Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.

Association of HER2DX with pathological complete response and survival outcomes in HER2-positive breast cancer.

BACKGROUND: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status. MATERIALS AND METHODS: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status. RESULTS: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk. CONCLUSIONS: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

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.

CSI-ISC--Concepts for smooth integration of health care information system components into established processes of patient care.

OBJECTIVES: The introduction of information system components (ISCs) usually leads to a change in existing processes, e.g. processes of patient care. These processes might become even more complex and variable than before. An early participation of end users and a better understanding of human factors during design and introduction of ISCs are key factors for a successful introduction of ISCs in health care. Nonetheless no specialized methods have been developed until now to systematically support the integration of ISCs in existing processes of patient care while taking into account these requirements. In this paper, therefore, we introduce a procedure model to implement Concepts for Smooth Integration of ISCs (CSI-ISC). METHODS: Established theories from economics and social sciences have been applied in our model, among them the stress-strain-concept, the contrastive task analysis (KABA), and the phase model for the management of information systems. RESULTS: CSI-ISC is based on the fact that while introducing new information system components, users experience additional workload. One essential aim during the introduction process therefore should be to systematically identify, prioritize and ameliorate workloads that are being imposed on human beings by information technology in health care. To support this, CSI-ISC consists of a static part (workload framework) and a dynamic part (guideline for the introduction of information system components into existing processes of patient care). CONCLUSIONS: The application of CSI-ISC offers the potential to minimize additional workload caused by information system components systematically. CSI-ISC rationalizes decisions and supports the integration of the information system component into existing processes of patient care.

Medical informatics education needs information system practicums in health care settings--experiences and lessons learned from 32 practicums at four universities in two countries.

OBJECTIVES: To report about the themes and about experiences with practicums in the management of information systems in health care settings (health information management) for medical informatics students. METHODS: We first summarize the topics of the health information management practicums/projects that the authors organized between 1990 and 2003 for the medical informatics programs at Heidelberg/Heilbronn, Germany, UMIT, Austria, as well as for the informatics program at the University of Leipzig, Germany. Experiences and lessons learned, obtained from the faculty that organized the practicums in the past 14 years, are reported. RESULTS: Thirty (of 32) health information management practicums focused on the analysis of health information systems. These took place inside university medical centers. Although the practicums were time-intensive and required intensively tutoring students with regard to health information management and project management, feedback from the students and graduates was mainly positive. DISCUSSION: It is clearly recommended that students specializing in medical informatics need to be confronted with real-world problems of health information systems during their studies.

The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.

The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 protein after ionizing radiation with some dependence on dose. Other protein products which participate in this signal transduction pathway, including p21WAF1/CIP1, Gadd45, and Mdm2, are also suboptimally induced in AT cells after ionizing radiation. Induction of p53 is also abnormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with UV-C irradiation or the topoisomerase inhibitors, etoposide and camptothecin. These results demonstrate a specific defect in this p53-dependent signal transduction pathway in AT cells. Potential models for this observed specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA ends.

Primary systemic therapy in operable breast cancer.

PURPOSE: Laboratory studies suggest that primary systemic therapy (PST) could improve control of micrometastatic disease and impact on overall survival (OS). This article examines the rationale for and preclinical and clinical data of PST in operable breast cancer and the potential role of intermediate biomarkers as predictive and/or prognostic factors for response and survival. DESIGN AND METHOD: We conducted an extensive literative review (including MEDLINE) on preclinical studies, single-arm feasibility studies, large randomized single- and multi-institutional trials, and laboratory correlate studies of PST in breast cancer. RESULTS: Small trials in locally advanced disease showed high initial rates of response and local control. Six randomized clinical trials (RCTs) of PST for palpable, operable breast cancer have been reported since 1991 (from 204 to 1,523 patients each). These data clearly show a small but significant (less than 10%) absolute increase in the use of breast-conservation treatment (BCT) with similar rates of local control. Although one study showed better disease-free survival (DFS) and another showed better OS, most studies did not show any survival advantage of primary versus adjuvant systemic therapy. Thus far, pathologic complete response seems to be the best predictor of survival, but clinical response assessment correlates poorly with pathologic response. Pilot studies demonstrated feasibility of procuring tissue at diagnosis and after treatment for assays of potential intermediate biomarkers. Initial data suggest a potential correlation between markers of proliferation and apoptosis and in vivo chemotherapy sensitivity. CONCLUSION: Thus far, RCTs of PST versus standard adjuvant therapy have not shown any clear benefit for DFS or OS in early breast cancer. Ongoing trials should determine if specific subsets of patients at risk would benefit from additional systemic therapy and the potential role of intermediate biomarkers in identifying such women. Although PST results in a small increase in the rate of BCT with similar rates of local control, current PST strategies should not replace standard adjuvant approaches. Rather, they represent an acceptable alternative to women with palpable, operable tumors and an excellent arena for clinical trials.

