FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Inappropriate helicopter emergency medical services transports: results of a national cohort utilization review.

BACKGROUND: Medical transport using helicopter emergency medical services (HEMS) has rapidly proliferated over the past decade. Because of issues of cost and safety, appropriate utilization is of increasing concern. OBJECTIVE: This study sought to describe the medical appropriateness of HEMS transports, using established guidelines, in a large national patient cohort. METHODS: A review was performed of all flights designated as inappropriate by a large national air medical company, Air Evac EMS Inc. (which operates Air Evac Lifeteam [AEL]), for the period from January 1, 2009, through December 31, 2009. Every flight was reviewed initially through a resource utilization process as well as a utilization review process. Medical appropriateness review criteria were derived from the Medicare Benefit Policy Manual and industry guidelines outlined by the Commission on Accreditation of Medical Transport Systems (CAMTS), Air Medical Physicians Association (AMPA) position papers, the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report (MMWR) Guidelines for Field Triage, and published clinical peer-reviewed articles, as well as previous interactions with Medicare contractors and reimbursement appeal decisions. Higher scrutiny was given to flights of <30 or >100 miles. Records indicating a possible inappropriate flight (i.e., review criteria were not satisfied, but special circumstances existed) were further reviewed by a senior quality assurance/quality improvement (QA/QI) nurse and/or senior medical director and were categorized. RESULTS: During the study period, 27,697 flights were completed and reviewed, with 582 (2.1%) flights identified for further review by a senior QA/QI nurse and/or senior medical director. Of those, 367 (1.3%) were determined to be medically inappropriate flights. Inappropriate flights were most often on-scene flights (59.9%), were most often for adult patients (92.9%; median age 56.9 years; 25-75% interquartile range 42-75 years), and most often represented medical diagnoses (57.8%). CONCLUSIONS: Based on established criteria, only 1.3% of total flights were determined to be inappropriate. This large national cohort demonstrated compliance with current industry standards.

Outcome measures for emergency medicine residency graduates: do measures of academic and clinical performance during residency training correlate with American Board of Emergency Medicine test performance?

OBJECTIVES: Emergency medicine (EM) residency programs are increasingly asked to have measurable outcomes of residents' performance. Successful completion of the written and oral American Board of Emergency Medicine (ABEM) examinations is one key outcome. In the clinical practice of EM, emergency physicians (EPs) are often measured by their clinical productivity (patients per hour). This study explored the correlation between these measures of academic and clinical performance and hypothesized that clinical productivity would have a positive association with ABEM performance. METHODS: A prospective written survey was sent to all EPs completing training at an established Midwest 3-year EM residency program between 1994 and 2005 (53,000 annual visits in 1994 to 65,000 annual visits in 2005). Physicians self-reported their national ABEM written and oral board scores in a blinded fashion. Simulated oral board scores and senior written in-training examination scores were also recorded. Postgraduate Year 3 (PGY3) clinical productivity was calculated as annual patient encounters divided by hours worked. Correlations among these variables were assessed by Pearson's correlation coefficient, with p < 0.05 being considered statistically significant. Multiple regression analysis was performed for ABEM oral and written examination scores. RESULTS: Fifty-six of 85 residents responded to the initial survey. There was no significant correlation between clinical productivity and ABEM scores, either written (r = -0.021, p = 0.881) or oral (r = -0.02, p = 0.879). There was also no significant correlation between productivity and simulated oral board scores (r = 0.065, p = 0.639) of PGY3 in-training scores (r = 0.078, p = 0.57). As previously reported, there were positive and significant correlations between PGY3 in-service scores and ABEM written examination scores (r = 0.60, p < 0.0001), as well as ABEM oral and written examination scores (r = 0.51, p < 0.0001). Multiple regression analysis revealed only the PGY3 in-training examination was a significant predictor of the ABEM oral and written scores (p < 0.001). CONCLUSIONS: PGY3 resident clinical productivity, when measured as patients per hour, correlated poorly with academic performance when measured by written and oral ABEM scores. The PGY3 in-training examination was predictive of the ABEM written and oral examination scores.

Diagnostic utility of the genital Gram stain in ED patients.

