Usability of Electronic Patient-Reported Outcome Measures for Older Patients With Cancer: Secondary Analysis of Data from an Observational Single Center Study.

BACKGROUND: Patient-reported outcomes are considered the gold standard for assessing subjective health status in oncology patients. Electronic assessment of patient-reported outcomes (ePRO) has become increasingly popular in recent years in both clinical trials and practice. However, there is limited evidence on how well older patients with cancer can complete ePRO assessments. OBJECTIVE: We aimed to investigate how well adult patients with cancer of different age ranges could complete ePRO assessments at home and in a treatment facility and to identify factors associated with the ability to complete questionnaires electronically. METHODS: This retrospective longitudinal single-center study involved survivors of cancer who participated in inpatient rehabilitation. Patients completed ePRO assessments before rehabilitation at home (T1) and after rehabilitation at the facility (T2). We analyzed the rate of patients who could complete the ePRO assessment at T1 and T2, the proportion of patients who required assistance, and the time it took patients to complete standardized questionnaires. Multivariate logistic regression analyses were conducted to identify predictors of ePRO completion rate and the need for assistance. RESULTS: Between 2017 and 2022, a total of 5571 patients were included in this study. Patients had a mean age of 60.3 (SD 12.2) years (range 18 to 93 years), and 1135 (20.3%) of them were classified as geriatric patients (>70 years). While more than 90% (5060/5571) of all patients completed the ePRO assessment, fewer patients in the age group of >70 years (924/1135, 81.4% at T1 vs 963/1135, 84.8% at T2) completed the assessment. Approximately 19% (1056/5571) of patients reported a need for assistance with the ePRO assessment at home, compared to 6.8% (304/4483) at the institution. Patients older than 70 years had a significantly higher need for assistance than those in younger age groups. Moreover, a gender difference was observed, with older women reporting a higher need for assistance than men (71-80 years: women requiring assistance 215/482, 44.6% vs men 96/350, 27.4%; P<.001 and >80 years: women 102/141, 72.3% vs men 57/112, 50.9%; P<.001). On average, patients needed 4.9 (SD 3.20) minutes to remotely complete a 30-item questionnaire (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and patients in the older age groups took significantly longer compared to younger age groups. Lower age and higher physical functioning were the clearest predictors for both the ePRO completion rate and the need for assistance in the multivariate regression analysis. CONCLUSIONS: This study's results indicate that ePRO assessment is feasible in older individuals with cancer, but older patients may require assistance (eg, from relatives) to complete home-based assessments. It may be more feasible to conduct assessments in-house in this population. Additionally, it is crucial to carefully consider which resources are necessary and available to support patients in using ePRO devices.

Associations of Age and Sex with the Efficacy of Inpatient Cancer Rehabilitation: Results from a Longitudinal Observational Study Using Electronic Patient-Reported Outcomes.

Cancer rehabilitation is thought to increase the quality of life (QOL) and functioning of cancer survivors. It remains, however, uncertain whether subgroups benefit equally from rehabilitation. We wished to investigate the outcomes of multimodal rehabilitation according to age, sex and functioning. Patients of an Austrian rehabilitation center routinely completed the EORTC QLQ-C30 and the hospital anxiety and depression scale (HADS) questionnaires prior to (T1), and after rehabilitation (T2). To compare the outcomes between age groups (i.e., <40, 41-69, and ≥70 years), sex, and the Norton scale risk status, repeated measures of analyses of variance were calculated. A total of 5567 patients with an average age of 60.7 years were included, of which 62.7% were female. With T1 indicating the cancer survivors' needs, older and high-risk patients reported lower functioning (all p < 0.001) and a higher symptom burden for most scales (all p < 0.05) before rehabilitation. Regardless of age, sex or risk status, the patients showed at a least small to medium improvement during rehabilitation for anxiety, depression, and most functioning and symptom scales. Some between-group differences were observed, none of which being of a relevant effect size as determined with the Cohen's d. In conclusion, QOL is improved by rehabilitation in all patients groups, independently from age, sex, or the risk status.

Large Improvements in Health-Related Quality of Life and Physical Fitness during Multidisciplinary Inpatient Rehabilitation for Pediatric Cancer Survivors.

