Plk1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling.

Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner. Gene-expression analysis identified an AR-independent synergy-specific gene set signature upregulated upon abiraterone treatment that is dominated by pathways related to mitosis and the mitotic spindle. Abiraterone treatment alone caused defects in mitotic spindle orientation, failure of complete chromosome condensation, and improper cell division independently of its effects on AR signaling. These effects, although mild following abiraterone monotherapy, resulted in profound sensitization to the antimitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cancer cell death and entosis. In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared with either agent alone. Overall, this work establishes a mechanistic basis for the phase II clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment. SIGNIFICANCE: Abiraterone treatment induces mitotic defects that sensitize cancer cells to Plk1 inhibition, revealing an AR-independent mechanism for this synergistic combination that is applicable to a variety of cancer types.

Ambulatory Pain Management in the Pediatric Patient Population.

PURPOSE OF REVIEW: Outpatient surgery in the pediatric population has become increasingly common. However, many patients still experience moderate to severe postoperative pain. A poor understanding of the extent of pain after pediatric ambulatory surgery and the lack of randomized control studies of pain management of the outpatient necessitate this review of scientific evidence and multimodal analgesia. RECENT FINDINGS: A multimodal approach to pain management should be applied to the ambulatory setting to decrease postoperative pain. These include non-pharmacological techniques, multimodal pharmacologics, and neuraxial and peripheral nerve blocks. Postoperative pain management in pediatric ambulatory surgical patients remains suboptimal at most centers due to limited evidence-based approach to postoperative pain control. Pediatric ambulatory pain management requires a multipronged approach to address this inadequacy.

Rapidly lethal secondary hemophagocytic lymphohistiocytosis predicted by fluorodeoxyglucose positron-emission tomography/computed tomography.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare disease with either an indolent or aggressive course. A 29-year-old male presented with fever, polyarthralgias, splenomegaly, retroperitoneal adenopathy, and laboratory findings consistent with Epstein-Barr-mediated sHLH. Consistent with a prior survival analysis by Kim et al., splenic maximum standardized uptake value (SUVmax) >2.52 and bone marrow SUVmax >3.13 on 18F- fuorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) predicted an aggressive disease with poor treatment response. Despite optimal treatment, the patient rapidly progressed to death within 3 months of symptom onset. This case underscores the potential lethal nature of sHLH, and the evolving role of 18FDG-PET/CT in predicting disease severity and treatment response.

Inferior vena cava syndrome on skeletal scintigraphy secondary to metastatic prostate cancer.

This interesting image illustrates an unusual case of inferior vena cava (IVC) syndrome from prostate cancer retroperitoneal adenopathy initially identified with skeletal scintigraphy. IVC syndrome is an infrequent occurrence resulting from extrinsic compression or intraluminal occlusion of the vessel. Whole-body planar skeletal scintigraphy showed a stable left sacroiliac metastasis and increased soft tissue uptake throughout the lower hemibody up to the lower chest level. Computed tomography (CT) demonstrated extrinsic compression of the IVC from metastatic retroperitoneal adenopathy. This represents a rare presentation of IVC syndrome in prostate cancer with characteristic appearance on skeletal scintigraphy of Fisherman's Wader's sign, that should prompt confirmatory anatomic imaging.

Symmetric, bilateral upper and lower extremity lucent lesions in a patient with Gaucher's disease on enzyme replacement therapy.

We report a case of a 6-year old girl with known type 3 Gaucher's Disease on enzyme replacement therapy who developed bilateral, symmetric osteolytic lesions in her humeri and femurs. While this manifestation of Gaucher's disease has been previously documented, it is an exceedingly rare variation. We observe that this patient shares 2 commonalities with 3 other patients reported in the literature to present with this phenotype. First, the patient's L444P/L444P genotype, present in approximately 11% of all Gaucher's patients, was also seen in these other patients. Second, like the other patients, this patient was treated with enzyme replacement therapy. It is unknown whether there is a correlation between these 2 independent variables and this rare phenotype, and further investigation may be warranted.

Bilateral End-Organ Endophthalmitis in Setting of Serratia marcescens Urosepsis on 18F-FDG PET/CT.

Endogenous endophthalmitis is an uncommon infection of the internal tissues of the eye resulting from a bloodborne infection. We present the case of an 89-year-old man with Serratia marcescens urosepsis with multifocal end-organ infection on F-FDG PET/CT including aortitis, splenic abscess, septic arthritis, thoracolumbar discitis-osteomyelitis, and culture-confirmed bilateral endogenous endophthalmitis. Endophthalmitis-related intraconal ocular space uptake was clearly distinguishable from normal conal space extraocular muscle activity. Although sepsis responded to treatment, endophthalmitis led to complete vision loss. This case report presents PET/CT description of a rare and difficult-to-treat Serratia marcescens endogenous endophthalmitis, which usually has a poor visual outcome.