OBJECTIVE: The study aimed to determine the diagnostic usefulness of the genital Gram stain in an emergency department (ED) population. METHODS: A linked-query of an urban, tertiary-care, university- affiliated hospital laboratory database was conducted for all completed Chlamydia trachomatis and Neisseria gonorrhoeae DNA probes, Trichomonas vaginalis wet preps, and genital Gram stains performed on ED patient visits between January and December 2004. Positive criteria for a Gram stain included greater than 10 white blood cells per high-power field, gram-negative intracellular/extracellular diplococci (suggesting N gonorrhoeae), clue cells (suggesting T vaginalis), or direct visualization of T vaginalis organisms. DNA probes were used as the gold standard definition for N gonorrhoeae and C trachomatis infection. RESULTS: Of 1511 initially eligible ED visits, 941 were analyzed (genital Gram stain and DNA probe results both present), with a prevalence of either C trachomatis or N gonorrhoeae of 11.4%. A positive genital Gram stain was 75.7% sensitive and 43.3% specific in diagnosing either C trachomatis and/or N gonorrhoeae infection, and 80.4% sensitive and 32.2% specific when the positive cutoff was lowered to more than 5 white blood cells/high-power field. No Gram stains were positive for T vaginalis (with 47 positive wet mounts), and clue cells were noted on 117 Gram stains (11.6%). CONCLUSION: Gram stains in isolation lack sufficient diagnostic ability to detect either C trachomatis or N gonorrhoeae infection in the ED.

The impact of partial breast reconstruction using reduction techniques on postoperative cancer surveillance.

BACKGROUND: Partial breast reconstruction using reduction techniques has recently increased in popularity. Some fear that combining breast conservation therapy with partial breast reconstruction alters the architecture and will affect patterns of local recurrence and make postoperative cancer surveillance more difficult. The purpose of this series was to evaluate long-term postoperative cancer surveillance. METHODS: The authors retrospectively reviewed the charts and mammograms of patients (n = 17; average follow-up, 6.3 years) who underwent the oncoplastic reduction technique before 2004. Mammography sensitivity was determined by measuring breast density, qualitative changes, and time until mammographic stabilization was determined. These data were compared with those of a control group from the same time period who underwent breast conservation therapy alone (n = 17; average follow-up, 5.9 years). RESULTS: Typical mammographic findings, including architectural distortion, cysts, and calcifications, were similar between the two groups. There was no significant difference in breast density scores. The oncoplastic reduction group had longer times to mammographic stabilization (21.2 versus 25.6 months, p = 0.23). There was a trend toward a greater number of postoperative mammograms and ultrasounds in the study group when indexed per follow-up year. The rate of tissue sampling in the study group was significantly higher (53 percent) than that in the control group (18 percent). CONCLUSIONS: The oncoplastic reduction technique remains safe and effective, without significantly affecting postoperative surveillance. Mammographic findings were similar to those observed in patients with breast conservation therapy alone, and sensitivity was not affected. It takes longer to achieve mammographic stability and more patients in the oncoplastic group will require additional diagnostic testing.

The use of fluorescein dye as a predictor of mastectomy skin flap viability following autologous tissue reconstruction.

BACKGROUND: The skin sparing mastectomy continues to allow improvement in the esthetic outcome after immediate autologous breast reconstruction. However, native skin flap necrosis does occur and can significantly jeopardize the result. The purpose of this series was to evaluate objectively the utility of fluorescein dye as a tool to assist with evaluation of eventual flap viability or flap necrosis. METHODS: Fifty consecutive periareolar mastectomy flaps were evaluated after autologous reconstruction. Patient demographics and risk factors were queried. The mastectomy skin flaps were evaluated clinically for viability and managed appropriately. Flap inset was performed. Intravenous fluorescein dye was then given, and areas of nonfluorescence were marked (size and location documented). Photodocumentation was performed intraoperatively and 1 week postoperatively. Areas of skin survival and skin necrosis were documented, and comparisons were made. RESULTS: The type of reconstructions included TRAM flap (n = 31), and latissimus dorsi with expander (n = 19), with an average age of 50 years (range: 38-68 years). Patient demographics included previous radiation therapy (n = 5), smoking history (n = 14), hypertension (n = 13), and previous breast scars (n = 16). Skin fluorescence corresponded with flap survival (n = 48/50), giving a positive predictive value of 96%. Two flaps (1 patient) had some skin necrosis despite full fluorescence; however, she was eventually diagnosed with hepatitis C vasculitis. Of the 21 flaps with areas of nonfluorescence, skin necrosis was present in 5 of 21, a negative predictive value of 25%. The majority of areas of nonfluorescence were less than 4 cm2 and had full flap survival (n = 16/21). Two flaps with nonfluorescence of <4 cm2 and previous radiation therapy had skin necrosis. All flaps with areas >4 cm2 had skin necrosis, unless proximally located on the skin flaps. CONCLUSIONS: Fluorescein dye is a sensitive test for determining native mastectomy skin flap viability after autologous reconstruction; however, viability is underpredicted. Location on the skin flaps, size of nonfluorescence, as well as history of radiation therapy should be taken into consideration. Areas of nonfluorescence <4 cm2 typically survive, except in the irradiated breast. Any area of nonfluorescence >4 cm2 typically does not survive, except when located more proximally on the flap.

