A phase II study of bevacizumab in combination with vinorelbine and trastuzumab in HER2-positive metastatic breast cancer.

We aimed to evaluate the efficacy and feasibility of combining trastuzumab/vinorelbine with bevacizumab in patients with first-or second-line HER2-positive, metastatic breast cancer (MBC). Eligible patients had HER2-positive measureable MBC, with no more than one prior line of chemotherapy, and were treated with trastuzumab (4 mg/kg × 2 mg/kg weekly thereafter), vinorelbine (25 mg/m(2) weekly), and bevacizumab (10 mg/kg every 2 weeks). Co-primary endpoints were (a) the proportion of patients alive and progression-free at 1 year and (b) safety profile/feasibility. Feasibility was defined as a rate of grade 3/4 non-hematologic toxicity attributable to protocol-based therapy <20 %. Twenty-nine patients were enrolled (n = 22 first-line, n = 7 second-line). Median age was 48 years (range 37-68). The median number of cycles received was 8 (1-23) and median duration on treatment was 7.4 months (range 1-22). The study was closed early due to higher-than-expected rates of grade 3/4 non-hematologic toxicities, with 50 events in 20 patients. A total of six patients (21 %) were taken off study for treatment-related toxicity. Most common treatment-related toxicities included fatigue (n = 7), febrile neutropenia (n = 4), and headache (n = 3). At 1 year, 8/22 first-line (36 %) and 2/7 second-line (29 %) patients were alive and progression-free. Median PFS was 9.9 months and 7.8 months in the first- and second-line cohorts, respectively. Objective responses were observed in 16/22 (73 %) and 5/7 (71 %) patients in the first- and second-line settings. Although the combination of vinorelbine, trastuzumab, and bevacizumab showed notable activity in HER2-positive MBC, the proportion of first-line patients alive and progression-free at 1 year was deemed unlikely to reach the pre-defined threshold for declaring success. Additionally, unacceptable toxicity was observed, at rates greater than previously reported with vinorelbine/trastuzumab or vinorelbine/bevacizumab doublet combinations.

Treatment of high-grade anal dysplasia in high-risk patients: outcome at an urban community health centre.

Human immunodeficiency (HIV)-infected patients and men who have sex with men (MSM) have a higher rate of high-grade anal intraepithelial neoplasia (HGAIN), a likely precursor to anal cancer. This retrospective study describes the outcome of treating MSM with incident biopsy-proven HGAIN in an urban community health setting with access to outpatient ablation or operative treatment. The main outcome was freedom from HGAIN at follow-up. One hundred and fifty-three met inclusion criteria; 86 (56%) were HIV-infected. Eighty (52%) received outpatient ablation, 49 (61%) had a follow-up within nine months. Among those, 26 (53%) were free of high-grade disease, 19 (39%) had high-grade disease; and 4 (8%) had unknown grading. In a logistic regression model, a lower extent of anal disease (1 quadrant versus 2, 3 or 4 quadrants) at the time of treatment was significantly associated with a lower probability of high-grade disease (P value 0.04). HGAIN could be managed in a community health setting; however, systems are needed to ensure follow-up care.

Does neoadjuvant bevacizumab increase surgical complications in breast surgery?

BACKGROUND: Neoadjuvant chemotherapy is being increasingly used in operable breast cancer. There are limited data on the safety of bevacizumab (bev) in the neoadjuvant setting. We sought to explore the safety of neoadjuvant cisplatin/bev in a protocol for triple negative breast cancer (TNBC). MATERIALS AND METHODS: A total of 51 patients with confirmed TNBC were enrolled in a single-arm trial of neoadjuvant cisplatin plus bev. Of the 51 patients, 28 with confirmed TNBC were enrolled in our trial of single-agent neoadjuvant cisplatin. Two-sided Fisher exact test were used for comparing the 2 trials. RESULTS: The 51 patients received neoadjuvant protocol therapy with cisplatin/bev and underwent definitive local therapy. Breast conserving therapy (BCT) was performed in 29 (57%) and mastectomy with or without reconstruction in 22 (43%). Postoperative complications were reported in 22 patients (43%); 4 (8%) required explanation of expanders. Also, 28 patients completed neoadjuvant cisplatin therapy. BCT was performed in 13 (46%) and mastectomy with or without reconstruction in 15 (54%). Postoperative complications were reported in 11 patients (39%). None of the 5 reconstructions were lost. We compared all toxicities between the two trials (P = .81 NS), and wound healing related complications between the two trials (P = .10 NS). CONCLUSIONS: Cisplatin/bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically, use of expanders/implants may be problematic for patients treated with bev. However, this was a single-arm trial; randomized controlled studies will be needed to determine the optimal use of bevacizumab in the timing of breast cancer surgery.

