MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.

Drug-induced linear IgA bullous dermatosis in a patient with a vancomycin-impregnated cement spacer.

Linear IgA bullous dermatosis (LABD) is an autoimmune blistering rash caused by IgA autoantibodies against the epidermal basement membrane zone. It commonly is drug induced, often in association with systemic vancomycin. We report a case of a previously healthy 77-year-old man who developed a diffuse macular rash and hemorrhagic bullae on the left leg 10 days after placement of a vancomycin-impregnated cement spacer (VICS) during a revision knee arthroplasty and initiation of postoperative treatment with intravenous (IV) vancomycin. The lesions initially were limited to the leg in which the hardware was placed, but the patient later developed painful palmoplantar and oropharyngeal blisters as well as edematous, erythematous plaques on the back and buttocks. A punch biopsy from a lesion on the left thigh revealed neutrophil-rich subepidermal bullae, and immunofluorescence revealed linear IgA and C3 deposition along the dermoepidermal junction, confirming a diagnosis of LABD. This report illustrates the importance of considering antibiotic-impregnated cement spacers, which frequently are used to manage prosthetic joint infections, as potential culprits in patients with cutaneous eruptions.

Skin cancer in the military: A systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel.

BACKGROUND: Occupational sun exposure is a well-studied risk factor for skin cancer development, but more work is needed to assess melanoma and nonmelanoma skin cancer risk among US military personnel to improve education and screening efforts in this population. OBJECTIVE: To conduct an extensive review of skin cancer risks for US military personnel to inform preventive education, diagnosis, and treatment efforts to better protect these individuals from future skin cancer development. METHODS: A systematic review of published studies on the subject of melanoma and nonmelanoma skin cancer in military personnel was conducted. RESULTS: A total of 9 studies describing skin cancer incidence in the US military were identified, with 4 studies specific to melanoma. The study findings reveal an increased risk for melanoma associated with service in the military or prisoner of war status. Service in tropical environments was associated with an increased incidence of both melanoma and nonmelanoma skin cancer among World War II soldiers. Two studies found that increased melanoma risk was also branch dependent, with the highest rates among the United States Air Force. Several of the reviewed studies implicated increased sun exposure during military service and lack of sufficient sun protection as the causes of higher rates of skin cancer among US military and veteran populations as compared with among the nonmilitary population in the United States. LIMITATIONS: The reviewed articles have variable results; a prospective randomized controlled trial would be helpful to develop interventions that mitigate skin cancer risk in the US military. CONCLUSION: This review identifies an abundance of evidence for an increased risk for skin cancer development among US active duty and veteran populations.

Erythematous plaques and papules on a premature infant.

A 2240 gram boy was born at 33.2 weeks gestation with nonblanching, deeply erythematous plaques and papules on the back, flanks, and scalp (Figure 1). His mother was GBS positive and on antibiotic suppression for prior cutaneous MRSA and urinary tract infections. Intrapartum intravenous Penicillin G was administered, and the amniotic sac was artificially ruptured 4 hours prior to delivery to facilitate labor. The delivery was uncomplicated without concern for chorioamnionitis, but the patient initially required CPAP for respiratory distress with 1-minute and 5-minute Apgar scores of 7 and 8, respectively. A skin punch biopsy is shown (Figure 2).

Impaired bone formation in Pdia3 deficient mice.

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] is crucial for normal skeletal development and bone homeostasis. Protein disulfide isomerase family A, member 3 (PDIA3) mediates 1α,25(OH)2D3 initiated-rapid membrane signaling in several cell types. To understand its role in regulating skeletal development, we generated Pdia3-deficient mice and examined the physiologic consequence of Pdia3-disruption in embryos and Pdia3+/- heterozygotes at different ages. No mice homozygous for the Pdia3-deletion were found at birth nor were there embryos after E12.5, indicating that targeted disruption of the Pdia3 gene resulted in early embryonic lethality. Pdia3-deficiency also resulted in skeletal manifestations as revealed by µCT analysis of the tibias. In comparison to wild type mice, Pdia3 heterozygous mice displayed expanded growth plates associated with decreased tether formation. Histomorphometry also showed that the hypertrophic zone in Pdia3+/- mice was more cellular than seen in wild type growth plates. Metaphyseal trabecular bone in Pdia3+/- mice exhibited an age-dependent phenotype with lower BV/TV and trabecular numbers, which was most pronounced at 15 weeks of age. Bone marrow cells from Pdia3+/- mice exhibited impaired osteoblastic differentiation, based on reduced expression of osteoblast markers and mineral deposition compared to cells from wild type animals. Collectively, our findings provide in vivo evidence that PDIA3 is essential for normal skeletal development. The fact that the Pdia3+/- heterozygous mice share a similar growth plate and bone phenotype to nVdr knockout mice, suggests that PDIA3-mediated rapid membrane signaling might be an alternative mechanism responsible for 1α,25(OH)2D3's actions in regulating skeletal development.

Pediatric tectal plate gliomas: clinical and radiological progression, MR imaging characteristics, and management of hydrocephalus.