Effects of radiation therapy on pedicled transverse rectus abdominis myocutaneous flap breast reconstruction.

Radiotherapy is being increasingly used in the treatment of breast cancer after breast conservation as well as after total mastectomy. The effect of radiation on pedicled transverse rectus abdominis myocutaneous (TRAM) flap reconstruction is examined. A retrospective review of 199 patients undergoing 232 pedicled TRAM flap reconstructions was performed to identify patients who received radiotherapy. Patients were stratified into 5 groups by the use and timing of radiation as well as the timing of the reconstruction. The overall esthetic appearances were assessed by blinded reviewers. The incidence of flap complications was 34.2% in the immediate nonirradiated group, 10.7% in the delayed nonirradiated group, 44% in the post-TRAM radiation group, 60% in the immediate pre-TRAM radiation group, and 33% in the delayed pre-TRAM radiation group (P = 0.010). Patients who had immediate TRAM flap reconstruction and did not receive radiation had a better global esthetic outcome (P < 0.001) than the other 4 groups. The esthetic outcome was similar whether radiation was administered pre- or post-TRAM flap reconstruction. Radiation therapy has a deleterious effect on the esthetic outcome of pedicled TRAM flap reconstruction whether administered before or after reconstruction. There was no difference in TRAM flap complications in any of the groups that received radiation therapy.

Salvage of infected spinal hardware with paraspinous muscle flaps: anatomic considerations with clinical correlation.

PURPOSE: Infected spinal stabilization devices represent a significant reconstructive challenge by threatening spinal stability and increasing the risk of neurologic complications. This study provides an anatomic and clinical investigation of posterior midline trunk reconstruction using paraspinous muscle flaps as the primary method of repair. METHODS: We retrospectively analyzed a series of 25 consecutive patients (mean age, 57.2 years; range, 32-78 years) with complex spinal wounds, reconstructed with paraspinous muscle flaps, at a single university healthcare system. To help define the versatility of these muscle flaps, we also performed cadaveric dissections with lead oxide injections in 10 specimens, with an emphasis on regional blood supply, flap width, and arc of rotation. RESULTS: From 1994 to 2000, we successfully reconstructed 25 patients with complex spinal wounds, using 49 paraspinous muscle flaps as the primary method of reconstruction. Hardware present in 22 patients was replaced or retained in 17 cases. Long-term spinal fusion with preservation of neurologic status was observed in all patients, with no cases of dehiscence or reinfection. Wound complications included cerebrospinal fluid leak (1), skin necrosis (1), sinus tracts (3), and seroma (2). Mean length of stay was 24 days (range, 8-57 days). One postoperative death occurred. Paraspinous dissections and injections confirmed a segmental type IV blood supply with medial and lateral perforators, arising from intercostal vessels superiorly and lumbar and sacral vessels inferiorly. Flap width was 8 cm at the sacral base, 5 cm at the level of the inferior scapular angle, and 2.5 cm at the first thoracic vertebra. CONCLUSIONS: Paraspinous muscle flaps can be used as the primary reconstructive option to cover and preserve spinal hardware, control local infection, and enable long-term spinal stabilization. Cadaveric dissections confirmed the usefulness of paraspinous flaps, which can be based upon lateral or medial perforators and can be safely mobilized to reliably reconstruct complex spinal wounds.

