Patient satisfaction with treatments for moderate-to-severe plaque psoriasis in clinical practice.

BACKGROUND: Treatment satisfaction among patients with moderate-to-severe psoriasis has not been studied and compared across treatments using a validated instrument. OBJECTIVES: To assess patient-reported satisfaction with systemic and phototherapy treatments for moderate-to-severe psoriasis in clinical practice and to correlate satisfaction with disease severity and quality-of-life measures. METHODS: This was a cross-sectional study of 1182 patients with moderate-to-severe psoriasis in the Dermatology Clinical Effectiveness Research Network in the U.S.A. Patients receiving either topical therapies only; monotherapy with oral systemic therapies, biologics or narrowband ultraviolet B phototherapy; or combination therapy with biologics and methotrexate completed the Treatment Satisfaction Questionnaire for Medication version II. RESULTS: Median unadjusted overall satisfaction scores were highest for patients receiving biologic monotherapies, biologic-methotrexate combinations, or phototherapy (83.3); scores were lowest for those receiving topical therapies only or acitretin (66.7). In fully adjusted models, compared with patients receiving methotrexate monotherapy, those receiving adalimumab, etanercept, ustekinumab, phototherapy or adalimumab with methotrexate had significantly higher median overall satisfaction scores by 7.2-8.3 points, while those receiving topical therapies only had significantly lower overall satisfaction by 8.9 points. Adjusted convenience scores were lowest for patients receiving topical therapies only or infliximab. Modest but significant correlations were found between the overall satisfaction subscale and both the Psoriasis Area and Severity Index (ρ = -0.36, P < 0.001) and the Dermatology Life Quality Index (ρ = -0.47, P < 0.001). CONCLUSIONS: Discernible differences were found in treatment satisfaction among therapies, particularly regarding treatment effectiveness and convenience. Further application of treatment satisfaction measures may inform treatment decisions and guideline development.

Early rehospitalization after kidney transplantation: assessing preventability and prognosis.

Early rehospitalization after kidney transplantation (KT) is common and may predict future adverse outcomes. Previous studies using claims data have been limited in identifying preventable rehospitalizations. We assembled a cohort of 753 adults at our institution undergoing KT from January 1, 2003 to December 31, 2007. Two physicians independently reviewed medical records of 237 patients (32%) with early rehospitalization and identified (1) primary reason for and (2) preventability of rehospitalization. Mortality and graft failure were ascertained through linkage to the Scientific Registry of Transplant Recipients. Leading reasons for rehospitalization included surgical complications (15%), rejection (14%), volume shifts (11%) and systemic and surgical wound infections (11% and 2.5%). Reviewer agreement on primary reason (85% of cases) was strong (kappa = 0.78). Only 19 rehospitalizations (8%) met preventability criteria. Using logistic regression, weekend discharge (odds ratio [OR] 1.59, p = 0.01), waitlist time (OR 1.10, p = 0.04) and longer initial length of stay (OR 1.42, p = 0.03) were associated with early rehospitalization. Using Cox regression, early rehospitalization was associated with mortality (hazard ratio [HR] 1.55; p = 0.03) but not graft loss (HR 1.33; p = 0.09). Early rehospitalization has diverse causes and presents challenges as a quality metric after KT. These results should be validated prospectively at multiple centers to identify vulnerable patients and modifiable processes-of-care.

Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study.

Hepatitis C virus (HCV) infection is associated with systemic inflammation and metabolic complications that might predispose patients to atherosclerosis. However, it remains unclear if HCV infection increases the risk of acute myocardial infarction (MI). To determine whether HCV infection is an independent risk factor for acute MI among adults followed in general practices in the United Kingdom (UK), a retrospective cohort study was conducted in The Health Improvement Network, from 1996 through 2008. Patients ≥18 years of age with at least 6 months of follow-up and without a prior history of MI were eligible for study inclusion. HCV-infected individuals, identified with previously validated HCV diagnostic codes (n = 4809), were matched on age, sex and practice with up to 15 randomly selected patients without HCV (n = 71 668). Rates of incident MI among patients with and without a diagnosis of HCV infection were calculated. Adjusted hazard ratios were estimated using Cox proportional hazards regression, controlling for established cardiovascular risk factors. During a median follow-up of 3.2 years, there was no difference in the incidence rates of MI between HCV-infected and -uninfected patients (1.02 vs 0.92 events per 1000 person-years; P = 0.7). HCV infection was not associated with an increased risk of incident MI (adjusted HR, 1.10; 95% confidence interval [CI], 0.67-1.83). Sensitivity analyses including the exploration of a composite outcome of acute MI and coronary interventions yielded similar results (adjusted HR, 1.16; 95% CI, 0.77-1.74). In conclusion, HCV infection was not associated with an increased risk of incident MI.