Phase I trial of pegylated liposomal doxorubicin and docetaxel in advanced breast cancer.

PURPOSE: To develop a combination of pegylated liposomal doxorubicin (Doxil; Alza Pharmaceuticals, Palo Alto, CA) and docetaxel (Taxotere; Aventis Pharmaceutical, Parsipanny, NJ) that can be safely used for the treatment of advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with locally advanced (n = 10) or metastatic (n = 31) breast cancer received Doxil (30-, 40-, or 45-mg/m(2) intravenous [IV] infusion over 30 to 60 minutes), followed 1 hour later by docetaxel (60 or 75 mg/m(2) by IV infusion over 1 hour) in cohorts of three to six patients. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, prolonged neutropenia, or grade 3 to 4 nonhematologic toxicity that occurred during cycle 1. RESULTS: In conjunction with docetaxel 75 mg/m(2) every 4 weeks, the MTD of Doxil was 30 mg/m(2) and required granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. Without G-CSF, the MTD was docetaxel 60 mg/m(2) and Doxil 30 mg/m(2) every 3 weeks; only 1 (7%) out of 15 patients treated at this dose level had cycle 1 DLT. Infusion reactions were common with Doxil with the recommended infusion schedule during the first cycle (55%) but were reduced with a modified schedule (7%). There was no clinically significant cardiac toxicity. Objective response occurred in eight of nine assessable patients with stage III disease and in 16 (52%) of 31 patients (95% confidence interval, 34% to 70%) with stage IV disease. CONCLUSION: The recommended dose and schedule of this combination for further evaluation is Doxil 30 mg/m(2) and docetaxel 60 mg/m(2) given every 3 weeks without G-CSF. When used with G-CSF, it is Doxil 30 mg/m(2) and docetaxel 75 mg/m(2) every 4 weeks.

Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: an Eastern Cooperative Oncology Group Study.

PURPOSE: Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles. PATIENTS AND METHODS: Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15 minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3 weeks for four to six cycles. RESULTS: Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION: The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.

Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group pilot study.

PURPOSE: A phase II study of ifosfamide, carboplatin, and prolonged oral administration of etoposide (ICE) in patients with untreated extensive-disease (ED) small-cell lung cancer (SCLC) was conducted to assess toxicities, response, and median survival. PATIENTS AND METHODS: Between July 1990 and August 1992, 35 patients were treated. ICE doses were ifosfamide 5 g/m2 by 24-hour continuous intravenous (CIV) infusion with mesna on day 1, carboplatin 300 mg/m2 intravenously (IV) on day 1, and etoposide 50 mg/m2 orally on days 1 to 21 every 4 weeks for up to six to eight cycles (schedule I). Because of severe hematologic toxicity in the first 18 patients, the last 17 patients received ifosfamide 3.75 mg/m2 IV on day 1, carboplatin 300 mg/m2 IV on day 1, and etoposide 50 mg orally on days 1 to 14 (schedule II). RESULTS: Nine of 18 patients (50%) on schedule I had 13 episodes of severe hematologic toxicity (one death), and only two (11%) received full doses on cycle 2. However, with schedule II, only four of 17 patients (24%) developed severe hematologic toxicity, and eight (47%) received full doses on cycle 2. Objective responses were observed in 29 of 35 patients (83%) (schedule 1, 16 of 18 patients [89%]; schedule II, 13 of 17 patients [76%]). There were eight (23%) complete responses (CRs) and 21 (60%) partial responses (PRs). The median survival duration was 8.3 months, and 1- and 2-year survival rates were 37% and 14%, respectively. CONCLUSION: ICE with oral etoposide has comparable activity with other regimens in ED SCLC. However, the 2-year survival rate may be higher and ICE with the lower doses of schedule II could be given safely with acceptable toxicity. Further studies of ICE compared with standard two-drug regimens are warranted.

