John Brendan Maurice Mullen
Publication (last 5 years)
Bethune GC, Mullen JB, Chang MC. Detecting intratumoral heterogeneity in routine breast-HER2 testing: low yield of testing multiple blocks. Ann Diagn Pathol. 2015 Dec;19(6):385-90. doi: 10.1016/j.anndiagpath.2015.08.001. Epub 2015 Aug 15.

 


Abstract
BACKGROUND:
Intratumoral heterogeneity can lead to uncertainty in breast carcinoma HER2 testing, both with respect to pathology reporting and clinical significance. The standard practice is to perform breast biomarker testing on a single representative section of tumor; however, concern over heterogeneity often leads to testing on additional tissue blocks. Our objective was to assess the diagnostic yield of testing multiple blocks of a single invasive breast carcinoma.
METHODS:
We performed a retrospective review of 139 consecutive cases (between 2006 and 2012) in which clinical HER2 testing was performed in multiple blocks. Tumor characteristics and HER2 studies (both immunohistochemistry and data from in situ hybridization) were reviewed. Regional differences in morphology and HER2 immunoreactivity were recorded. In situ hybridization was performed in 25 of 139 of the cases; patterns of genetic heterogeneity were reviewed. We audited discordances in HER2 result between blocks.
RESULTS:
Testing of multiple blocks yielded no additional HER2 information in 134 (96.4%) of 139 cases. Morphologic differences or heterogeneity in HER2 expression was observed in 22 (15.8%) of 139 of cases. Only 5 of these showed differences in HER2 between blocks, of which 4 were associated with equivocal HER2 immunohistochemistry, and 4 were high-grade.
CONCLUSIONS:
In the vast majority of cases, even those with heterogeneity, testing of a single block is sufficient for an accurate HER2 determination. High-grade tumors with equivocal HER2 status and observable heterogeneity are more likely to yield a different result on testing of additional blocks.
Lo KC, Yildiz C, Zhu Y, Lambourne MD, Mullen JB, Samplaski MK, Jarvi KA, McKerlie C. Human fetal testicular tissue xenotransplantation – A platform to study the effect of gonadotropins on human germ cell development in utero. J Urol. 2015;[Epub ahead of print]. Same as Jarvi_2
Wang C, Armstrong SM, Sugiyama MG, Tabuchi A, Krauszman A, Kuebler WM, Mullen B, Advani S, Advani A, Lee WL. Influenza Primes Human Lung Microvascular Endothelium to Leak upon Exposure to Staphylococcus aureus. Am J Respir Cell Mol Biol. 2015 Oct;53(4):459-70.

 


Abstract
A major cause of death after influenza virus infection is lung injury due to a bacterial superinfection, yet the mechanism is unknown. Death has been attributed to virus-induced immunosuppression and bacterial overgrowth, but this hypothesis is based on data from the preantibiotic era and animal models that omit antimicrobial therapy. Because of diagnostic uncertainty, most patients with influenza receive antibiotics, making bacterial overgrowth unlikely. Respiratory failure after superinfection presents as acute respiratory distress syndrome, a disorder characterized by lung microvascular leak and edema. The objective of this study was to determine whether the influenza virus sensitizes the lung endothelium to leak upon exposure to circulating bacterial-derived molecular patterns from Staphylococcus aureus. In vitro as well as in vivo models of influenza followed by S. aureus superinfection were used. Molecular mechanisms were explored using molecular biology, knockout mice, and human autopsy specimens. Influenza virus infection sensitized human lung endothelium to leak when challenged with S. aureus, even at low doses of influenza and even when the pathogens were given days apart. Influenza virus increased endothelial expression of TNFR1 both in vitro and in intact lungs, a finding corroborated by human autopsy specimens of patients with influenza. Leak was recapitulated with protein A, a TNFR1 ligand, and sequential infection caused protein A-dependent loss of IκB, cleavage of caspases 8 and 3, and lung endothelial apoptosis. Mice infected sequentially with influenza virus and S. aureus developed significantly increased lung edema that was protein A and TNFR1 dependent. Influenza virus primes the lung endothelium to leak, predisposing patients to acute respiratory distress syndrome upon exposure to S. aureus.
Samplaski MK, Dimitromanolakis A, Lo KC, Grober ED, Mullen B, Garbens A, Jarvi KA. The relationship between sperm viability and DNA fragmentation rates. Reprod Biol Endocrinol. 2015;13:42. Same as Jarvi_6
Satkunasivam R, Ordon M, Hu B, Mullen B, Lo K, Grober E, Jarvi K. Hormone abnormalities are not related to the erectile dysfunction and decreased libido found in many men with infertility. Fertil Steril. 2014;101:1594-8. Same as Jarvi_10
Yildiz C, Mullen B, Jarvi K, McKerlie C, Lo KC. Effect of different cryoprotectant agents on spermatogenesis efficiency in cryopreserved and grafted neonatal mouse testicular tissue. Cryobiology. 2013;67:70-5. Same as Jarvi_26
Drabovich AP, Dimitromanolakis A, Saraon P, Soosaipillai A, Batruch I, Mullen B, Jarvi K, Diamandis EP. Differential diagnosis of azoospermia with proteomic biomarkers ECM1 and TEX101 quantified in seminal plasma. Sci Transl Med. 2013;5:212ra160. Same as Jarvi_24
Bethune GC, Mullen JB, Chang MC. HER2 testing of multifocal invasive breast carcinoma: how many blocks are enough? Am J Clin Pathol. 2013;140:588-92.