Validity of The Health Improvement Network (THIN) for the study of psoriasis.

BACKGROUND: Psoriasis is a common disease frequently studied in large databases. To date the validity of psoriasis information has not been established in The Health Improvement Network (THIN). OBJECTIVES: To investigate the validity of THIN for identifying patients with psoriasis and to determine if the database can be used to determine the natural history of the disease. METHODS: First, we conducted a cross-sectional study to determine if psoriasis prevalence in THIN is similar to expected. Second, we created a cohort of 4900 patients, aged 45-64 years, with a psoriasis diagnostic Read Code and surveyed their general practitioners (GPs) to confirm the diagnosis clinically. Third, we created models to determine if psoriasis descriptors (extent, severity, duration and dermatologist confirmation) could be accurately captured from database records. RESULTS: Psoriasis prevalence was 1·9%, and showed the characteristic age distribution expected. GP questionnaires were received for 4634 of 4900 cohort patients (95% response rate), and psoriasis diagnoses were confirmed in 90% of patients. Duration of disease in the database showed substantial agreement with physician query (κ = 0·69). GPs confirmed that the psoriasis diagnosis was corroborated by a dermatologist in 91% of patients whose database records contained a dermatology referral code associated with a psoriasis code. We achieved good discrimination between patients with and without extensive disease based on the number of psoriasis codes received per year (area under curve = 0·8). CONCLUSIONS: THIN is a valid data resource for studying psoriasis and can be used to identify characteristics of the disease such as duration and confirmation by a dermatologist.

Modification of the cutaneous dermatomyositis disease area and severity index, an outcome instrument.

BACKGROUND: Validated outcome measures in dermatology help standardize and improve patient care. A scoring system of skin disease severity in dermatomyositis known as the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) has been developed. OBJECTIVES: To simplify and improve the tool for clinical research and care, we modified the CDASI and validated the new version, v2. METHODS: The original CDASI has four activity and two damage measures. The modified CDASI has three activity and two damage measures. The skin disease of 20 patients with dermatomyositis was evaluated by the same dermatologist using both the original and the modified CDASI. Global validation measures were implemented to assess overall skin disease state, skin disease activity and skin damage. Spearman's rho (r(sp)), adjusted for multiple observations on subjects, was used to determine the relationship between the two versions of the CDASI and their correlation with the physician global measures (PGMs). RESULTS: The total score and activity and damage subscores of the original and the modified CDASI correlated perfectly with each other (r(sp) = 0.99, 1.00, 1.00). The PGM-overall skin scale correlated with the total scores (r(sp) = 0.72, r(sp) = 0.76) and activity subscores (r(sp) = 0.68, r(sp) = 0.63) but not with the damage subscores (r(sp) = 0.14, r(sp) = 0.15) of the original and the modified CDASI, respectively. However, the PGM-activity and PGM-damage scales correlated with the activity (r(sp) = 0.76, r(sp) = 0.75) and damage subscores (r(sp) = 0.90, r(sp) = 0.90), respectively, of the original and the modified CDASI. CONCLUSIONS: The modified CDASI is perfectly correlated with the original CDASI. It has equally good concurrent validity with the PGM-overall skin and PGM-activity scales. The CDASI subscores have equally good concurrent validity with the PGM-activity and PGM-damage scales. We suggest that PGMs of skin disease activity and damage should be assessed separately for greater specificity. The modified CDASI is a refined and equally as useful outcome measure.

Reliability, validity and responsiveness to change of the Patient Report of Extent of Psoriasis Involvement (PREPI) for measuring body surface area affected by psoriasis.