3D volumes constructed from pixel-based images by digitally clearing plant and animal tissue.

Construction of three-dimensional volumes from a series of two-dimensional images has been restricted by the limited capacity to decrease the opacity of tissue. The use of commercial software that allows colour-keying and manipulation of two-dimensional images in true three-dimensional space allowed us to construct three-dimensional volumes from pixel-based images of stained plant and animal tissue without generating vector information. We present three-dimensional volumes of (1) the crown of an oat plant showing internal responses to a freezing treatment, (2) a sample of a hepatocellular carcinoma from a woodchuck liver that had been heat-treated with computer-guided radiofrequency ablation to induce necrosis in the central portion of the tumour, and (3) several features of a sample of mouse lung. The technique is well suited to images from large sections (greater than 1 mm) generated from paraffin-embedded tissues. It is widely applicable, having potential to recover three-dimensional information at virtually any resolution inherent in images generated by light microscopy, computer tomography, magnetic resonance imaging or electron microscopy.

Tolerability of and adherence to combination oral therapy with gefitinib and capecitabine in metastatic breast cancer.

PURPOSE: This phase I study explored gefitinib (G) and capecitabine (C) in metastatic breast cancer (MBC). METHODS: Sequential cohorts (n = 3) received G and escalating C on a 14 day on/7 day off schedule, with a validation cohort (n = 10) at the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was defined in cycle 1. The primary endpoint was safety; secondary endpoints included response and adherence. RESULTS: About 19 patients were treated for a median of 5 cycles. No patients in sequential cohorts experienced DLT; C MTD was 2,000 mg/m(2)/day when paired with daily G 250 mg. In the validation cohort, four experienced serious toxicities, including diarrhea, mucositis, and palmarplantar dysesthesia. At the MTD, 6 (46%) required a C dose reduction, and 3 (23%) came off study for toxicity. One partial response was observed (8%, 95% CI 0.2-38.5%); five had stable disease >24 weeks (26, 95% CI 9-51%). Patients missed few drug doses, with the suggestion of overadherence to therapy. CONCLUSIONS: In this phase I study of G and C in MBC, a C MTD was identified, and significant toxicity was observed. About 8% demonstrated a response, with 26% maintaining stable disease. The possibility of overadherence, as suggested in this study, may have implications for other trials of oral antineoplastic therapy.

The impact of sharing results of a randomized breast cancer clinical trial with study participants.

BACKGROUND: There has been growing interest in providing clinical trial participants with study results yet only limited information exists regarding the process and impact of sharing results. We sought to evaluate patient perceptions of how results had been shared from a large randomized cooperative group trial, and the impact of learning results. PATIENTS AND METHODS: A subset of women who participated in NCCTG 9831 (A Phase III Trial of Adjuvant Chemotherapy with or without Trastuzumab for Women with HER2-positive Breast Cancer) were mailed surveys after the preliminary study results were released to the public and mailed to participants. RESULTS: One hundred and 67 of 228 surveys sent (73%) were returned; 61% reported receiving trastuzumab on study; 4% reported recurrent disease. Ninety-five percent of participants were glad they received results; 81% were satisfied with how results were shared; 23% were more anxious after learning the results. Sixty-nine percent correctly interpreted the results. Logistic regression revealed that satisfaction with the process of receiving results was associated with satisfaction with treatment (P = 0.04), and increased anxiety was associated with dissatisfaction with treatment (0.02), incorrect interpretation of results (0.04), and not having received trastuzumab (P < 0.0001). CONCLUSION: Sharing results directly with study participants is met with overwhelmingly favorable responses from patients, although some may not initially understand the findings. The potential for increased anxiety should be considered, and psychosocial support may be required by some. A plan to share results should be routinely and prospectively considered in the design of cancer clinical trials.

Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density.

Matrix extracellular phosphoglycoprotein (MEPE), a member of the Small Integrin Binding Ligand N-linked Glycoprotein (SIBLING) family, is primarily expressed in normal bone and has been proposed as a phosphaturic factor because of high expression and secretion in oncogenic hypophosphatemic osteomalacia tumors. In order to begin to address the role of MEPE in normal human physiology, we developed a competitive ELISA to measure serum levels of MEPE. The ELISA was used to characterize the distribution pattern in a population consisting of 114 normal adult subjects. The mean value of MEPE was 476 +/- 247 ng/ml and levels decreased significantly with increasing age. MEPE levels were also significantly correlated with serum phosphorus and parathyroid hormone (PTH). In addition, MEPE levels correlated significantly with measures of bone mineral density in the femoral neck and total hip in a subset of 50 elderly subjects. The results are consistent with MEPE being involved in phosphate and bone metabolism in a normal population.

An evaluation of hybrid methods for matching biomedical terminologies: mapping the gene ontology to the UMLS.

Integration of disparate biomedical terminologies is becoming increasingly important as links between biological science and clinical medicine grow. Mapping concepts in the Gene Ontology (GO) to the UMLS may help further this integration and allow for more efficient information exchange among researchers. Using a gold standard of GO term--UMLS concept mappings provided by the NCI, we examined the performance of various published and combined mapping techniques, in order to maximize precision and recall. We found that for the previously published techniques precision varied between (0.61-0.95), and recall varied from (0.65-0.90), whereas for the hybrid techniques, precision varied between (0.66-0.97), and recall from (0.59-0.93). Our study reveals the benefits of using mapping techniques that incorporate domain knowledge, and provides a basis for future approaches to mapping between distinct biomedical vocabularies.

Linking biomedical language information and knowledge resources: GO and UMLS.

Integration of various informatics terminologies will be an essential activity towards supporting the advancement of both the biomedical and clinical sciences. The GO consortium has developed an impressive collection of biomedical terms specific to genes and proteins in a variety of organisms. The UMLS is a composite collection of various medical terminologies, pioneered by the National Library of Medicine. In the present study, we examine a variety of techniques for mapping terms from one terminology (GO) to another (UMLS), and describe their respective performances for a small, curated data set attained from the National Cancer Institute, which had precision values ranging from 30% (100% recall) to 95% (74% recall). Based on each technique's performance, we comment on how each can be used to enrich an existing terminology (UMLS) in future studies and how linking biological terminologies to UMLS differs from linking medical terminologies.

The effect of intravenous pamidronate on bone mineral density, bone histomorphometry, and parameters of bone turnover in adults with type IA osteogenesis imperfecta.

The type IA osteogenesis imperfecta (OI) phenotype is characterized by multiple fractures, blue sclerae, and minimal skeletal deformity without dentinogenesis imperfecta. The object of this study was to determine the effect of treatment with intravenous pamidronate (30 mg) every 3 months on bone density and bone histomorphometry in adults with type IA OI. After an initial iliac crest bone biopsy eight subjects, 5 women and 3 men, entered a treatment program lasting 21-30 months. Five subjects, all women, completed the study which included a posttreatment iliac crest bone biopsy. Pamidronate treatment led to significant increases in bone mineral density (BMD), measured by DXA, in the lumbar spine at 12 months (P = 0.05) and in the femur neck (P = 0.02) at 24 months. Significant increases in BMD were also seen in femoral trochanter at 12 months (P = 0.05) and at 24 months (P = 0.02), and in Ward's triangle at 12 months (P = 0.02) and 24 months (P = 0.05). Mean osteocalcin levels decreased 32%, C-terminal procollagen peptide and bone alkaline phosphatase declined 12% and 47% at 15 and 21 months, respectively. Deoxypyridinoline crosslink excretion decreased 31%. Posttreatment bone biopsy revealed a significant 6.3% increase in mean bone trabecular volume (P = 0.01). Mean cortical thickness increased from 848 mm to 1384 mm (P = 0.01) and cortical porosity decreased 13.2% (P = 0.01). Bone formation rate increased significantly in all 5 patients from 6.6 to 15.3 mm2/yr (P = 0.01). Mineral apposition rate was unchanged. These results indicate that intravenous pamidronate, 30 mg every 3 months, may have significant effects on bone density and histomorphometry in adults with type IA OI. Responses at higher doses remain to be evaluated.

Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus.

The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159-1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Variability signatures distinguish verbal from nonverbal counting for both large and small numbers.

Humans appear to share with animals a nonverbal counting process. In a nonverbal counting condition, subjects pressed a key a numeral-specified number of times, while saying "the" at every press. The mean number of presses increased as a power function of the target number, with a constant coefficient of variation (c.v.), both within and beyond the proposed subitizing range (1-4 or 5), suggesting small numbers are represented on the same continuum as larger numbers and subject to the same noise process (scalar variability). By contrast, when subjects counted their presses out loud as fast as they could, the c.v. decreased as the inverse square root of the target value (binomial variability instead of scalar variability). The unexpected power-law relation between target value and mean number of presses in nonverbal counting suggests a new hypothesis about the development of the function relating number symbols to mental magnitudes.

When further learning fails: stability and change following repeated presentation of text.

Kay (1955) presented a text passage to participants on a weekly basis and found that most errors and omissions in recall persisted despite repeated re-presentation of the text. Experiment I replicated and extended Kay's original research, demonstrating that after a first recall attempt there was very little evidence of further learning, whether measured in terms of further acquisition or error correction, over three more presentations of the text passages. Varying the schedule of presentations and tests had little effect, although performance was better when intermediate trials included both presentation and test than when only presentations or tests occurred. Experiment 2 explored whether this 'failure of further learning' effect could be overcome by (a) warning participants against basing their recall on their previous recall efforts and specifically directing them to base their recall upon the passages, (b) making each presentation more distinctive, or (c) drawing participants' attention to areas that would benefit from further learning by requiring them to tally their omissions and errors. The effect persisted in all cases. The findings have serious implications for the learning of text material.

Domain specificity and variability in cognitive development.

There are core-specific and noncore-specific domains of knowledge, but only the core-specific domains benefit from innate skeletal structures. Core skeletal domains are universally shared, even though their particular foci may vary; individuals vary extensively in terms of the noncore domains they acquire.

Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination.

With accumulating evidence indicating the importance of cytotoxic T lymphocytes (CTLs) in containing human immunodeficiency virus-1 (HIV-1) replication in infected individuals, strategies are being pursued to elicit virus-specific CTLs with prototype HIV-1 vaccines. Here, we report the protective efficacy of vaccine-elicited immune responses against a pathogenic SHIV-89.6P challenge in rhesus monkeys. Immune responses were elicited by DNA vaccines expressing SIVmac239 Gag and HIV-1 89.6P Env, augmented by the administration of the purified fusion protein IL-2/Ig, consisting of interleukin-2 (IL-2) and the Fc portion of immunoglobulin G (IgG), or a plasmid encoding IL-2/Ig. After SHIV-89.6P infection, sham-vaccinated monkeys developed weak CTL responses, rapid loss of CD4+ T cells, no virus-specific CD4+ T cell responses, high setpoint viral loads, significant clinical disease progression, and death in half of the animals by day 140 after challenge. In contrast, all monkeys that received the DNA vaccines augmented with IL-2/Ig were infected, but demonstrated potent secondary CTL responses, stable CD4+ T cell counts, preserved virus-specific CD4+ T cell responses, low to undetectable setpoint viral loads, and no evidence of clinical disease or mortality by day 140 after challenge.

Is radiation alone adequate treatment to the axilla for patients with limited axillary surgery? Implications for treatment after a positive sentinel node biopsy.