Rehabilitation is a key element in improving health-related quality of life (HRQOL) for pediatric cancer survivors. The aim of this study was to present data from a multidisciplinary inpatient rehabilitation treatment. Children took part in a four-week multidisciplinary family-oriented inpatient rehabilitation. A total of 236 children (>5−21 years) and 478 parents routinely completed electronic patient-reported outcomes (ePROs), performance-based assessments, and clinician-rated assessments before (T1) and at the end (T2) of rehabilitation. HRQOL was assessed with the PedsQL generic core and PedsQL cancer module. Data were analyzed using repeated measures analysis of variance (ANOVA). Statistically significant improvements with medium to large effect sizes were observed for most HRQOL scales (η2 = 0.09−0.31), as well as performance-based and clinician-rated assessments for physical activity and functional status (η2 > 0.28). Agreement between children's PROs and parents' proxy ratings was lower before (rICC = 0.72) than after (rICC = 0.86) rehabilitation. While the concordance between children and parents' assessment of changes during rehab was low to moderate (r = 0.19−0.59), the use of the performance score led to substantially increased scores (r = 0.29−0.68). The results of this naturalistic observational study thus highlight the benefits of multidisciplinary pediatric inpatient rehabilitation for childhood cancer survivors. The use of the performance score is recommended in this field.

Evaluation by electronic patient-reported outcomes of cancer survivors' needs and the efficacy of inpatient cancer rehabilitation in different tumor entities.

OBJECTIVE: We investigated cancer survivors' health-related quality of life (HRQOL), specific deficiencies related to underlying disease or treatment, and benefits of rehabilitation in a large variety of cancer entities. PATIENTS AND METHODS: Electronic patient-reported outcomes were performed as clinical routine procedures. Cancer survivors underwent a 3-week multidisciplinary inpatient rehabilitation. Twenty-one different cancer entities were analyzed separately before (T0) and by the end (T1) of rehabilitation. HRQOL, symptoms, and functions were assessed with EORTC-QLQ-C30 questionnaire, psychological distress with Hospital Anxiety and Depression Scale (HADS). RESULTS: Four thousand four hundred one of 5912 rehabilitants were evaluable, having completed both questionnaires at T0 and T1. All function mean scores and HRQOL were lower than in Austrian normal population, while levels of anxiety, depression, and all symptom scores were higher. HRQOL was particularly low in lung, liver, and bladder cancer patients. Maximum anxiety levels were observed in patients with breast and thyroid cancer patients, the highest levels of depression in liver and brain cancer patients. Fatigue was severe in patients with lung, liver, esophageal, bladder cancer, and myeloma patients. Mean scores were also high for pain and insomnia. In the group of all rehabilitants, a highly significant improvement of global HRQOL, anxiety, depression, and all function and symptom scores was observed at T1 (p < 0.001). We noted significant improvement of HRQOL, anxiety, depression, fatigue, emotional, social, role, and physical functions in each cancer entity with medium to large effect sizes. Other recorded symptoms were reduced in the majority of cancers. CONCLUSION: Rehabilitation effectively improves psychological distress and HRQOL as a part of treatment for various cancers.

How to implement routine electronic patient-reported outcome monitoring in oncology rehabilitation.

BACKGROUND: Implemenation of patient-reported outcomes (PRO) like quality of life can add the patient's perspective to traditional clinical outcomes of cancer rehabilitation in a structured and standardized way. AIM: To present useful steps for a successful implementation of routine electronic patient-reported outcomes (ePRO) monitoring. The presented steps are exemplified by describing the procedure applied in an Austrian inpatient cancer rehabilitation centre. METHODS: The suggested implementation steps are presented based on the structure of the replicating effective programmes framework, which was used for developing a pragmatic implementation strategy. RESULTS: We scheduled alternating trainings and process evaluations for audit and enhancement of procedures. In this way, the ePRO participation rates could be improved. Stakeholder involvement led to initiatives that included the integration of ePRO data into the medical discharge letter and the implementation of follow-up assessments. DISCUSSION: Tailored changes in assessment procedures enabled the successful implementation of ePRO, which has been shown to be feasible before and after cancer rehabilitation. The continuous involvement of stakeholders paved the way for further projects initiated by medical staff as users themselves (inclusion of PRO data in the discharge letter and a comprehensive ePRO follow-up using a versatile online patient portal).

Improvement of quality of life and psychological distress after inpatient cancer rehabilitation : Results of a longitudinal observational study.