The challenge of ubiquitous computing in health care: technology, concepts and solutions. Findings from the IMIA Yearbook of Medical Informatics 2005.

OBJECTIVES: To review recent research efforts in the field of ubiquitous computing in health care. To identify current research trends and further challenges for medical informatics. METHODS: Analysis of the contents of the Yearbook on Medical Informatics 2005 of the International Medical Informatics Association (IMIA). RESULTS: The Yearbook of Medical Informatics 2005 includes 34 original papers selected from 22 peer-reviewed scientific journals related to several distinct research areas: health and clinical management, patient records, health information systems, medical signal processing and biomedical imaging, decision support, knowledge representation and management, education and consumer informatics as well as bioinformatics. A special section on ubiquitous health care systems is devoted to recent developments in the application of ubiquitous computing in health care. Besides additional synoptical reviews of each of the sections the Yearbook includes invited reviews concerning E-Health strategies, primary care informatics and wearable healthcare. CONCLUSIONS: Several publications demonstrate the potential of ubiquitous computing to enhance effectiveness of health services delivery and organization. But ubiquitous computing is also a societal challenge, caused by the surrounding but unobtrusive character of this technology. Contributions from nearly all of the established sub-disciplines of medical informatics are demanded to turn the visions of this promising new research field into reality.

Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy.

Current dosing strategies for anticancer drugs result in wide interindividual pharmacokinetic variability. Here, we explored the influence of age, body size, concomitant drugs, dose, infusion duration, and sex on the clearance for doxorubicin and docetaxel in 243 individual patients. Patients received doxorubicin (n=110) or docetaxel (n=152) as monotherapy or in combination chemotherapy regimens. The mean (+/-S.D.) clearance was 63.6+/-22.7 L/h for doxorubicin and 42.8+/-14.9 L/h for docetaxel. Normalisation for body surface area (BSA) reduced the interindividual variability by only <1.7%. Doxorubicin clearance was significantly reduced when administered at doses >50 mg/m(2) or in combination with cyclophosphamide. Upper extremes of body size were associated with increased clearance for both drugs, whereas no consistent effect of age on clearance was discerned. Overall, these findings suggest that incorporation of variables in addition to BSA should be considered in routine dosing strategies for doxorubicin and docetaxel.

Use of SERMs for the adjuvant therapy of early-stage breast cancer.

Tamoxifen was the first in a class of drugs now commonly referred to as selective estrogen receptor modulators or SERMs. SERMs exhibit tissue-specific estrogenic agonist/antagonist activity through their ability to bind to the estrogen receptor alpha (ER) protein and interact with coregulatory proteins, thereby modulating transcription of estrogen target genes. Since its first approval by the United States Food and Drug Administration (FDA) in 1977, tamoxifen has been found to (a) lower the risk of recurrence and death for women with early-stage hormone receptor-positive breast cancer, irrespective of menopausal and node status or use of adjuvant chemotherapy; (b) reduce the risk of invasive breast cancer following breast conservation in women with ductal carcinoma in situ (DCIS); and (c) reduce the risk of breast cancer in high-risk women. Toremifene is the only other SERM approved by the FDA for breast cancer treatment. However, it offers no clear clinical advantage over tamoxifen in the adjuvant or metastatic settings. Several other SERMs are in various phases of clinical development. In addition, strategies to combine SERMs with other endocrine therapy like ovarian suppression or aromatase inhibitors are active areas of investigations. At present, SERMs are recognized as the first targeted and relatively nontoxic medical therapy for women with high-risk or steroid hormone receptor-positive breast cancer.

Tumor targeting by conjugation of DHA to paclitaxel.