PURPOSE: To estimate the possible efficacy of axillary radiation therapy (AXRT) following a positive sentinel node biopsy (SNB), we evaluated the risk of regional nodal failure (RNF) for patients with clinical Stage I or II, clinically node-negative invasive breast cancer treated with either no dissection or a limited dissection (LD) defined as removal of 5 nodes or less followed by AXRT. MATERIALS AND METHODS: From 1978 to 1987, 292 patients underwent AXRT in the absence of axillary dissection; 126 underwent AXRT following LD. The median dose to the axilla was 46 Gy. The median dose to the supraclavicular fossa was 45 Gy. Among patients found to have positive nodes on LD, adjuvant chemotherapy and tamoxifen were administered to 81% and 7% of subjects, respectively. All patients had potential 8-year follow-up. RESULTS: Six of the 418 patients (1. 4%) developed RNF as a first site of failure within 8 years. Among these 6 patients (1.4%) with RNF as the first site of failure, 4 had simultaneous distant and regional recurrences; and 2 had isolated axillary failures. Three of the 292 patients (1%) with no axillary dissection, none of 84 patients with pathologically negative nodes and 3 of 42 patients (7%) with pathologically involved nodes had RNF as a first site of failure. Radiation pneumonitis developed in 5 patients (1.2%), brachial plexopathy in 5 (1.2%) and arm edema in 4 (1.2%). In all cases, radiation pneumonitis and brachial plexopathy were transient. CONCLUSION: These results imply that AXRT may be an effective and safe alternative to completion dissection for treatment of the axilla following a positive SNB. Further studies comparing these two options in specific patient subgroups are needed.

Multisite comparison of methods for the quantitation of the surface expression of CD38 on CD8(+) T lymphocytes. The ACTG Advanced Flow Cytometry Focus Group.

We evaluated the effect of specimen processing variations and quantitation methods on quantitative determination of CD38 expression on CD8 T lymphocytes. Neither lysing reagent (ammonium chloride versus BD FACSlyse), fixation (paraformaldehyde versus no final fixation step), nor acquisition delay (acquisition within 6 h after fixation versus 24 h after fixation) had a significant effect on CD38 relative fluorescent intensity or CD38 quantitative estimates (RFI or antibodies bound per cell). The only significant difference in fluorescent intensity and CD38 antibodies bound per cell (ABC) was encountered when whole blood was held for 24 h prior to staining and fixation and then acquired after another 24-h hold. However, for all sample processing methods above, the CD4 biologic calibrator and QuantiBRITE bead methods gave significantly different estimates of CD38 intensity. In many cases, however, these differences are relatively small and were more pronounced in certain laboratories. We conclude that there is some flexibility in sample processing methods for quantitative CD38 determination; however, it is preferable for a laboratory to employ one method of fluorescence quantitation calculation consistently because small differences are detected between different methods. Cytometry (Comm. Clin. Cytometry) 42:174-179, 2000.

Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence.

PURPOSE: To examine the relationship between pathologic margin status and outcome at 8 years after breast-conserving surgery and radiation therapy. PATIENTS AND METHODS: The study population comprised 533 patients with International Union Against Cancer/American Joint Committee on Cancer clinical stage I or II breast cancer who had assessable margins, who received at least 60 Gy to the primary tumor bed, and who had more than 8 years of potential follow-up. Each margin was scored (according to the presence of invasive or in situ disease that touched the inked surgical margin) as one of the following: negative, close, focally positive, or extensively positive. Outcome at 8 years was calculated using crude rates of first site of failure. A polychotomous logistic regression analysis was performed. Median follow-up time was 127 months. RESULTS: At 8 years, patients with close margins and those with negative margins both had a rate of local recurrence (LR) of 7%. Patients with extensively positive margins had an LR rate of 27%, whereas patients with focally positive margins had an intermediate rate of LR of 14%. In the polychotomous logistic regression model, margin status and the use of systemic therapy were the only two variables that had significant effects on the risk ratio of LR to remaining alive and free of disease. Among the 45 patients with focally positive margins who received systemic therapy, the crude LR rate was 7% at 8 years (95% confidence interval, 1% to 20%). CONCLUSION: Pathologic margin status and the use of adjuvant systemic therapy are the most important factors associated with LR among patients treated with breast-conserving surgery and radiation therapy.