1057 Background: Endocrine therapy (ET), particularly aromatase inhibitors (AIs), for estrogen receptor (ER)-positive breast cancer can lead to acquired ESR1 mutations ( mESR1) driving endocrine resistance and tumor progression. Treatments for mBC with mESR1 are limited, especially after progression on ET/cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) combinations. In ELAINE 2, LAS, a next-generation ET (breast ER antagonist) plus Abema had a median progression-free survival (PFS) of ~13 mos, objective response rate (ORR) of 33%, and 24-wk clinical benefit rate (CBR) of 62% with a favorable safety profile in patients with resistant mESR1 mBC (Damodaran S, et al. J Clin Oncol. 2022;40:16 suppl 1022). Here, we report ELAINE 2 data with longer patient follow up (Jan 31, 2023). Methods: In this open-label, phase 2, single-arm study, 29 women with mESR1, ER+/HER2- mBC that progressed on prior ET took oral LAS 5 mg/day and Abema 150 mg BID until disease progression/toxicity. The primary endpoint was safety/tolerability; secondary included PFS, CBR, and ORR. Data were summarized descriptively with no formal hypothesis testing. Results: Patients (median age 60 yrs) had received a median of 2 prior therapy lines for mBC; all but one had prior CDK4/6i exposure and 14 (48%) had prior chemotherapy for mBC. LAS/Abema was well tolerated with primarily grade 1/2 treatment-emergent adverse events (most commonly diarrhea, nausea, fatigue, and vomiting). One treatment withdrawal occurred due to grade 2 diarrhea. No deaths occurred. LAS dose was not reduced; Abema dose was reduced to 100 mg BID in 6 (21%) patients. Median PFS was 56.0 wks (~13 mos) and CBR 65.5% (95% CI, 47.3‒80.1). Median overall survival was not estimable. In 18 patients with measurable lesions, ORR was 55.6% (95% CI, 33.7‒75.4), with median time to response of 5.7 mos and median duration of response of 6.4 mos. Seventy-six percent, 56%, and 39% of patients were progression free at 6, 12, and 18 mos, respectively. Three (10%) patients had scan-identified venous thromboembolic events, with one symptomatic pulmonary embolism and one symptomatic deep vein thrombosis. In 26 patients with evaluable baseline and wk 4 ctDNA, ESR1 mutant allele fraction decreased from baseline to wk 4 in 81% of patients and was not detected in 54%. Conclusions: With longer ELAINE 2 follow up, LAS/Abema continues to be well tolerated with clinically meaningful efficacy in women with mESR1, ER+/HER2- mBC that had progressed on ET and CDK4/6is. Decreases in mESR1 ctDNA suggest effective target engagement of LAS. The PFS (median ~13 mos) and ORR (56%) with LAS/Abema are promising and a confirmatory phase 3 study (ELAINE 3) will begin in 2023. If ELAINE 2 results are confirmed, the combination of LAS and Abema would address a critical unmet need, providing a practice changing option for treating mESR1 breast cancer. Clinical trial information: NCT04432454 .

Background Dysphagia palliation in inoperable esophageal cancer continues to be a challenge. Self-expandable metal stents have been the mainstay of endoscopic palliation but have a significant risk of adverse events (AEs). Liquid nitrogen spray cryotherapy is an established modality that can be used with systemic therapy. This study reports the outcomes of cryotherapy, including dysphagia and quality of life (QoL), in patients receiving systemic therapy. Methods This was a prospective multicenter cohort study of adults with inoperable esophageal cancer who underwent cryotherapy. QoL and dysphagia scores before and after cryotherapy were compared. Results 55 patients received 175 cryotherapy procedures. After a mean of 3.2 cryotherapy sessions, mean QoL improved from 34.9 at baseline to 29.0 at last follow-up (P < 0.001) and mean dysphagia improved from 1.9 to 1.3 (P = 0.004). Patients receiving more intensive cryotherapy (≥ 2 treatments within 3 weeks) showed a significantly greater improvement in dysphagia compared with those not receiving intensive therapy (1.2 vs. 0.2 points; P = 0.003). Overall, 13 patients (23.6 %) received another intervention (1 botulinum toxin injection, 2 stent, 3 radiation, 7 dilation) for dysphagia palliation. Within the 30-day post-procedure period, there were three non-cryotherapy-related grade ≥ 3 AEs (all deaths). The median overall survival was 16.4 months. Conclusion In patients with inoperable esophageal cancer receiving concurrent systemic therapy, adding liquid nitrogen spray cryotherapy was safe and associated with improvement in dysphagia and QoL without causing reflux. More intensive treatment showed a greater improvement in dysphagia and should be considered as the preferred approach.

This commentary is on the original article by Chiron et al on pages 1607–1616 of this issue.

Background and Aims: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. Approach and Results: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: −21%, TXR140; −16%, TXR140 + CVC; −13%, TXR90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR140, −2.5 kg; TXR140 + CVC, −1.7 kg; TXR90 + CVC, −1.0 kg; and CVC, −0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR140, CVC, TXR140 + CVC, and TXR90 + CVC groups, respectively. Conclusions: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

ImportanceTumor necrosis factor α (TNF) inhibitor–induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor–induced psoriasiform eruptions in children.Design, Setting, and ParticipantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor–treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor–induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and RelevanceIn this case series, paradoxical TNF inhibitor–induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.