BACKGROUND: With the growing number of cancer survivors worldwide the need for high quality cancer rehabilitation after primary treatment is steadily increasing. The aim of the present study was to investigate change of psychological distress and health-related quality of life (HRQOL) during multidisciplinary inpatient cancer rehabilitation in a large sample of cancer survivors suffering from different cancer entities. METHODS: We analyzed data from routine HRQOL and distress monitoring at a cancer inpatient rehabilitation center. Cancer survivors completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and the Hospital Anxiety and Depression Scale (HADS) before and after multidisciplinary rehabilitation treatment. Changes of patients' functioning and symptoms were analyzed using repeated measures analysis of variance (ANOVA) and effect sizes (Cohens' d). Patients' pretreatment and posttreatment scores were compared to reference data from the German general population. RESULTS: A total of 939 patients (mean age 58.6 years, SD 11.9 years; 59.9% women) who attended rehabilitation from January 2014 to September 2015 were included in the analysis. We found clinically meaningful improvement in almost all domains of the EORTC QLQ-C30 as well as in anxiety and depression (HADS). The largest improvements were found for the QLQ-C30 subscales emotional functioning (d = 0.78), fatigue (d = 0.65), and social functioning (d = 0.56). CONCLUSIONS: We found clinically meaningful improvements of patients' HRQOL, anxiety and depression during an oncological inpatient rehabilitation treatment. Our results warrant further prospective controlled studies to evaluate the long-term effectiveness of inpatient rehabilitation.

Cancer rehabilitation in Austria--aspects of Physical Medicine and Rehabilitation.

In Austria, cancer rehabilitation is an important issue in the management of cancer patients. Survival rates and survival time of cancer patients are increasing, and cancer rehabilitation is an important part in the treatment and care of cancer patients with the goal to improve functional status, quality of life, and (social) participation. Today, in Austria there are approximately 600 beds for inpatient rehabilitation. The field of outpatient rehabilitation will maybe be expanded after evaluating the existing pilot projects. Beside other specialities, the field of Physical Medicine and Rehabilitation (PM&R) plays an important role in cancer rehabilitation. In cancer rehabilitation, especially activating modalities from PM&R such as exercise are very important and well-accepted parts to improve functional status, quality of life, and participation of patients.

RBM24 is a major regulator of muscle-specific alternative splicing.

Cell-type-specific splicing generates numerous alternatively spliced transcripts playing important roles for organ development and homeostasis, but only a few tissue-specific splicing factors have been identified. We found that RBM24 governs a large number of muscle-specific splicing events that are critically involved in cardiac and skeletal muscle development and disease. Targeted inactivation of RBM24 in mice disrupted cardiac development and impaired sarcomerogenesis in striated muscles. In vitro splicing assays revealed that recombinant RBM24 is sufficient to promote muscle-specific exon inclusion in nuclear extracts of nonmuscle cells. Furthermore, we demonstrate that binding of RBM24 to an intronic splicing enhancer (ISE) is essential and sufficient to overcome repression of exon inclusion by an exonic splicing silencer (ESS) containing PTB and hnRNP A1/A2 binding sites. Introduction of ESS and ISE converted a constitutive exon into an RMB24-dependent alternative exon. We reason that RBM24 is a major regulator of alternative splicing in striated muscles.

Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: a dose-finding study.

Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low-dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer.

T-cell lymphoproliferative disorder potentially induced by imatinib in a patient with GIST.

BACKGROUND: A 71-year-old male patient was diagnosed as having a KIT-positive gastrointestinal stromal tumor located at the gastric antrum. With no signs of distant metastasis, the patient primarily underwent gastric surgery with antrectomy and Billroth-I-reconstruction. Owing to tumor size and mitotic index, the patient was considered at high risk of tumor relapse and thus was entered into a clinical trial to receive adjuvant imatinib treatment. 4 months after initiation of imatinib treatment, the patient presented with several newly discovered subcutaneous and intra-abdominal tumor lesions. Imatinib treatment had been tolerated well until then. INVESTIGATIONS: Physical examination, blood tests, biopsies of the subcutaneous tumor lesions, tumor morphology and immunohistochemistry, PCR for the T-cell receptor gamma genes, sequential CT and PET-CT. DIAGNOSIS: Monoclonal T-cell lymphoproliferative disorder, potentially induced by imatinib. MANAGEMENT: Imatinib was stopped, after which the tumor lesions spontaneously regressed and, eventually, complete remission was achieved.

