Presbyterian Hospital (New York City)

BACKGROUND:Endovascular transvenous embolization of spinal cerebrospinal fluid-venous fistulas (CVFs) has been shown in small studies to be a safe and effective treatment for spontaneous intracranial hypotension (SIH). OBJECTIVE:To validate the safety and effectiveness of this procedure and to describe catheterization techniques available to safely perform these embolization procedures. RESULTS:A total of 21 patients with confirmed CVF underwent 23 endovascular embolization procedures; 18 (86%) patients achieved both clinical and radiographic resolution of their SIH. There were no major neurologic complications from any procedure. One patient had postoperative pulmonary embolism and deep vein thrombosis. The most common side effects were prolonged symptoms of rebound intracranial hypertension (29%) and prolonged back pain with radiculopathy (24%). The azygous vein was used for catheterizing the level of interest in 83% of embolization procedures; the lumbar ascending vein was used for catheterization in 17% of the procedures; and direct catheterization of the segmental/foraminal vein at the level of interest was performed in 61% of the procedures. The epidural venous plexus was accessed and traversed to the level of interest in 39% of the procedures. CONCLUSION:Endovascular transvenous embolization of CVF is a safe, well-tolerated, and effective treatment for SIH. Given the variability of the venous anatomy, there are multiple routes of catheterization that can be performed to access the level of interest when performing these procedures.

Purpose/Objective(s) Prognostic gene expression testing of primary tumor tissue has become widely adopted for localized prostate cancer risk stratification. Recent retrospective analyses of clinical trials have examined such testing in metastatic hormone-sensitive disease but little has been reported outside of this context. Here we examine the Decipher prostate genomic classifier (GC) used in the context of routine clinical practice. Materials/Methods Clinical and transcriptomic data from clinical use of the GC between 2013-2022 were linked with real-world data (RWD) aggregated from insurance claims, pharmacy records, and electronic health record (EHR) data. Patients were anonymously linked between datasets by deterministic methods through a de-identification engine using encrypted tokens. A hierarchical claims-based algorithm was used to identify de novo distant metastasis in the patient’s record. De novo metastasis was defined using administrative claims and diagnosis codes within 90 days from initial prostate cancer diagnosis and at least 90 days earlier than non-prostate cancer diagnosis (if present), excluding a set of codes identifying metastases without specification of sites or for pelvic lymph node metastases. The distribution of GC scores in these samples was compared to localized prostate cancer after matching on baseline clinical and pathological factors drawn from 116,971 patients who received GC testing. Results A total of 92,976 patients with Decipher prostate GC were successfully linked to RWD, including 53,871 from biopsy and 39,105 from radical prostatectomy (RP) tests. De novo metastases were identified in 194 patients (0.21%) and compared to a matched set of 13,192 patients with localized disease. Among patients with de novo metastasis, the median age at Decipher testing was 69 years (IQR 63, 75), median percentage of positive cores was 58% (IQR 33-92%), median PSA was 14 ng/mL (IQR 6.3- 47) and 70% had NCCN high or very high-risk disease at diagnosis. Compared to the matched set 25% of metastatic patients had PSA > 50 vs. 5% for localized patients. Median Decipher score for metastatic patients was 0.88 (IQR 0.56, 0.98) compared to 0.69 (IQR 0.44, 0.9) and 0.46 (0.29, 0.68) in the matched and unmatched localized patient cohorts, respectively. Conclusion Using the largest linkage of transcriptomic and clinical data to date, we developed algorithms to identify de-novo metastatic disease from a cohort of patients tested with a GC. These patients tended to have high PSA and NCCN risk groups at time of diagnosis and accordingly had substantially elevated GC scores. This unique resource could be leveraged to enhance understandings of de novo metastatic disease biology, patterns of care and treatment effectiveness.

BACKGROUND:Mutations in ESR1 are the most common mechanism of acquired resistance to treatment with an aromatase inhibitor plus a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor for advanced breast cancer. Camizestrant, a next-generation selective estrogen-receptor (ER) degrader and complete ER antagonist, has shown antitumor activity in ER-positive advanced breast cancer. METHODS:We tested patients with advanced breast cancer with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative tumors for ESR1 mutations in circulating tumor DNA (ctDNA) once every 2 to 3 months. All the patients had received at least 6 months of first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Patients who were found to have an ESR1 mutation and did not have radiologic progression were assigned in a 1:1 ratio to switch to camizestrant (75 mg once daily) with a continued CDK4/6 inhibitor plus placebo in place of an aromatase inhibitor or to continue to receive an aromatase inhibitor plus a CDK4/6 inhibitor plus placebo in place of camizestrant. The primary outcome was investigator-assessed progression-free survival. RESULTS:A total of 3256 patients were tested for an ESR1 mutation. The 315 eligible patients were assigned to switch to camizestrant (157 patients) or to continue to receive an aromatase inhibitor (158 patients). At an interim analysis at a median follow-up of 12.6 months, the median progression-free survival was 16.0 months (95% confidence interval [CI], 12.7 to 18.2) in the camizestrant group and 9.2 months (95% CI, 7.2 to 9.5) in the aromatase-inhibitor group (hazard ratio for progression or death, 0.44; 95% CI, 0.31 to 0.60; P<0.0001). The median time until a deterioration in the patient-reported global health status and quality of life occurred was 21.0 months with camizestrant and 6.4 months with an aromatase inhibitor (hazard ratio, 0.54; 95% CI, 0.34 to 0.84). The frequency of discontinuation because of adverse events was 1.3% with camizestrant and 1.9% with an aromatase inhibitor. CONCLUSIONS:In patients with ER-positive, HER2-negative advanced breast cancer with an ESR1 mutation that emerged during treatment, those who were switched to camizestrant with continuation of a CDK4/6 inhibitor during first-line therapy had significantly longer progression-free survival than those who maintained the aromatase-inhibitor combination. (Funded by AstraZeneca; SERENA-6 ClinicalTrials.gov number, NCT04964934.).

