EGFR V834L and L858R Comutation Is Associated With Response to Osimertinib in Non-Small-Cell Lung Cancer.

Up-front osimertinib leads to clinical benefit in EGFR V834L and L858R comutated NSCLC.

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy.

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Mitral Annulus Disjunction and Arrhythmic Mitral Valve Prolapse: Emerging Role of Cardiac Magnetic Resonance Imaging in the Workup.

Mitral valve prolapse is a commonly described entity with a highly variable and benign course. However, it is associated with ventricular arrhythmias and sudden cardiac death in a small subset of patients. Recent studies have yielded insight into myocardial mechanics and the causation of ventricular arrhythmias in these groups of patients. Mitral annular disjunction (MAD) characterized by detachment of mitral annulus from left ventricular myocardium is associated with morphological and functional remodeling of the left ventricular myocardium. Resultant fibrosis acts as a substrate of ventricular arrhythmia and sudden cardiac death. We present two such cases of arrhythmic mitral valve prolapse associated with MAD. Cardiac magnetic resonance imaging provides excellent morphological information and also helps in the assessment of fibrosis.

Myocardial Strain Imaging Using Feature Tracking Method of Cardiac MRI: Our Initial Experience of This Novel Parameter as an Additional Diagnostic Tool.

Background Left ventricular ejection fraction (LVEF) is used as quantitative parameter to evaluate myocardial function. However, interobserver variation, limited reproducibility, and dependence on pre-load and after-load reduces its accuracy. The fall in LVEF occurs very late, when myocardial dysfunction is already advanced. Myocardial strain measurements (especially global longitudinal strain) is a new parameter to detect myocardial dysfunction before derangements in LVEF. The aim of this article is to share our experience of this novel diagnostic tool. Methods Feature tracking method of strain assessment is performed using routine long and short axis cine images of cardiac MRI (CMR). Dedicated post-processing CMR software can perform off-line analysis and provide results in form of color-coded maps, percentage values as well as strain over time curve for each myocardial segments. Results Global longitudinal strain (GLS) is more sensitive than LVEF and can identify sub-clinical left ventricular (LV) dysfunction in various cardiomyopathies. It is also an important prognostic marker in serial assessment of heart failure patients. Regional differences in strain parameters can provide clues in hypertrophic cardiomyopathy as well as amyloidosis. GLS is recommended as routine measurement in patients undergoing chemotherapy to detect LV dysfunction prior to fall in LVEF. Strain imaging can be applied to guide placement of the LV pacing lead in patients receiving cardiac resynchronization therapy. More clinical data is needed to evaluate its role in ischemic heart disease. Conclusion Strain imaging can identify LV dysfunction earlier than conventional methods and this opens a new perspective in risk stratification and therapeutic decision-making of various cardiac pathologies.

BiTE-ing into Prostate Cancer with Bispecific T-cell Engagers.

Targeting prostate-specific membrane antigen (PSMA) has important therapeutic ramifications, more recently including immune oncology. Data were recently presented on the preclinical efficacy of a half-life extended bispecific T-cell engager, AMG 160, which binds PSMA and CD3 to induce T-cell-driven cytolytic activity against prostate cancer.See related article by Deegen et al., p. 2928.

Utility of 3D CT Rib Study in Presurgical Planning of Autologous Ear Graft for Pinna Reconstruction in Microtia.

Purpose The aim of this study was to demonstrate the utility of three-dimensional computed tomography (3D) CT rib study in presurgical planning to select the autologous rib cartilage graft for pinna reconstruction. Materials and Methods Total of 35 patients of microtia for autologous rib graft from April 2017 to February 2020 were evaluated in this study. All patients had a plain low-dose multislice CT chest. The length of costal cartilages of sixth to ninth ribs bilaterally and width and height of sixth and seventh rib costal cartilage synchondrosis were measured in 3D reconstructed true size coronal images with best possible length displayed. All patients had high-resolution computed tomography (HRCT) temporal studies done to evaluate for associated anomalies in external canal, middle ear cavities, and inner ear structures. Eleven patients had simultaneous HRCT temporal bone done after plain CT chest and rest who had done recent prior study were reviewed without repetition of study. Results There were 19 males and 16 females for 3D CT rib study. Average age of the participants was 16.5 years. The average width of synchondrosis of sixth and seventh rib was 15.4 mm on right side and 14.7 mm on left side, average height of synchondrosis was 28.5 mm on right side and 30.7 mm on left side. Average length of the eighth rib costal cartilage was 88.6 mm on the right side and 90.5 mm on the left side. Average length of the ninth rib was 63.2 mm on the right side and 58.2 mm on the left side. Costal cartilage calcifications were present in 9 patients. Conclusion Preoperative 3D CT rib study provides accurate measurements of rib stock for sculpting autologous ear graft.