Targeting an anti-cancer drug to tumors should increase the Area Under the drug concentration-time Curve (AUC) in tumors while decreasing the AUC in normal cells and should therefore increase the therapeutic index of that drug. Anti-tumor drugs typically have half-lives far shorter than the cell cycle transit times of most tumor cells. Tumor targeting, with concomitant long tumor exposure times, will increase the proportion of cells that move into cycle when the drug concentration is high, which should result in more tumor cell killing. In an effort to test that hypothesis, we conjugated a natural fatty acid, docosahexaenoic acid (DHA), through an ester bond to the paclitaxel 2'-oxygen. The resulting paclitaxel fatty acid conjugate (DHA-paclitaxel) does not assemble microtubules and is non-toxic. In the M109 mouse tumor model, DHA-paclitaxel is less toxic than paclitaxel and cures 10/10 tumored animals, whereas paclitaxel cures 0/10. One explanation for the conjugate's greater therapeutic index is that the fatty acid alters the pharmacokinetics of the drug to increase its AUC in tumors and decrease its AUC in normal cells. To test that possibility, we compared the pharmacokinetics of DHA-paclitaxel with paclitaxel in CD2F1 mice bearing approximately 125 mg sc M109 tumors. The mice were injected at zero time with a bolus of either DHA-paclitaxel or paclitaxel formulated in 10% cremophor/10% ethanol/80% saline. Animals were sacrificed as a function of time out to 14 days. Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DHA-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets paclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i.v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v. paclitaxel. The tumor concentration of paclitaxel derived from i.v. paclitaxel drops rapidly, so that by 16 h it has fallen to the same concentration (2.8 microM) as after an equi-toxic concentration of DHA-paclitaxel. In plasma, paclitaxel AUC after an MTD dose of DHA-paclitaxel is approximately 0.5% of DHA-paclitaxel AUC. Thus, the increase in tumor AUC and the limited plasma AUC of paclitaxel following DHA-paclitaxel administration are consistent with the increase in therapeutic index of DHA-paclitaxel relative to paclitaxel in the M109 mouse tumor model. A phase I clinical study has been completed at The Johns Hopkins Hospital to evaluate the safety of DHA-paclitaxel in patients with a variety of solid tumors. Twenty-one patients have been treated to date. The recommended phase II dose is 1100 mg/m(2), which is equivalent to 4.6 times the maximum approved paclitaxel dose on a molar basis. No alopecia or significant peripheral neuropathy, nausea, or vomiting have been observed. Asymptomatic, transient neutropenia has been the primary side effect. Eleven of 22 evaluable phase I patients transitioned from progressive to stable disease, as assessed by follow-up CT. Significant quality of life improvements have been observed. Thus, DHA-paclitaxel is well tolerated in patients and cures tumors in mice by targeting drug to tumors.

Adjuvant systemic management of early stage carcinoma of the breast.

In the last three decades, there has been a gradual, though significant change in the treatment of early stage breast cancer. For almost a century, physicians advocated an "anatomical view" of the dissemination of this disease, which justified a more radical and mutilating treatment strategy. Finally in the mid-1970s, results from large randomized trials began to show that either mastectomy or lumpectomy with radiation therapy were appropriate treatment for women with early stage disease. These results suggested that breast cancer can actually be a systemic disease ("biological view") even in early stages. This hypothesis was confirmed when large randomized clinical trials demonstrated the effectiveness of adjuvant systemic therapy in controlling micrometastatic disease in women with node-positive and node negative disease. As we approach the end of this century, most patients with early stage disease will be offered some form of adjuvant systemic therapy, before or after local treatment with surgery, with or without local radiation therapy. There has been a lot of interest on the proper sequence of the therapeutic modalities, in particular with the recent publication of larger randomized trials of primary systemic therapy. This specific topic is discussed elsewhere in this issue by Singletary.

Medical Imaging Informatics and Medical Informatics: opportunities and constraints. Findings from the IMIA yearbook of Medical Informatics 2002.

OBJECTIVES: The Yearbook of Medical Informatics is published annually by the International Medical Informatics Association (IMIA) and contains a selection of recent excellent papers on medical informatics research (http://www.yearbook.uni-hd.de). The 2002 Yearbook of Medical Informatics took as its theme the topic of Medical Imaging Informatics. In this paper, we will summarize the contributions of medical informatics researchers to the development of medical imaging informatics, discuss challenges and opportunities of imaging informatics, and present the lessons learned from the IMIA Yearbook 2002. RESULTS AND CONCLUSIONS: Medical informatics researchers have contributed to the development of medical imaging methods and systems since the inception of this field approximately 40 years ago. The Yearbook presents selected papers and reviews on this important topic. In addition, as usual, the Yearbook 2002 also contains a variety of papers and reviews on other subjects relevant to medical informatics, such as Bioinformatics, Computer-supported education, Health and clinical management, Health information systems, Knowledge processing and decision support, Patient records, and Signal processing.