BACKGROUND:Zanidatamab, a dual human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody, previously demonstrated encouraging antitumour activity and a manageable safety profile in patients with treatment-refractory HER2-expressing gastro-oesophageal adenocarcinoma. Here, we evaluated the antitumour activity and safety of zanidatamab plus chemotherapy in first-line HER2-positive advanced gastro-oesophageal adenocarcinoma. METHODS:This phase 2 trial enrolled patients in Canada, South Korea, and the USA who were aged 18 years and older with untreated, metastatic, or advanced HER2-positive gastro-oesophageal adenocarcinoma (HER2 IHC 3+ or 2+ by local or central assessment [part 1]; HER2 IHC 3+ or 2+ with FISH+ by central assessment [part 2]). Eligible patients, with an Eastern Cooperative Oncology Group performance status of 0 or 1 received zanidatamab intravenously plus standard chemotherapy (CAPOX [capecitabine plus oxaliplatin], FP [5-fluorouracil [5-FU] plus cisplatin], or modified FOLFOX6 [mFOLFOX6; leucovorin, 5-FU, and oxaliplatin]). In our study, part 1 aimed to characterise the safety and tolerability of zanidatamab and find the recommended dose when administered with combination chemotherapy and part 2 aimed to evaluate the antitumour activity of zanidatamab administered with combination chemotherapy in patients receiving first-line treatment for HER2-expressing advanced gastro-oesophageal adenocarcinoma. Two dosing schemes for zanidatamab were used in this study: a weight-based regimen and a two-tiered flat dosing regimen. In the CAPOX and FP groups, patients received either 30 mg/kg zanidatamab or 1800 mg or 2400 mg (patients weighing <70 kg and ≥70 kg, respectively) every 3 weeks. In the CAPOX group, patients also received 1000 mg/m2 capecitabine orally twice daily on days 1-14 every 3 weeks, plus 130 mg/m2 oxaliplatin intravenously every 3 weeks. In the FP cohort, patients also received 80 mg/m2 cisplatin intravenously every 3 weeks, plus 800 mg/m2 5-FU per day continuous intravenous infusion on days 1-5 every 3 weeks. In the mFOLFOX6 group, patients received either 20 mg/kg zanidatamab or 1200 mg or 1600 mg for patients weighing under 70 kg or 70 kg and above, respectively, every 2 weeks, plus 400 mg/m2 intravenous leucovorin every 2 weeks, 85 mg/m2 intravenous oxaliplatin every 2 weeks, and 1200 mg/m2 5-FU per day as a continuous intravenous infusion for 48 h every 2 weeks. mFOLFOX6-1 included the administration of a 400 mg/m2 5-FU intravenous bolus on days 1 and 15; mFOLFOX6-2 omitted this 5-FU bolus. The primary endpoints of part 1 were safety and tolerability, which included frequencies of dose-limiting toxicities and dose reductions of zanidatamab and chemotherapy. The primary antitumour activity endpoint of part 2 was confirmed objective response rate assessed in the response-evaluable analysis set. Secondary endpoints included objective response rate, duration of response, disease control rate, clinical benefit rate, progression-free survival, and overall survival. Safety outcomes were assessed in all treated patients. We report the results from an interim analysis. This trial is registered at ClinicalTrials.gov (NCT03929666) and is complete for enrolment. FINDINGS:Between Aug 29, 2019, and Feb 18, 2022, 46 patients were enrolled (39 [85%] were male; seven [15%] were female; 28 [61%] were white, 17 [37%] were Asian, and 43 [93%] were not Hispanic or Latino). Median follow-up was 47·9 months (IQR 39·2-53·7); eight (17%) patients were on treatment and 19 (41%) were in survival follow-up. The confirmed objective response rate was 76·2% (95% CI 60·5-87·9) with a median duration of response of 18·7 months (95% CI 10·4-44·1). The median progression-free survival was 12·5 months (95% CI 8·2-21·8) and median overall survival was 36·5 months (23·6-not estimable). The disease control rate was 88·1% (95% CI 74·4-96·0) and clinical benefit rate was 78·6% (95% CI 63·2-89·7). In part 1, there were no dose-limiting toxicities in six patients treated with zanidatamab plus CAPOX. One (50%) of two patients treated with zanidatamab plus FP had dose-limiting toxicities of diarrhoea and acute kidney injury (both grade 3). Two dose-limiting toxicities of diarrhoea (both grade 3) occurred in 2 (15%) of 13 patients receiving 5-FU 400 mg/m2 bolus on day 1 and 15 as part of the zanidatamab plus mFOLFOX6-1 regimen. 30 (65%) patients had treatment-related grade 3 or 4 adverse events. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (18 [39%]; five [24%] in the 21 patients after implementing mandatory antidiarrhoeal prophylaxis) and hypokalaemia (ten [22%]). Six (13%) patients discontinued zanidatamab due to adverse events. No treatment-related deaths occurred. INTERPRETATION:Zanidatamab plus chemotherapy as first-line treatment of HER2-positive advanced gastro-oesophageal adenocarcinoma demonstrated clinically meaningful and durable antitumour activity, with a manageable safety profile. FUNDING:Jazz Pharmaceuticals, Zymeworks.

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.