Therapeutic response to pazopanib: case report and literature review on molecular abnormalities of aggressive prolactinomas.

Introduction: Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study, we present a case of a patient with an APRL who had a trial of multiple therapeutic modalities with the aim to provide a review of molecular abnormalities and management of APRLs by corroborating our experience with previous literature. Methods: A total of 268 articles were reviewed and 46 were included. Case reports and series, and studies that investigated the molecular and/or genetic analysis of APRLs were included. Special care was taken to include studies describing prolactinomas that would fall under the APRL subtype according to the European Society of Endocrinology guidelines; however, the author did not label the tumor as "aggressive" or "atypical". Addiontionally, we present a case report of a 56-year-old man presented with an invasive APRL that was resistant to multiple treatment modalities. Results: Literature review revealed multiple molecular abnormalities of APRLs including mutations in and/or deregulation of ADAMTS6, MMP-9, PITX1, VEGF, POU6F2, CDKN2A, and Rb genes. Mismatch repair genes, downregulation of microRNAs, and hypermethylation of specific genes including RASSF1A, p27, and MGMT were found to be directly associated with the aggressiveness of prolactinomas. APRL receptor analysis showed that low levels of estrogen receptor (ER) and an increase in somatostatin receptors (SSTR5) and epidermal growth factor receptors (EGFR) were associated with increased invasiveness and higher proliferation activity. Our patient had positive immunohistochemistry staining for PD-L1, MSH2, and MSH6, while microarray analysis revealed mutations in the CDKN2A and POU6F2 genes. Despite undergoing two surgical resections, radiotherapy, and taking dopamine agonists, the tumor continued to progress. The patient was administered pazopanib, which resulted in a positive response and the patient remained progression-free for six months. However, subsequent observations revealed tumor progression. The patient was started on PD-L1 inhibitor pembrolizumab, yet the tumor continued to progress. Conclusion: APRLs are complex tumors that require a multidisciplinary management approach. Knowledge of the molecular underpinnings of these tumors is critical for understanding their pathogenesis and identifying potential targets for precision medical therapy.

Negative Cultures for Cerebrospinal Fluid Samples taken from the Myelomeningocele Sac on the Day of Repair.

OBJECTIVE: Our goal was to evaluate the intraoperative laboratory analysis of cerebrospinal fluid (CSF) aspirated from the myelomeningocele (MMC) sac prior to the repair to determine if there was bacterial growth in the culture. METHODS: This was a retrospective analysis of the CSF cultures of 45 MMC patients operated on during the years of 2002 to 2013 at the University Pediatric Hospital. Before repairing the defect, the sac area was cleaned and three milliliters of CSF were drawn and sent for analysis for red blood cells, white blood cells, glucose level, protein level, chloride level, gram stain and culture. The CSF sample results were analyzed for irregularities in the values before proceeding with placement of a ventricular shunt. RESULTS: All the CSF samples that were studied had at least 1 abnormal value in their results, even though none grew any pathogens in the cultures analyzed. CONCLUSION: Upon CSF analysis, we found increased levels of CSF protein and other abnormal values in this population; however, none of the cultures grew any pathogens. This finding is an important tool in the evaluation of the possible etiologies of and therapeutic approaches for future shunt problems in this group of patients.

Time of Surgery in the Outcome of Cervical Spinal Cord Injury: the University of Puerto Rico Experience.

OBJECTIVE: The purpose of this study was to determine the effect of the timing of surgery on the neurological function of patients with a cervical spinal cord injury. METHODS: Retrospectively, an analysis was done of patients who underwent decompression and/or spinal cord stabilization surgeries from 2010 through 2014 for cervical trauma. All patients were older than 18 years of age, had had surgery at our facility, and had made at least 1 follow-up visit. American Spinal Injury Association (ASIA) Impairment Scale (AIS) scores were compared for patients who underwent early surgeries (less than 72 hours after trauma) and for those who underwent late surgeries (more than 72 hours after trauma). RESULTS: There were a total of 107 patients. Sixty-two patients had spinal cord injuries. The average age was 38.6 years, and 84% of the participants were male. The most common mechanism of trauma was motor vehicle accident. Twenty-nine percent of the patients developed neurogenic shock and 27% experienced respiratory failure during the first week after admission. Seventeen patients died during the study period. A multivariate analysis of AIS score improvement revealed that the only significant factor was incomplete neurological injury. There was no significant difference in the percentage of patients that improved with early surgery compared to that of those that improved after late surgery. CONCLUSION: Traumatic cervical spinal cord injury is associated with high mortality and morbidity. Early surgery was not associated with an improved neurological outcome at long-term follow-up. The benefit of early surgery was seen only in terms of decreasing each patient's length of hospital stay.

Targeted Delivery of Nanoparticulate Cytochrome C into Glioma Cells Through the Proton-Coupled Folate Transporter.

In this study, we identified the proton-coupled folate transporter (PCFT) as a route for targeted delivery of drugs to some gliomas. Using the techniques of confocal imaging, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and small interfering (siRNA) knockdown against the PCFT, we demonstrated that Gl261 and A172 glioma cells, but not U87 and primary cultured astrocytes, express the PCFT, which provides selective internalization of folic acid (FA)-conjugated cytochrome c-containing nanoparticles (FA-Cyt c NPs), followed by cell death. The FA-Cyt c NPs (100 µg/mL), had no cytotoxic effects in astrocytes but caused death in glioma cells, according to their level of expression of PCFT. Whole-cell patch clamp recording revealed FA-induced membrane currents in FA-Cyt c NPs-sensitive gliomas, that were reduced by siRNA PCFT knockdown in a similar manner as by application of FA-Cyt c NPs, indicating that the PCFT is a route for internalization of FA-conjugated NPs in these glioma cells. Analysis of human glioblastoma specimens revealed that at least 25% of glioblastomas express elevated level of either PCFT or folate receptor (FOLR1). We conclude that the PCFT provides a mechanism for targeted delivery of drugs to some gliomas as a starting point for the development of efficient methods for treating gliomas with high expression of PCFT and/or FOLR1.

Efficacy of Hydromer-Coated and Antibiotic- Impregnated Shunt Systems in Reducing Early Shunt Infections in the Pediatric Population.

OBJECTIVE: Shunt infection is the most common complication following a Cerebrospinal fluid (CSF) diversion procedure with devastating consequences. This study analyzes the efficacy of different shunt systems in reducing early shunt infections in the pediatric population. METHODS: Retrospective case study analysis of 177 pediatric patients with hydrocephalus de novo shunted using hydromer-coated (HC) shunt systems, antibiotic-impregnated (AI) shunt systems and standard non impregnated shunt systems was performed and compared for the incidence of shunt infection in the early postoperative period. RESULTS: Group A consisted of standard shunt systems with 63 patients, Group B were HC shunt systems with 67 patients and group C consisted of 47 patients with antibiotic-impregnated shunt systems. Mean age in Group A was 1.36 +/- 3.36 years Mean age in Group B was 2.32 +/- 4.69 years. Mean age in Group C: 0.64 +/- 1.70 years. In terms of shunt infections, HC group had 4 shunt infections (6.25%), as compared to the control group, where 7 patients (10.45%) had infections. The AI group had 1 infection (2.13%). When comparing HC systems versus Standard Non-Impregnated There were 3 shunt malfunction in Group A (4.8%), 2 shunt malfunction in group B (3.3%) and 0 shunt malfunction in Group C (0%). CONCLUSION: Hydromer-coated shunt systems and antibiotic-impregnated shunt system represent a superior alternative to standard shunt systems for the reduction of shunt infection in the early post operative period.