Citations

Abstract Ki-67 proliferation marker-based response monitoring will be prospectively tested in the ALternate Treatment for ER positive NeoAdjuvant TrEatment (ALTERNATE) trial. Tumor Ki-67 will be analyzed after one month of neoadjuvant anastrozole, fulvestrant or the combination to detect early resistance (Ki-67 >10%) for triage to alternate treatment (chemotherapy/investigational agent). Ki-67 will be repeated on the surgical specimen after 24 weeks to detect PEPI-0 cases (path Stage 0/1/2A and Ki-67 ≤2.7%), which will be managed without adjuvant chemotherapy. A CLIA-approved Ki-67 assay was required by CTEP/FDA. FDA reviewed-components included the CONFIRM anti-Ki-67 (30-9) Rabbit Monoclonal Primary Antibody, the Benchmark XT platform and the VENTANA iScan Coreo scanner. The validation process was as follows: Step 1 was a TMA-based bridging study between a SP6-based research assay to the 30-9 CLIA assay using visual point counting (VPC); Step 2 trained a scoring SOP using Companion Algorithm Ki-67 (30-9) image analysis software with triage to VPC when certain observations were flagged; Step 3 was an independent test of the SOP using relevant patient outcome-associated samples from the P024 and POL neoadjuvant endocrine studies with two independent pathology analyses. STEP 1: Bridging Research to CLIA. Using a 28-case TMA, and VPC, the intra-class correlation (ICC) for agreement measure of Ki-67 10% cut-point (CP) between research Ki-67 and CLIA Ki-67 was 0.96 (CI 0.92-0.98). The Cohen's simple kappa for agreement measure was 0.78 (CI 0.55-1.0). STEP 2: Scanner-based Algorithm training. An SOP for the image analysis was developed by reviewing discordant cases in two independent reads at the 10% and 2.7% CP in a training set (N+ disease from P024 N = 61). Histology features that led to inaccurate scoring from the image analysis included: streaming /fascicular tumor cells, a large amount of intervening stromal cells, heavy immune cell infiltration, sparse scattered tumor cells, faint staining, and plump stromal cells. These cases were flagged for VPC. The final Ki-67 scoring SOP used image analysis with triage to VPC when necessary (required in 16% of cases). STEP 3: Scoring Algorithm Validation. The Ki-67 SOP was run on T1/2 N0 cases from the P024 trial N = 58. The% positive agreement for the combined scanner and VPC approach using the Ki-67 2.7% CP was 87.5% (95% CI 61.7- 98.5%); percent negative agreement 88.9% (95% CI: 65.3-98.6%). Minor discordance did not affect the ability to predict very similar survival outcomes (Log Rank P = 0.044 and P = 0.055). The data for the 10% CP was similar (N = 66), the percentage positive agreement was 100%; percent negative agreement 93.55% (95% CI: 78.58-99.21%). The survival predictions were again similar (P = 0.0001 and P = 0.0002). The FDA ruled the use of Ki-67 in the ALTERNATE trial is “no significant risk” because previous clinical trial data indicated the majority of patients with Stage 0/1/2A disease post neoadjuvant endocrine therapy already do not receive chemotherapy. Thus the use of Ki-67 reduces the risk of under-treatment of patients with low stage disease but aggressive biology. CTEP accepted these data on assay concordance and performance and the ALTERNATE trial will proceed. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-10.

Key Points Patients living in low SES neighborhoods had worse survival after DLBCL. Disparity was most striking in younger (non-Medicare) patients and after the introduction of rituximab.

AbstractBackgroundSurgical treatment and clinical management of foot pathology requires accurate, reliable assessment of foot deformities. Foot and ankle deformities are multi‐planar and therefore difficult to quantify by standard radiographs. Three‐dimensional (3D) imaging modalities have been used to define bone orientations using inertial axes based on bone shape, but these inertial axes can fail to mimic established bone angles used in orthopaedics and clinical biomechanics. To provide improved clinical relevance of 3D bone angles, we developed techniques to define bone axes using landmarks on quantitative computed tomography (QCT) bone surface meshes. We aimed to assess measurement precision of landmark‐based, 3D bone‐to‐bone orientations of hind foot and lesser tarsal bones for expert raters and a template‐based automated method.MethodsTwo raters completed two repetitions each for twenty feet (10 right, 10 left), placing anatomic landmarks on the surfaces of calcaneus, talus, cuboid, and navicular. Landmarks were also recorded using the automated, template‐based method. For each method, 3D bone axes were computed from landmark positions, and Cardan sequences produced sagittal, frontal, and transverse plane angles of bone‐to‐bone orientations. Angular reliability was assessed using intraclass correlation coefficients (ICCs) and the root mean square standard deviation (RMS‐SD) for intra‐rater and inter‐rater precision, and rater versus automated agreement.ResultsIntra‐ and inter‐rater ICCs were generally high (≥ 0.80), and the ICCs for each rater compared to the automated method were similarly high. RMS‐SD intra‐rater precision ranged from 1.4 to 3.6° and 2.4 to 6.1°, respectively, for the two raters, which compares favorably to uni‐planar radiographic precision. Greatest variability was in Navicular: Talus sagittal plane angle and Cuboid: Calcaneus frontal plane angle. Precision of the automated, atlas‐based template method versus the raters was comparable to each rater's internal precision.ConclusionsIntra‐ and inter‐rater precision suggest that the landmark‐based methods have adequate test‐retest reliability for 3D assessment of foot deformities. Agreement of the automated, atlas‐based method with the expert raters suggests that the automated method is a valid, time‐saving technique for foot deformity assessment. These methods have the potential to improve diagnosis of foot and ankle pathologies by allowing multi‐planar quantification of deformities.