Untangling the Multidisciplinary Care Web: Streamlining Care Through an Immune-Related Adverse Events (IRAE) Tumor Board.

Immune-related adverse events (IRAEs) are becoming increasingly common as the use of immune checkpoint inhibitors expands into more tumor types and treatment settings. Although the majority of IRAEs are mild and can be managed in the outpatient setting by the medical oncologist, severe IRAEs can be life threatening and often require complex care coordination among multiple providers. These providers include a variety of non-oncology specialists who have interest and expertise in managing IRAEs. Multiple systems-based solutions have been proposed in the literature, but these need to be tailored to the needs and resources of each practice setting. In this article, we highlight the challenges of IRAE care by presenting an illustrative case from our institution. We then describe the format and structure of the IRAE Tumor Board established at the University of Washington/Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Finally, we discuss how this tumor board attempts to address clinical issues related to complex IRAE presentations and provide IRAE education.

The Outcome of Patients With Localized Undifferentiated Pleomorphic Sarcoma of the Lower Extremity Treated at Stanford University.

BACKGROUND: As a diagnosis of exclusion, Undifferentiated Pleomorphic Sarcoma (UPS) has unclear clinical characteristics. The objective of this retrospective cohort study is to investigate which clinical and prognostic factors of primary lower-extremity UPS will determine failure. METHODS: We retrospectively reviewed 55 primary lower-extremity UPS cases treated at Stanford between 1998 and 2015. Overall Survival (OS) and Disease-Free Survival (DFS) curves were calculated. Univariate Fisher's Exact Tests were used to examine relationships between disease recurrence, treatment, patient factors, tumor characteristics, and surgical margins. RESULTS: 5-year DFS and OS rates were 60% (95% CI, 45%-72%) and 68% (95% CI, 53%-79%), respectively. The 5-year DFS rate for patients with positive margins was 33.3% (95% CI, 5%-68%) compared with 63% (95% CI, 47%-76%) for patients with negative margins. (Log-rank, P=0.03). The OS rate for those with disease recurrence was 42% % (95% CI, 16%-67%) compared with 76% (95% CI, 59%-87%) for patients who did not have disease recurrence (log-rank, P=0.021). Local failure occurred more frequently with omission of radiation therapy (Fisher's exact test, P=0.009). CONCLUSIONS: Positive surgical margins are an important prognostic factor for predicting relapse in UPS. Relapse of any kind led to worse OS. Radiation therapy improved local control of disease but had no statistically significant effect on DFS, highlighting the need for improved diagnostics to identify those at highest risk for hematogenous metastasis and for selection of patients for adjuvant systemic treatment.

Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension.

Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders.

Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice.

Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration, and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically interferon-γ (IFN-γ) and interleukin-17A (IL-17A), to sodium transporter regulation in the kidney during angiotensin-II (Ang-II) hypertension. C57BL/6J (wild-type) mice responded to Ang-II infusion (490 ng/kg per minute, 2 weeks) with a rise in blood pressure (170 mm Hg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ(-/-)) or IL-17A (IL-17A(-/-)) exhibited a blunted rise in blood pressure (<150 mm Hg), and both the genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, Ang-II infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter, and Ste20/SPS-1-related proline-alanine-rich kinase, in both the wild-type and the IL-17A(-/-) but not in IFN-γ(-/-) mice; epithelial Na channel abundance increased similarly in all the 3 genotypes. In the proximal nephron, Ang-II infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A(-/-) and IFN-γ(-/-), but not in wild-type; the Na-phosphate cotransporter decreased in all the 3 genotypes. Our results suggest that during Ang-II hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.