Kyle Strickland

Triple-negative breast cancers (TNBCs) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Further, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0−52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS.

OBJECTIVE: This study compares the number of units of red blood cells (RBCs) transfused in patients with placenta accreta spectrum (PAS) treated with or without a multidisciplinary algorithm that includes placental uterine arterial embolization (P-UAE) and selective use of either immediate or delayed hysterectomy. STUDY DESIGN: This is a retrospective study of deliveries conducted at a tertiary care hospital from 2001 to 2018 with pathology-confirmed PAS. Those with previable pregnancies or microinvasive histology were excluded. To improve the equity of comparison, analyses were made separately among scheduled and unscheduled cases, therefore patients were assigned to one of four cohorts as follows: (1) scheduled/per-algorithm, (2) scheduled/off-algorithm, (3) unscheduled/per-algorithm, or (4) unscheduled/off-algorithm. Primary outcomes included RBCs transfused and estimated blood loss (EBL). Secondary outcomes included perioperative complications and disposition. RESULTS: Overall, 95 patients were identified, with 87 patients meeting inclusion criteria: 36 treated per-algorithm (30 scheduled and 6 unscheduled) and 51 off-algorithm patients (24 scheduled and 27 unscheduled). Among scheduled deliveries, 9 (30.0%) patients treated per-algorithm received RBCs compared with 20 (83.3%) patients treated off-algorithm (p < 0.01), with a median (interquartile range [IQR]) of 3.0 (2.0, 4.0) and 6.0 (2.5, 7.5) units transfused (p = 0.13), respectively. Among unscheduled deliveries, 5 (83.3%) per-algorithm patients were transfused RBCs compared with 25 (92.6%) off-algorithm patients (p = 0.47) with a median (IQR) of 4.0 (2.0, 6.0) and 8.0 (3.0, 10.0) units transfused (p = 0.47), respectively. Perioperative complications were similar between cohorts. CONCLUSION: A multidisciplinary algorithm including P-UAE and selective use of delayed hysterectomy is associated with a lower rate of blood transfusion in scheduled but not unscheduled cases. KEY POINTS: · An algorithm with delayed hysterectomy had less transfusion in scheduled, but not unscheduled, cases.. · Over time, more cases were managed per algorithm; among scheduled cases, the transfusion rate and volume transfused decreased.. · There were similar transfusion outcomes among off-algorithm cases, regardless if delivery was scheduled..