 


Abstract
OBJECTIVES:
To determine the diagnostic yield of testing multiple blocks for HER2 in cases of multifocal breast carcinoma.
METHODS:
We identified 246 consecutive cases of multifocal invasive breast carcinoma in which HER2 was tested on more than 1 tumor focus. We performed an audit of all cases with respect to tumor size, grade, and histologic type.
RESULTS:
HER2 status was concordant between multiple foci in 230 (93.5%) of 246 cases, with the largest focus having the most positive HER2 result in 242 (98.4%) of 246 cases. We did not find a single case in which a smaller focus demonstrated a more positive HER2 status unless this focus was either higher grade or different histologically.
CONCLUSIONS:
Our findings support the evaluation of HER2 on the largest focus, with additional testing on smaller foci having a different histologic type or higher grade.
Domes T, Lo KC, Grober ED, Mullen JB, Mazzulli T and Jarvi K. The incidence and effect of bacteriospermia and elevated seminal leukocytes on semen parameters. Fertil Steril. 2012;97:1050-5. Same as Jarvi_32
Domes T, Lo KC, Grober ED, Mullen JB, Mazzulli T, Jarvi K. The utility and cost of Chlamydia trachomatis and Neisseria gonorrhoeae screening of a male infertility population. Fertil Steril. 2012;97:299-305. Same as Jarvi_37
Batruch I, Smith CR, Mullen BJ, Grober E, Lo KC, Diamandis EP and Jarvi KA. Analysis of seminal plasma from patients with non-obstructive azoospermia and identification of candidate biomarkers of male infertility. J Proteome Res. 2012;11:1503-11. Same as Jarvi_33
Kovac JR, Flood D, Mullen JB, Fischer MA. Diagnosis and treatment of azoospermia resulting from testicular sarcoidosis. J Androl. 2012;33:162-6.

 


 
Abstract
Genitourinary sarcoidosis is uncommon, with only rare documented cases of testicular involvement reported. We detail the case of a 37-year-old male who initially presented for azoospermia and secondary infertility. A testicular biopsy revealed nonnecrotizing granulomas and a chest x-ray identified perihilar lymphadenopathy and granulomatous lung nodules. A corticosteroid regimen was administered, and routine semen analyses were conducted. Significant improvements were noted after prednisone treatments. A successful in vivo fertilization was obtained. This is the first known case of testicular sarcoidosis diagnosed during investigations into azoospermia and secondary infertility which, after treatment with corticosteroids, resulted in natural fertilization.
Moskovtsev SI, Alladin N, Lo KC, Jarvi K, Mullen JB, Librach CL. A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage. Syst Biol Reprod Med. 2012;58:142-8. Same as Jarvi_31
Batruch I, Lecker I, Kagedan D, Smith C, Mullen B, Grober E, Lo K, Diamandis EP, Jarvi K. Proteomic analysis of seminal plasma from normal volunteers and post-vascectomy patients identifies over 2000 proteins and candidate biomarkers of the urogenital system. J Proteome Res. 2011;10:941-53. Same as Jarvi_44
Blankstein M, Byrick RJ, Richards RR, Mullen JB, Zdero R, Schemitsch EH. Pathophysiology of fat embolism: A rabbit model. J Orthop Trauma. 2011;25:674-80.

 


 
Abstract
OBJECTIVES:
The objective of this study was to assess the effects of fat embolism on rabbit physiology.
METHODS:
After anesthetic administration, both femoral condyles of the right knee only of 23 New Zealand white rabbits were exposed through a medial parapatellar approach to the knee. In the pulmonary fat embolism group (n = 15), the femoral canal was drilled in a retrograde fashion and then reamed and pressurized with a 1- to 1.5-mL cement injection. In the no-pressurization group (n = 4), after reaming, no cement was injected. In the control group (n = 4), the knee incision was immediately closed. Animals were then observed for 5 hours. Hemodynamics and blood gases were recorded at standard intervals. Postmortem, the lungs were removed en bloc and fixed for histologic assessment and quantitative histomorphometry.
RESULTS:
Four intraoperative deaths occurred in the pulmonary fat embolism group immediately after pressurization and may have been associated with hypotension and cardiac arrest. In the pulmonary fat embolism group, pulmonary artery pressure increased, and both mean arterial pressure and PaO2 decreased after pressurization. Approximately 2% of lung volume was occupied by intravascular fat and there were no signs of perivascular inflammation. Control and no-pressurization animals remained stable throughout the experiment.
CONCLUSIONS:
This model simulates pulmonary fat embolism after long-bone fractures. Despite cardiorespiratory dysfunction, there was no evidence of fat initiating pulmonary inflammation based on histologic data within the timeframe of the investigation.