ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors.

In the past year, four antibody-drug conjugates (ADC) were approved, nearly doubling the marketed ADCs in oncology. Among other attributes, successful ADCs optimize targeting antibody, conjugation chemistry, and payload mechanism of action. Here, we describe the development of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC for the treatment of small cell lung cancer (SCLC). We engineered a calicheamicin conjugate that lacks the acid-labile hydrazine linker that leads to systemic release of a toxic catabolite. We then screened a patient-derived xenograft library to identify SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs. Using RNA sequencing (RNA-seq) data from primary and xenograft SCLC samples, we identified seizure-related homolog 6 (SEZ6) as a surface-expressed SCLC target with broad expression in SCLC and minimal normal tissue expression by both RNA-seq and IHC. We developed an antibody targeting SEZ6 that is rapidly internalized upon receptor binding and, when conjugated to the calicheamicin linker drug, drives potent tumor regression in vitro and in vivo. These preclinical data suggest that ABBV-011 may provide a novel treatment for patients with SCLC and a rationale for ongoing phase I studies (NCT03639194).

Prostate Imaging and Data Reporting System Version 2 as a Radiology Performance Metric: An Analysis of 18 Abdominal Radiologists.

PURPOSE: To determine expected trained provider performance dispersion in Prostate Imaging and Data Reporting System version 2 (PI-RADS v2) positive predictive values (PPVs). METHODS: This single-center quality assurance retrospective cohort study evaluated 5,556 consecutive prostate MRIs performed on 4,593 patients. Studies were prospectively interpreted from October 8, 2016, to July 31, 2020, by 18 subspecialty-trained abdominal radiologists (1-22 years' experience; median MRIs per radiologist: 232, first-to-third quartile range [Q1-Q3]: 128-440; 13 interpreted at least 30 MRIs with a reference standard). Maximum prospectively reported whole-gland PI-RADS v2 score was compared to post-MRI biopsy histopathology obtained within 2 years. The primary outcome was PPV of MRI by provider stratified by maximum whole-gland PI-RADS v2 score. RESULTS: Median provider-level PPVs for the radiologists who interpreted ≥30 MRIs with a reference standard were PI-RADS 3 (22.1%; Q1-Q3: 10.0%-28.6%), PI-RADS 4 (49.2%; Q1-Q3: 41.4%-50.0%), PI-RADS 5 (81.8%; Q1-Q3: 77.1%-84.4%). Overall, the maximum whole-gland PI-RADS v2 score was PI-RADS 1 to 2 (34.6% [1,925]), PI-RADS 3 (8.5% [474]), PI-RADS 4 (21.0% [1,166]), PI-RADS 5 (18.3% [1,018]), no PI-RADS score (17.5% [973]). System-level (all providers) PPVs for maximum PI-RADS v2 scores were 20.0% (95% confidence interval [CI]: 15.7%-24.9%) for PI-RADS 3, 48.5% (95% CI: 44.8%-52.2%) for PI-RADS 4, and 80.1% for PI-RADS 5 (95% CI: 75.7%-83.9%). CONCLUSION: Subspecialty-trained abdominal radiologists with a wide range of experience can obtain consistent positive predictive values for PI-RADS v2 scores of 3 to 5. These data can be used for quality assurance benchmarking.

A survey of patients lost to follow-up after inferior vena cava filter placement.