Expression of multidrug resistance-associated ABC transporters in B-CLL is independent of ZAP70 status.

PURPOSE: To assess whether the poor prognosis of ZAP70-positive B-cell chronic lymphocytic leukemia (CLL) is associated with the overexpression of ABC transporter genes that are responsible for pleiotropic drug resistance. MATERIALS AND METHODS: The transcript level of ten drug transporters was analyzed using semiquantitative and quantitative RT-PCR in control hematopoietic cells, in 41 CLL patient samples and in 5 lymphoma cell lines. ZAP70 status was determined by immunoblotting. RESULTS: Of all analyzed transporters, MDR1, MDR2, MRP1, MRP4, MRP5, and MRP7 were expressed at a significantly higher level in B lymphocytes when compared with other hematopoietic cells in peripheral blood. A subgroup of 41 CLL patient samples showed similar or higher expression of these genes than control B cells, and CLL cells exhibited high expression when compared with multiple lymphoma cell lines. No significant correlation between ZAP70 expression and ABC transporter expression was observed. CONCLUSION: The ZAP70 status is independent of the multidrug resistance phenotype in CLL.

Immunotoxin BL22 induces apoptosis in mantle cell lymphoma (MCL) cells dependent on Bcl-2 expression.

Mantle cell lymphoma (MCL) is an incurable mature B cell proliferation, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL has an even worse prognosis and new treatment options are clearly needed. We analysed the effects of BL22, an immunotoxin composed of the Fv portion of an anti- CD22 antibody fused to a 38-kDa Pseudomonas exotoxin-A fragment on four MCL cell lines as well as on primary cells of four MCL patients. Apoptosis induction by BL22 was much more pronounced in MCL cell lines with low Bcl-2 expression (NCEB-1, JeKo-1 and JVM-2) compared to Granta-519 cells with high Bcl-2 expression. While the expression of the antiapoptotic protein Mcl-1 declined (NCEB-1, Granta-519), Bcl-2 levels remained unchanged in Granta-519 cells. However transfection of BCL2 cDNA into NCEB-1, JeKo-1 and JVM-2 cells significantly reduced BL22-mediated toxicity. Accordingly we examined the effects of Bcl-2 inactivation in Granta-519 cells using siRNA. Indeed, apoptosis induction was strongly enhanced in Granta-519 cells with silenced Bcl-2. Our results were confirmed in freshly isolated MCL-cells from patients with leukaemic MCL. We conclude that Bcl-2 expression is important for mediating resistance against the immunotoxin BL22 in MCL cells.

Histone deacetylase inhibitors induce a very broad, pleiotropic anticancer drug resistance phenotype in acute myeloid leukemia cells by modulation of multiple ABC transporter genes.

PURPOSE: Histone deacetylase inhibitors (HDACi) are being studied in clinical trials with the aim to induce cellular differentiation, growth arrest, and apoptosis of tumor cells. Recent reports suggest that the multidrug resistance-1 (MDR1) gene is regulated by epigenetic mechanisms. To investigate whether additional drug transporters are regulated by HDACi and how this affects cytotoxicity, acute myeloid leukemia (AML) cells were examined. EXPERIMENTAL DESIGN: AML cells were cultured in the presence of phenylbutyrate, valproate, suberoylanilide hydroxamic acid, or trichostatin A and analyzed for drug transporter expression and function as well as sensitivity to anticancer drugs. RESULTS: MDR1, breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRP) 7 and 8 were induced in a dose- and time-dependent manner as shown by semiquantitative PCR. The pattern of gene induction was cell line specific. Phenylbutyrate induced P-glycoprotein and BCRP expression and the efflux of drugs as determined with labeled substrates. KG-1a cells treated with phenylbutyrate developed resistance to daunorubicin, mitoxantrone, etoposide, vinblastine, paclitaxel, topotecan, gemcitabine, and 5-fluorouracil; as a result drug-induced apoptosis was impaired. Chromatin immunoprecipitation revealed the hyperacetylation of histone proteins in the promoter regions of MDR1, BCRP, and MRP8 on valproate treatment. Furthermore, an alternative MRP8 promoter was induced by HDACi treatment. CONCLUSIONS: Exposure of AML cells to HDACi induces a drug resistance phenotype broader than the "classic multidrug resistance," which might negatively affect treatment effectiveness.

