BackgroundHER2 gene copy status, and concomitant administration of trastuzumab (Herceptin), remains one of the best examples of targeted cancer therapy based on understanding the genomic etiology of disease. However, newly diagnosed breast cancer cases with equivocal HER2 results present a challenge for the oncologist who must make treatment decisions despite the patient's unresolved HER2 status. In some cases both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are reported as equivocal, whereas in other cases IHC results and FISH are discordant for positive versus negative results. The recent validation of array-based, molecular karyotyping for clinical oncology testing provides an alternative method for determination of HER2 gene copy number status in cases remaining unresolved by traditional methods.MethodsIn the current study, DNA extracted from 20 formalin fixed paraffin embedded (FFPE) tissue samples from newly diagnosed cases of invasive ductal carcinoma referred to our laboratory with unresolved HER2 status, were analyzed using a clinically validated genomic array containing 127 probes covering the HER2 amplicon, the pericentromeric regions, and both chromosome 17 arms.ResultsArray-based comparative genomic hybridization (array CGH) analysis of chromosome 17 resolved HER2 gene status in [20/20] (100%) of cases and revealed additional chromosome 17 copy number changes in [18/20] (90%) of cases. Array CGH analysis also revealed two false positives and one false negative by FISH due to "ratio skewing" caused by chromosomal gains and losses in the centromeric region. All cases with complex rearrangements of chromosome 17 showed genome-wide chromosomal instability.ConclusionsThese results illustrate the analytical power of array-based genomic analysis as a clinical laboratory technique for resolution of HER2 status in breast cancer cases with equivocal results. The frequency of complex chromosome 17 abnormalities in these cases suggests that the two probe FISH interphase analysis is inadequate and results interpreted using the HER2/CEP17 ratio should be reported "with caution" when the presence of centromeric amplification or monosomy is suspected by FISH signal gains or losses. The presence of these pericentromeric copy number changes may result in artificial skewing of the HER2/CEP17 ratio towards false negative or false positive results in breast cancer with chromosome 17 complexity. Full genomic analysis should be considered in all cases with complex chromosome 17 aneusomy as these cases are likely to have genome-wide instability, amplifications, and a poor prognosis.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic pauci-immune small vessel vasculitis. Its various presentations make AAV diagnosis challenging. Here, we present a case of AAV with thrombotic microangiopathy (TMA) and deep venous thrombosis (DVT). An 82-year-old Hispanic woman presented to the emergency department with malaise, lower extremity pain, and oliguria for three days. Her vital signs were normal, and her physical examination was unremarkable. The initial laboratory revealed thrombocytopenia (18 x 10 3 /µL), elevated creatinine (8.35 mg/dL), high lactic acid dehydrogenase (1627.5 U/L), an international normalized ratio of 1.6, and an activated partial thromboplastin time of 49 seconds. Urinalysis showed microscopic hematuria and proteinuria, and peripheral smear revealed schistocytes. She was admitted with concern for TMA. Further workup revealed an antinuclear antibody titer of 1:80, an ADAMTS13 level of 62%, a rheumatoid factor level of 151.7 IU/L, and myeloperoxidase (MPO)-ANCA level of 173 AU/mL. A computed tomography scan of the chest/abdomen/pelvis revealed pulmonary fibrosis and multifocal consolidations. She was also found to have extensive DVT of the lower extremities. Renal biopsy revealed early changes of TMA with one cellular crescent. She was diagnosed with AAV based on the kidney and lung findings, as well as the high titer MPO-ANCA. Her platelet count and creatinine improved significantly following treatment with plasma exchange, steroids, and rituximab. Unfortunately, she was then found to have an acute bowel perforation and expired. Even though typically rare, an increased incidence of venous thromboembolism (VTE) and TMA has been reported in patients with AAV. Its prompt recognition and treatment by clinicians are critical to mitigate the unfavorable outcomes from this condition.
INTRODUCTION: Pregnancy-induced atypical hemolytic uremic syndrome (p-aHUS), a disease caused by hyperactivation of the alternative complement pathway, can lead to renal ischemia and ESRD. We present two cases of p-aHUS and discuss both the disease process and treatment options. METHODS: The first case, a 31 yo female, underwent a cesarean delivery at 29 weeks due to preterm labor with breech presentation. She developed elevated BP, thrombocytopenia, and elevated serum creatinine postpartum. A nephrology consult confirmed the diagnosis of p-aHUS with elevated LDH and normal ADAMST13 levels. The second case is a 32 yo who underwent a suction D&C due to retained placenta after delivery of an IUFD. Laboratory values revealed thrombocytopenia and acute kidney injury (AKI). Again, Nephrology diagnosed p-aHUS. Both patients underwent plasmapheresis and Eculizumab therapy as soon as p-aHUS was diagnosed. Literature review for p-aHUS revealed the following conclusions: 1) risk factors include postpartum period, history of a cesarean delivery, and a genetic mutation in the CFH gene; 2) other causes of thrombocytopenia, AKI, and hemolytic anemia in pregnancy include pre-E and TTP 3) TTP can be ruled out with a normal ADAMST13 and pre-E can be ruled out by an LDH <1000; and 4) immediate diagnosis and treatment helps to prevent kidney injury. CONCLUSION: Given the rarity of the disease, there is little research involved in p-aHUS. However it is it is important for clinicians to have a strong suspicion for p-aHUS and to initiate treatment immediately to decrease morbidity including ESRD.
Infective endocarditis (IE) is still seen globally with acute kidney injuries remaining a common complication of the disease. Histological specimens often display either diffuse or focal endocapillary proliferation as well as neutrophilic infiltration in endocarditis-related renal disease. C3-dominant glomerulonephritis (C3GN) utilizes mechanisms of complement activation unique from IE-associated glomerulonephritis. In C3GN, micrographic review may reveal scattered accumulation of C3 fragments with subepithelial hump formation and mesangial electron-dense deposits that help solidify the diagnosis of this recently discovered pathological phenomenon. Herein, we summarize a clinical case of likely IE-related C3GN without hypocomplementemia in a patient with a single kidney to help compare and contrast the key elements of each process.A 27-year-old Hispanic man with a past medical history of nephrectomy for renal donation presented to a community hospital with a high fever and altered sensorium. A serum creatinine of 6.98 mg/dL with unknown baselines, nephrotic-range proteinuria, and severe rhabdomyolysis plus methicillinsensitive Staphylococcus aureus bacteremia were quickly discovered after admission. A later transesophageal echocardiogram showed a hypermobile vegetation along the anterior mitral valve leaflet confirming suspected IE. The patient's serum C3 and C4 complement levels and antinuclear, myeloperoxidase, and proteinase-3 antibody titers were all within normal limits. A renal biopsy pursued in the etiological investigation of this non-oliguric acute kidney injury revealed a single subepithelial electron-dense deposit and granular immunofluorescent C3 staining in peripheral mesangial segments. Dominant C3 deposition without associated immunoglobulins can result from in situ localization of bacterial antigens promoting plasmin activation to recruit neutrophils and monocytes to initiate leukocytemediated damage. Immunosuppressive therapies for C3GN triggering antibody-independent activation of the alternative or lectin complement pathways may be merited where disease remission becomes difficulty to achieve.
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