OBJECTIVE: The objective of this study was to determine the demographics and subjective rationale for failure to present for retrieval of patients who had an inferior vena cava (IVC) filter placed. METHODS: Between January 1, 2010, and September 12, 2017, there were 242 patients who had retrievable IVC filters placed. Demographics and indications for filter placement were retrospectively analyzed. All patients who failed to have the filter retrieved were contacted by Institutional Review Board-approved telephone survey to delineate the reason that the filter was not removed. RESULTS: Of 242 patients with IVC filters placed, 53 (22%) patients presented for filter retrieval at Abington-Jefferson Health. Patients who presented for filter retrieval were statistically younger (46 years vs 65 years; P < .001). The most common indication for filter placement in both groups was preoperative placement for bariatric surgery, but this percentage was higher in the group that presented for filter retrieval (70% [37/53] in the retrieved group vs 47% [88/189] in the nonretrieved group; P = .018). After telephone survey that reached 146 patients, it was determined that 46 (32%) patients who did not return for filter retrieval were told to keep the filter in place secondary to comorbidities, 28 (19%) did not remember being instructed to follow up for retrieval, and 18 (12%) did not want another procedure. Twenty-four patients were deceased at the time of telephone survey (16%). The remainder of the patients had the filter removed at an outside institution or gave another reason. CONCLUSIONS: Our study documented a disappointingly low rate of filter retrieval. Patients with IVC filters who failed to present for retrieval were more likely to be older and frequently did not understand the complications of leaving a filter in place and the need to have the filter retrieved. Patient education should be increased to better capture patients with IVC filters and to improve retrieval rates, but our study showed that a significant percentage of patients do not have filters retrieved because of comorbidities or they do not want another procedure.

ASK1 contributes to fibrosis and dysfunction in models of kidney disease.

Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.

Endovascular management of the patent inferior mesenteric artery in two cases of uncontrolled type II endoleak after endovascular aneurysm repair.

CONTEXT: Endovascular aneurysm repair (EVAR) has well documented advantages over traditional open repair and has been widely adopted as the alternative treatment modality for abdominal aortic aneurysm. However, endoleaks specifically type II can be a significant problem with this technique leading to aortic sac expansion and potential rupture. A large number of type II endoleaks are caused by persistent inferior mesenteric artery (IMA) retrograde bleeding. Various methods to try to manage this complication have been previously described. IMA embolization via the marginal artery of Drummond, however, has not been adequately popularized as an alternative less invasive approach to the treatment of type II endoleak. CASE REPORT: Two men, ages 77 and 81, underwent uneventful EVAR for 5.5 and 5.0 cm infrarenal abdominal aortic aneurysms, respectively, using Zenith Cook(®) bifurcated stent grafts. Computed tomography angiography at 1 and 6 months postoperatively demonstrated small type II endoleaks in both cases which were followed clinically. Subsequent follow-up tomography scan at 12 months revealed persistent type II endoleaks related to retrograde filling from the IMA with significant enlargement of the aneurysm sacs. Both patients underwent successful IMA coil embolization via the marginal artery of Drummond. CONCLUSIONS: Percutaneous IMA embolization using standard endovascular techniques to access the marginal artery of Drummond is an alternative, and in our opinion, preferred technique for controlling type II endoleaks caused by a persistently patent IMA.

Retrohepatic hematoma causing caval compression after blunt abdominal trauma.

Blunt injury to the inferior vena cava (IVC) is a rare event, which occurs in 1% to 10% of blunt-trauma patients. Injuries usually result from deceleration, which causes atriocaval rupture or tearing of the hepatic veins, and are sometimes complicated by uncontrollable hemorrhage. An unusual case of focal extrinsic compression of the vessel caused by retrohepatic hemorrhage is reported, which ultimately has required no operative intervention and seems to have had no long-term ill effects. The literature on blunt injury to the IVC is reviewed, which includes a review of posttraumatic Budd-Chiari syndrome.

Leiomyosarcoma of the major peripheral arteries: case report and review of the literature.

We describe a case of primary intramural, extraluminal leiomyosarcoma of the common iliac artery. The patient presented with pelvic and leg pain and pheochromocytoma-like symptoms. The diagnosis was made intraoperatively, the tumor was resected, vascular reconstruction was performed, and postoperative radiation therapy was administered. Primary leiomyosarcoma of a major peripheral artery is extremely rare, and this report examines the clinical presentation, treatment, and prognosis of these patients.