Ifosfamide, epirubicin and etoposide rituximab in refractory or relapsed B-cell lymphoma: analysis of remission induction and stem cell mobilization.

Chemotherapy with ifosfamide, epirubicin and etoposide (IEV) is an effective treatment regimen for refractory/relapsed non-Hodgkin lymphoma (NHL). Rituximab has been shown to improve response rates, progression-free survival and overall survival in B-cell NHL. This study included 85 patients who were treated with IEV or rituximab-IEV (R-IEV) for refractory/relapsed B-cell NHL. The overall response rate was 40.7% (IEV) versus 68.8% (R-IEV). Fever occurred after 23.4% of IEV and 19.4% of R-IEV cycles. 94.9% of patients mobilized sufficient numbers of CD34+ cells (IEV) versus 93.8% (R-IEV). Fifty-five patients (64.7%) proceeded to high-dose therapy after IEV+/-rituximab. The median survival time was 60.0 months (IEV) and 19.5 months (R-IEV), and has not been reached for patients who received high-dose therapy. The addition of rituximab to IEV salvage chemotherapy increases the response rates in B-cell NHL without affecting stem cell mobilization, but overall survival for patients proceeding to high-dose chemotherapy is not improved.

Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex.

A 19-year old patient with tuberous sclerosis presented with a renal angiomyolipoma. Because animal trials of tuberous sclerosis showed an effect of rapamycin on renal tumors, our patient was administered rapamycin for 6 months. During this time, the renal angiomyolipoma shrank significantly, regrew during an 8-month period, and decreased in size again after readministration of rapamycin.

Efficacy of consolidation high-dose chemotherapy with ifosfamide, carboplatin and etoposide (HD-ICE) followed by autologous peripheral blood stem cell rescue in chemosensitive patients with metastatic soft tissue sarcomas.

BACKGROUND: Prognosis of patients with metastatic soft tissue sarcomas (MSTS) is poor even after response to doxorubicin-based chemotherapy. We report phase II data of high-dose chemotherapy and peripheral blood stem cell (PBSC) rescue in patients with MSTS responding to AI-G chemotherapy. PATIENTS AND METHODS: From 1997 to 2002, 55 patients with MSTS were prospectively treated with 4 cycles of AI-G (doxorubicin 75 mg/m(2), ifosfamide 6 g/m(2) with G-CSF support). Responders received 2 further cycles of AI-G with collection of PBSCs. High-dose chemotherapy consisted of ifosfamide 12 g/m(2), carboplatin 1.2 g/m(2) and etoposide 1.2 g/m(2) (HD-ICE) followed by reinfusion of PBSCs. RESULTS: Twenty-one of 55 patients (38%) were assessed as responders (3 complete response, 18 partial response). All but 2 patients refusing treatment received high-dose chemotherapy with PBSC rescue leading to grade IV hematologic toxicity without severe infections in all patients. No toxic death occurred. After a median follow-up time of 30 months, the median progression-free time was 12 months and survival time was 22 months for the entire group. By intent-to-treat analysis the probability of 5-year progression-free survival was significantly higher for patients allocated to HD-ICE compared to patients receiving second-line chemotherapy after failure of AI-G (14 vs. 3%; p = 0.003). The estimated 5-year overall survival between the 2 groups was different (27% vs. not reached) but did not reach significance (p = 0.08). CONCLUSION: HD-ICE is feasible and promising in patients with chemosensitive MSTS. A randomized phase III trial is warranted to further define the role of HD-ICE as consolidation treatment in these patients.

Phase I clinical and pharmacokinetic study of BBR 3576, a novel aza-anthrapyrazole, administered i.v. every 4 weeks in patients with advanced solid tumors: a phase I study group trial of the Central European Society of Anticancer-Drug Research (CESAR).

BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.

In vitro and in vivo spiral CT to determine bone mineral density: initial experience in patients at risk for osteoporosis.