Disorders of potassium.

Potassium disorders are the most common electrolyte abnormality identified in clinical practice. Presenting symptoms are similar for both hypo- and hyperkalemia, primarily affecting the cardiac, neuromuscular, and gastrointestinal systems. Generally, mild hypokalemia is the most common potassium disorder seen clinically;however, severe complications can occur. Hyperkalemia is less common but more serious, especially if levels are rising rapidly. The etiologies and treatments for both hypo- and hyperkalemia are discussed, with special emphasis on the role medications play in the etiologies of each.

Immediate endoscopic latissimus dorsi flap: risk or benefit in reconstructing partial mastectomy defects.

Management of the partial mastectomy defect has become a common entity as a result of the improved popularity and equivalent survival associated with breast conservation therapy (BCT). Numerous reconstructive options have been proposed in select patients following BCT in an attempt to maintain esthetic results. Thirty-nine women underwent simultaneous endoscope-assisted latissimus muscle transfer at the time of resection and were included in this review. The average follow-up was 3.7 years. Patient demographics and tumor characteristics were discussed. Donor site morbidity was acceptable. Tumor recurrence was experienced in 6 patients (15%) following lumpectomy and latissimus reconstruction. Two patients had local recurrence, and 4 had distant recurrence. Thirty-three patients (85%) had no evidence of disease at long-term follow-up. Lumpectomy and latissimus flap transfer was the definitive reconstructive procedure in 33 of the 39 patients (85%). Patients who subsequently required completion mastectomy were easily reconstructed with a TRAM flap or implants. As the management of partial mastectomy defects continues to challenge the plastic surgeon, we are noticing a shift away from immediate simultaneous reconstructions based on arguments regarding the appropriateness from an oncological and reconstructive perspective. Stringent patient selection, confirmation of negative margins, and possibly delaying the latissimus flap transfer will maximize the benefits of this reconstructive modality while limiting the risk.

Generation and characterization of a constitutively active Stat3 protein.

Stats are latent transcription factors involved in normal cellular signaling in response to cytokine or growth factor stimulation. Constitutive activation of Stats (primarily Stat3 and Stat5) has been implicated in growth dysregulation and oncogenesis. Furthermore, increased activation of Stats has been observed in several human tumors and tumor-derived cell lines. To assess the contribution of aberrant Stat activation in oncogenesis, we have created a chimeric molecule between Stat3beta and a portion of the Herpes simplex virus VP16 activation domain. The resulting protein, Stat3beta-VAD (VP16 activation domain), is tyrosine phosphorylated on Y705 and can bind DNA in the absence of upstream activation by c-Src or epidermal growth factor (EGF). Unlike Stat3alpha and Stat3beta, Stat3beta-VAD robustly activates transcription of several reporter genes without cytokine or growth factor stimulation. In addition, we show marked upregulation of the endogenous c-myc and c-fos genes upon inducible expression of Stat3beta-VAD in COS-7 cells. Our protein displays the constitutive transcriptional activation of Stat3alpha seen in human tumors and will be a valuable tool in screens for Stat3-regulated genes. In response to the established Stat3 involvement in human cancers, Stat3beta-VAD will also facilitate assessing the contribution of other cancer signaling cascades in the context of aberrant Stat3alpha activity in cancer development and progression.

Identification of a high-affinity phosphopeptide inhibitor of Stat3.

Stat3 is a latent transcription factor that exhibits elevated activity in a variety of human cancers. To find a lead peptide for peptidomimetic drug development we synthesized and tested phosphopeptides derived from known receptor docking sites and found Y(p)LPQTV as the optimal sequence. SAR studies showed that each residue from pY to pY+3 provided binding energy.

Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2).

