Citations

Purpose In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.

ObjectivesTo investigate the dose‐dependent effect of androgen deprivation therapy on community‐acquired respiratory infections in patients with localized prostate cancer.MethodsWe identified 52 905 men diagnosed with localized prostate cancer within the Surveillance, Epidemiology and End Results‐Medicare database between 1991 and 2006. We compared those who did not receive androgen deprivation therapy with those who received androgen deprivation therapy within 2 years of diagnosis, calculated as monthly equivalent doses (<7, 7–11, >11 doses), or orchiectomy. Adjusted Cox hazard models were fitted to predict the risk of community‐acquired respiratory infections (acute sinusitis, acute bronchitis, [severe] pneumonia) in patients treated with medical androgen deprivation therapy versus orchiectomy versus none.ResultsOverall, 43.4% received medical androgen deprivation therapy. These patients more likely experienced respiratory events compared with those who did not receive androgen deprivation therapy or who underwent orchiectomy (62.2% vs 54.5% vs 47.8%, P < 0.001). The risk of experiencing any respiratory event increased with the number of doses received. For example, men receiving >11 doses of androgen deprivation therapy were at greatest risk of acute sinusitis, acute bronchitis and pneumonia (HR 1.13, 1.26 and 1.15, respectively, all P < 0.001), except severe pneumonia. Furthermore, we did not detect any relationship between orchiectomy and respiratory events. Study limitations include the utilization of a retrospective population‐based dataset.ConclusionsIncreased exposure to medical androgen deprivation therapy for men with localized prostate cancer is associated with a higher risk of community‐acquired respiratory infections. Our results suggest that respiratory complications represent potentially underreported complications of medical androgen deprivation therapy.

This edition of the Video Supplement entitled “Microsurgery of the Third Ventricle, Pineal Region, and Tentorial Incisura” highlights approaches to accessing the third ventricle for surgical resection of a variety of pathologies. The third ventricle has critical neurovascular anatomy that must always be respected to prevent patient harm. Visualization of critical anatomy in three dimensions from a surgeon' line of sight is important when planning the optimum surgical approach. Some of the keys to safely operating in this region include thoughtful head positioning, limitation of brain retraction, and the use of trajectories which capitalize on CSF cisterns and fissures. Some of the videos included in this volume illustrate standard operations while others depict more unique and innovative approaches that take advantage of these surgical windows. We hope you enjoy the videos included in this supplement.

AbstractBACKGROUNDFor many years, basic and clinical researchers have taken advantage of the analytical sensitivity and specificity afforded by mass spectrometry in the measurement of proteins. Clinical laboratories are now beginning to deploy these work flows as well. For assays that use proteolysis to generate peptides for protein quantification and characterization, synthetic stable isotope–labeled internal standard peptides are of central importance. No general recommendations are currently available surrounding the use of peptides in protein mass spectrometric assays.CONTENTThe Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling, as well as approaches to the interpretation of the data generated by mass spectrometric protein assays. Additionally, the importance of carefully characterized reference materials—in particular, peptide standards for the improved concordance of amino acid analysis methods across the industry—is highlighted. The alignment of practices around the use of peptides and the transparency of sample preparation protocols should allow for the harmonization of peptide and protein quantification in research and clinical care.

Purpose Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. Patients and Methods Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites). Results One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies. Conclusion Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.

BackgroundTrastuzumab has substantially improved overall survival and reduced the risk of disease recurrence in patients with human epidermal growth factor receptor type II (HER‐II)–positive breast cancer. However, this benefit may be at the increased risk of cardiotoxicity. We aimed to explore the early subclinical left and right ventricular as well as atrial dysfunction, in trastuzumab‐treated patients with HER‐II–positive breast cancer, using velocity vector imaging.MethodsEchocardiography images were acquired in 50 patients with HER‐II–positive breast cancer undergoing trastuzumab therapy. All patients had baseline and 3–6 months and 12–15 months of follow‐up echocardiograms after initiation of trastuzumab therapy. Subendocardial borders of all the cardiac chambers were traced from the apical views to obtain volumetric and deformation indices.ResultsMean age was 60 ± 13 years. Left ventricular (LV) ejection fraction as well as conventional indices of right ventricular (RV) function did not change with trastuzumab. The RV peak systolic global longitudinal strain (GLε) significantly decreased (−24.53 ± 6.03 vs. −21.28 ± 5.11 vs. −21.84 ± 5.15, baseline vs. first and second follow‐ups, P = 0.01). LV peak systolic GLε was reduced by 1.19 at early follow‐up (P < 0.05). Left atrial reservoir and booster pump functions as well as right atrial reservoir function were reduced through follow‐up as well.ConclusionsThe RV exhibited greater change in strain after trastuzumab treatment when compared to the LV. Atria function was reduced by trastuzumab as well. The repercussion of these findings and their potential implication will warrant further study.