PURPOSE: To evaluate, both experimentally and in vivo, if nondedicated standard spiral computed tomography (CT) may be used to obtain reliable bone mineral density (BMD) data. MATERIALS AND METHODS: Twenty lumbar spine specimens from human cadavers were examined with standard quantitative CT and spiral CT. In addition, 50 patients with a history of lymphoma and chemotherapy were examined. These patients underwent long-term follow-up CT to rule out tumor recurrence. Quantitative CT was performed before contrast medium administration to assess potential posttherapeutic osteoporosis. In addition, fracture status of the spine was determined. Mean BMD values and SDs were calculated, and relationships between measurements obtained with quantitative CT and spiral CT were assessed with linear regression analysis and two-tailed tests of significance (t test). A linear fit was used to calculate quantitative CT data from spiral CT values. RESULTS: For the specimens, a coefficient of determination (r(2) = 0.99, P <.001) was found between BMD measurements obtained with quantitative CT and those obtained with spiral CT. Mean BMD in specimens was 63.6 mg/mL +/- 36.6 with quantitative CT and 74.4 mg/mL +/- 38.2 with spiral CT. Mean BMD in patients was 105.0 mg/mL +/- 34.6 with quantitative CT and 139.5 mg/mL +/- 42.7 with contrast medium-enhanced spiral CT. A coefficient of determination (r(2) = 0.91, P <.001) was obtained between these measurements. Mean BMD from L1 through L3 vertebrae was calculated, and spiral CT data were multiplied by 0.77 to yield quantitative CT data. Differences in BMD were significant (P <.05) for patients with (n = 9) and those without fractures (n = 41), as determined with spiral CT and quantitative CT. CONCLUSION: Correlations between BMD data obtained with spiral CT and standard quantitative CT were highly significant. By using a conversion factor, BMD measurements can be determined with routine abdominal spiral CT scans.

Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia by anti-CD22 immunotoxins.

B cells of chronic lymphocytic leukemia (CLL) are long-lived in vivo, possibly because of defects in apoptosis. We investigated BL22, an immunotoxin composed of the Fv portion of an anti-CD22 antibody fused to a 38-kDa Pseudomonas exotoxin-A fragment. B cells from 22 patients with CLL were immunomagnetically enriched (96% purity) and were cultured with BL22 or an immunotoxin that does not recognize hematopoietic cells. The antileukemic activity of BL22 was correlated with CD22 expression, as determined by flow cytometry. BL22 induced caspase-9 and caspase-3 activation, poly(adenosine diphosphate [ADP]-ribose)polymerase (PARP) cleavage, DNA fragmentation, and membrane flipping. Cell death was associated with the loss of mitochondrial membrane potential and the down-regulation of Mcl-1 and X-chromosomal inhibitor of apoptosis protein (XIAP). Furthermore, BL22 induced a proapoptotic 18-kDa Bax protein and conformational changes of Bax. Z-VAD.fmk abrogated apoptosis, confirming that cell death was executed by caspases. Conversely, interleukin-4, a survival factor, inhibited spontaneous death in culture but failed to prevent immunotoxin-induced apoptosis. BL22 cytotoxicity was markedly enhanced when combined with anticancer drugs including vincristine. We also investigated HA22, a newly engineered immunotoxin, in which BL22 residues are mutated to improve target binding. HA22 was more active than BL22. In conclusion, these immunotoxins induce caspase-mediated apoptosis involving mitochondrial damage. Combination with chemotherapy is expected to improve the efficacy of immunotoxin treatment.

Restoration of transgene expression in hematopoietic cells with drug-selectable marker genes.

Somatic gene therapy is supposed to cure life-threatening hematopoietic disorders but is limited by unstable transgene expression. Efficient gene transfer to hematopoietic progenitor cells does not ensure long-term gene expression. It would therefore be advantageous if the expression of transgenes could be restored in bone marrow. Transfer of drug resistance genes such as the multidrug resistance (MDR1) or mutated dihydrofolate reductase (DHFR) genes to hematopoietic cells protects them from the toxicity of anticancer drugs. In addition, transduced cells obtain a selective growth advantage in the presence of anticancer drugs. This can be used to introduce and enrich otherwise non-selectable genes by cotransfer to target cells. Bicistronic vectors have been constructed for coexpression of drug resistance genes and non-selectable, therapeutic genes with the use of an internal ribosomal entry-site (IRES). With the use of bicistronic vectors, expression and function of therapeutic genes have been increased in tissue culture and in animal models. Further preclinical investigations are needed to identify optimal conditions for selection.