OBJECT: Tectal plate gliomas are generally low-grade astrocytomas with favorable prognosis, and observation of the lesion and management of hydrocephalus remain the mainstay of treatment. METHODS: A cohort of patients with tectal plate gliomas at 2 academic institutions was retrospectively reviewed. RESULTS: Forty-four patients with a mean age of 10.2 years who harbored tectal plate gliomas were included in the study. The mean clinical and radiological follow-up was 7.6 ± 3.3 years (median 7.9 years, range 1.5-14.7 years) and 6.5 ± 3.1 years (median 6.5 years, range 1.1-14.7 years), respectively. The most frequent intervention was CSF diversion (81.8% of patients) followed by biopsy (11.4%), radiotherapy (4.5%), chemotherapy (4.5%), and resection (2.3%). On MR imaging tectal plate gliomas most commonly showed T1-weighted isointensity (71.4%), T2-weighted hyperintensity (88.1%), and rarely enhanced (19%). The initial mean volume was 1.6 ± 2.2 cm(3) and it increased to 2.0 ± 4.4 cm(3) (p = 0.628) at the last follow-up. Frontal and occipital horn ratio (FOHR) and third ventricular width statistically decreased over time (p < 0.001 and p < 0.05, respectively). CONCLUSIONS: The authors' results support existing evidence that tectal plate gliomas frequently follow a benign clinical and radiographic course and rarely require any intervention beyond management of associated hydrocephalus.

Return to system within 30 days of pediatric neurosurgery.

OBJECT: Quality assessment measures have not been well developed for pediatric neurosurgical patients. This report documents the authors' experience in extracting information from an administrative database to establish the rate of return to system within 30 days of pediatric neurosurgical procedures. METHODS: Demographic, socioeconomic, and clinical characteristics were prospectively collected in administrative, business, and operating room databases. The primary end point was an unexpected return to the hospital system within 30 days from the date of a pediatric neurosurgical procedure. Statistical methods were used to identify clinical and demographic factors associated with the primary end point. RESULTS: There were 1358 pediatric neurosurgical procedures performed in the Children's Healthcare of Atlanta operating rooms in 2012, with 37.4% of these surgeries being preceded by admissions through the emergency department. Medicare or Medicaid was the payor for 54.9% of surgeries, and 37.6% of surgeries were shunt related. There were 148 unexpected returns to the system within 30 days after surgery, and in 109 of these cases, the patient had a presenting complaint that was attributable to the index surgery (related returns). The most common complaints were headache, nausea, vomiting, or seizure after shunt revision or cranial procedures (n = 62). The next most common reason for re-presentation was for wound concerns (n = 30). Thirty-seven of the 109 related returns resulted in a reoperation. The monthly rate of related returns was 8.1% ± 2.5% over the 12-month study period. When using related returns as the dependent variable, the authors found that patients who underwent a shunt-related surgery were both more likely to unexpectedly return to the system (OR 1.86, p = 0.008) and to require surgery upon readmission (OR 3.28, p = 0.004). Because an extended hospitalization shortened the window of time for readmission after surgery, extended length of stay was protective against return to system within 30 days of surgery. Importantly, if related and unrelated returns were analyzed together as the dependent variable (n = 148), no independent clinical and demographic risk factor could be identified. CONCLUSIONS: Quality assessment measures need to be clearly and carefully defined, as the definition itself will impact the analytical results. Clinicians must play a leading role in the development of these measures to ensure their clinical meaningfulness.

Disruption of Pdia3 gene results in bone abnormality and affects 1alpha,25-dihydroxy-vitamin D3-induced rapid activation of PKC.

1,25-dihydroxy-vitamin D3 [1alpha,25(OH)2D3] is a critical regulator of bone development. Protein disulfide isomerase A3 (Pdia3) is a multifunctional protein that has been associated with rapid membrane-initiated signalling by 1alpha,25(OH)2D3 in several cell types. To identify the physiological roles of Pdia3 in skeletal development, we generated Pdia3-deficient mice. No homozygous mice were observed at birth, indicating that the targeted disruption of the Pdia3 gene resulted in embryonic lethality. Pdia3 deficiency also resulted in skeletal manifestations as revealed by muCT analysis of femurs from 15-week-old heterozygous mice. The Pdia3+/- mice had increased metaphyseal bone volume and trabeculae compared to Pdia3+/+ mice. In contrast, the area and thickness of cortical bone at the femoral mid-diaphysis of Pdia3+/+ mice significantly exceeded that of Pdia3+/- mice. In vitro studies in osteoblast-like MC3T3-E1 cells showed that silencing of Pdia3 abolished 1alpha,25(OH)2D3-induced rapid activation of protein kinase C (PKC) while overexpression of Pdia3 resulted in augmentation of PKC activity by 1alpha,25(OH)2D3. Taken together, these data indicated that Pdia3 plays a crucial role in 1alpha,25(OH)2D3-regulated bone formation and the Pdia3-PKC signalling pathway might be involved in this process.