Members of the normally latent family of transcription factors signal/inducers and activators of transcription (Stat) are activated in a number of human tumors and tumor-derived cell lines. In the case of Stat3, it is believed that this activation leads to the induction of survival signals as well as increased proliferation. In this study, we demonstrate that Stat3 is constitutively activated in glioma and medulloblastoma tumors and that the activated protein localizes predominantly to the tumor endothelial cells in the highly vascularized glioma tumors. Our efforts to elucidate potential mechanism(s) for this activated protein have shown that coexpression of Stat3alpha and the vascular endothelial growth factor receptor-2 (VEGFR-2) result in ligand-independent activation of Stat3alpha tyrosine phosphorylation and subsequent transcriptional activation in non-endothelial cells. We also show that activated Stat3alpha can increase transcription from the vascular endothelial growth factor (VEGF) gene. Taken together, these results suggest that the activated Stat3alpha found in brain tumors may be due to the endothelial tyrosine kinase VEGFR-2 and that Stat3alpha may play a central role in autocrine VEGF activation.

ErbB-2 activates Stat3 alpha in a Src- and JAK2-dependent manner.

Stats (signal transducer and activator of transcription) are latent transcription factors that translocate from the cytoplasm to the nucleus. Constitutive activation of Stat3 alpha by upstream oncoproteins and receptor tyrosine kinases has been found in many human tumors and tumor-derived cell lines. Constitutively activated Stat3 alpha is often correlated with the activation of ErbB-2, a member of the EGFR family. To explore the involvement of ErbB-2 in the activation of Stat3 and the mechanism underlying this event, an ErbB-2 point mutant was used as a model of constitutively activated receptor. Phenylalanine mutations (Y-->F) were made in the autophosphorylation sites of the receptor, and their ability to activate Stat3 alpha was evaluated. Our results suggest that Stat3 alpha and JAK2 associates with ErbB-2 prior to phosphorylation of the receptor and that full activation of Stat3 alpha by ErbB-2 requires the participation of other non-receptor tyrosine kinases. Both Src and Jak2 kinases contribute to the activation of Stat3 alpha but Src binds to ErbB-2 only when the receptor is phosphorylated. Our results also suggest that tyrosine 1139 may be important for Src homology 2 domain association because a mutant lacking this tyrosine reduces the ability of the Src homology 2 domain to bind to ErbB-2 and significantly decreases its ability to activate Stat3 alpha.

Apoptosis induced by adenovirus-mediated p53 gene transfer in human glioma correlates with site-specific phosphorylation.

Therapeutic replacement of the p53 gene using an adenovirus vector (Ad-p53) may be an effective alternative to conventional therapies for the treatment of glioma. We have previously demonstrated that the introduction of Ad-p53 into glioma cells containing mutant p53 induces apoptosis, whereas glioma cells containing wild-type p53 are resistant. However, Ad-p53 will enhance the radiosensitivity of wild-type p53 glioma cells by increasing their tendency for apoptosis. The mechanism underlying these different responses to Ad-p53 has not been elucidated to date. Because phosphorylation of p53 at serines 15, 20, and 392 may play a role in regulating p53-mediated apoptotic activity, we determined the phosphorylation status of exogenous p53 in mutant and wild-type gliomas after Ad-p53 transfer. Monolayer cultures of glioma cell lines expressing mutant p53 (U251 and U373) or wild-type p53 (U87 and D54) were infected with Ad-p53 and analyzed by Western blotting. High levels of exogenous p53 were detected in both cell lines after Ad-p53 transfer. However, only apoptotic mutant p53 cells expressed high levels of phospho-Ser15-p53 and phospho-Ser20-p53. The levels of phospho-Ser15-p53 and phospho-Ser20-p53 were very low in wild-type p53 cells after Ad-p53 infection alone. When wild-type p53 glioma cells were exposed to radiation after Ad-p53 infection, phospho-Ser15-p53 and phospho-Ser20-p53 were detected at high levels, and the cells subsequently underwent apoptosis; no change in serine 392 was detected. The induction of apoptosis and the expression of phospho-Ser15 and phospho-Ser20 in these cells were also enhanced by the combination of Ad-p53 and other DNA-damaging agents such as cisplatin and bichloroethyl nitrosourea. Furthermore, the expression of phospho-Ser15-p53 and phospho-Ser20-p53 correlated with the amount of apoptosis; the apoptotic activity of p53 in glioma cells was partially inhibited by a mutation of p53 at serine 15. These results suggest that phosphorylation of p53 at serine 15 and serine 20 is critical for apoptosis induction in p53 gene therapy for gliomas.