Key PointsAmino acid substitution at peptide-binding residues of the HLA class I molecule is associated with graft-versus-host disease and mortality. Avoidance of donor-recipient combinations that result in amino acid substitution at peptide-binding residues may improve transplant outcomes.

This study was to evaluate the efficacy and safety of acupuncture for chronic functional constipation. Randomized controlled trials were searched in several databases. The primary outcome was a change in the number of weekly spontaneous bowel movements. The secondary outcomes included colonic transit activity, effective rate, Cleveland Clinic Score, and health-related quality of life score. Meta-analysis was done by using RevMan 5.1. After strict screening, 15 RCTs were included, containing 1256 participants. All of them were conducted in China and published in Chinese journals. Meta-analysis indicated that acupuncture for chronic functional constipation was probably as effective as conventional medical therapy in the change of bowel movements. For the colonic transit activity, acupuncture might be the same as conventional medical therapy and could be better than sham acupuncture. For the Cleveland Clinic Score, acupuncture was unlikely inferior to conventional medical therapy and the deep acupuncture was better than normal depth acupuncture in abdominal region. No obvious adverse event was associated with acupuncture for constipation. In conclusion, acupuncture for chronic functional constipation is safe and may improve weekly spontaneous bowel movements, quality of life, and relevant symptoms. However, the evidence was limited by the small sample size and the methodological quality.

Purpose We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)– amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy. Patients and Methods Women with stages II to III HER2-positive breast cancers were eligible. They received trastuzumab once per week (4 mg/kg loading, then 2 mg/kg) and lapatinib 1000 mg once per day for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone–releasing hormone [LHRH] agonist if premenopausal). Pathologic response was assessed by ER status. Biopsies were obtained at baseline, weeks 2 and 8, and time of surgery. Results Sixty-six patients were enrolled, and 64 were eligible and evaluable for response. Median tumor size was 6 cm (range, 1.5 to 30 cm). Adverse events were mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 metabolic, GI, and liver (18%; 12 patients) and grade 4 liver toxicities (one patient) were also observed. Overall, in-breast pathologic complete response (pCR; yp T 0 - is ) was 27% (ER positive, 21%; ER negative, 36%). The rate of low-volume residual disease ( yp T 1a-b ) was 22% (ER positive, 33%; ER negative, 4%). Conclusion In patients with locally advanced HER2-positive breast cancer, our approach of targeted therapy only resulted in a high pCR rate without chemotherapy. Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study.

Rationale: Mutagenesis screening is a powerful genetic tool for probing biological mechanisms underlying vertebrate development and human diseases. However, the increased colony management efforts in vertebrates impose a significant challenge for identifying genes affecting a particular organ, such as the heart, especially those exhibiting adult phenotypes on depletion. Objective: We aim to develop a facile approach that streamlines colony management efforts via enriching cardiac mutants, which enables us to screen for adult phenotypes. Methods and Results: The transparency of the zebrafish embryos enabled us to score 67 stable transgenic lines generated from an insertional mutagenesis screen using a transposon-based protein trapping vector. Fifteen lines with cardiac monomeric red fluorescent protein reporter expression were identified. We defined the molecular nature for 10 lines and bred them to homozygosity, which led to the identification of 1 embryonic lethal, 1 larval lethal, and 1 adult recessive mutant exhibiting cardiac hypertrophy at 1 year of age. Further characterization of these mutants uncovered an essential function of methionine adenosyltransferase II, α a (mat2aa) in cardiogenesis, an essential function of mitochondrial ribosomal protein S18B (mrps18b) in cardiac mitochondrial homeostasis, as well as a function of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b) in adult cardiac hypertrophy. Conclusions: We demonstrate that transposon-based gene trapping is an efficient approach for identifying both embryonic and adult recessive mutants with cardiac expression. The generation of a zebrafish insertional cardiac mutant collection shall facilitate the annotation of a vertebrate cardiac genome, as well as enable heart-based adult screens.