BACKGROUND: The development of a simple, reliable, valid and responsive method for measuring the extent of skin involvement in psoriasis is important for use in epidemiological studies. OBJECTIVES: We sought to investigate the psychometric characteristics of the Patient Report of Extent of Psoriasis Involvement (PREPI), a single-question method for measuring body surface area affected by psoriasis. METHODS: This was a cross-sectional study of 140 patients with psoriasis, with an exploratory prospective longitudinal cohort component. Reliability was measured via a test-retest approach and criterion validity was investigated by comparing the PREPI with an assessment of body surface area of involvement by a dermatologist. We additionally compared Skindex-29 scores with the PREPI. To demonstrate responsiveness and establish a minimally important difference in the PREPI, we created receiver operating characteristic curves for the PREPI instrument. RESULTS: The test-retest reliability of the PREPI was nearly perfect [intraclass correlation coefficient (ICC) = 0.99, 95% confidence interval (CI) 0.97-0.99], and there was substantial agreement between patient and physician assessments (ICC = 0.82, 95% CI 0.75-0.87). The PREPI showed significant correlations with all Skindex-29 domains. We found the PREPI to be responsive to change and identified changes in the PREPI score that have good discrimination between patients with and without a minimally important clinical difference. CONCLUSIONS: Our study suggests that the PREPI is a reliable, valid and responsive measure of body surface area affected by psoriasis that may be useful for future epidemiological research.

Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K.

BACKGROUND: Severe psoriasis is associated with excess mortality and increased risk of cardiovascular death. Population-based data evaluating cause-specific mortality in patients with psoriasis are limited. OBJECTIVES: To describe cause-specific mortality in patients with severe psoriasis. METHODS: We performed a cohort study from 1987 to 2002 of patients ≥18 years using the General Practice Research Database. We compared patients with a psoriasis code and a history of systemic therapy consistent with severe psoriasis (n=3603) with patients with no history of psoriasis (n=14,330). Age- and sex-adjusted Cox models were created for each of the leading causes of death defined by the Centers for Disease Control. RESULTS: Patients with severe psoriasis were at increased risk of death from cardiovascular disease [hazard ratio (HR) 1·57, 95% confidence interval (CI) 1·26-1·96], malignancies (HR 1·41, 95% CI 1·07-1·86), chronic lower respiratory disease (HR 2·08, 95% CI 1·24-3·48), diabetes (HR 2·86, 95% CI 1·08-7·59), dementia (HR 3·64, 95% CI 1·36-9·72), infection (HR 1·65, 95% CI 1·26-2·18), kidney disease (HR 4·37, 95% CI 2·24-8·53) and unknown/missing causes (HR 1·43, 95% CI 1·09-1·89). The absolute and excess risk of death was highest for cardiovascular disease (61·9 and 3·5 deaths per 1000 patient-years, respectively). CONCLUSIONS: Severe psoriasis is associated with an increased risk of death from a variety of causes, with cardiovascular death being the most common aetiology. These patients were also at increased risk of death from causes not previously reported, such as infection, kidney disease and dementia. Additional studies are necessary to determine the degree to which excess causes of death are due to psoriasis, its treatments, associated behaviours, or other factors.

Impact of lymphedema and arm symptoms on quality of life in breast cancer survivors.

Lymphedema is one of many arm problems reported by breast cancer survivors. Understanding the impact of lymphedema on quality of life requires consideration that arm symptoms may occur with or without lymphedema. It was hypothesized that specific arm symptoms and pain, related or unrelated to lymphedema, would be more associated with quality of life outcomes than arm swelling. The relation of arm swelling and of arm symptoms and associated severity with a range of quality of life outcomes following breast cancer treatment was assessed in a diverse sample of 295 women, 141 of whom had a clinical diagnosis of lymphedema. Arm swelling (as defined by interlimb volume or circumference differences) and lymphedema severity (defined by Common Toxicity Criteria) were less correlated with quality of life than total number of arm symptoms and specific individual symptoms. Pain in the affected arm correlated with poor quality of life outcomes, regardless of arm swelling. When evaluating the impact of lymphedema on quality of life, arm swelling may not be as important as the total number and specific types of arm symptoms present, as these may be more informative about quality of life outcomes in survivors of breast cancer with and without lymphedema.

Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis.

BACKGROUND: Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments. OBJECTIVES: We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis. PATIENTS AND METHODS: CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients. RESULTS: Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures. CONCLUSIONS: It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.

Pharmacogenetic modulation of combined hormone replacement therapy by progesterone-metabolism genotypes in postmenopausal breast cancer risk.

Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999-2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided p(interaction) = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer.

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.

Optimization of oxygen tolerance extension in rats by intermittent exposure.

Optimization of oxygen tolerance extension by intermittent exposure was studied in groups of 20 rats exposed to systematically varied patterns of alternating oxygen and normoxic breathing periods at 4.0, 2.0, and 1.5 ATA. Oxygen periods of 20, 60, and 120 min were alternated with normoxic intervals that provided oxygen-to-normoxia ratios of 4:1, 2:1, 1:1, and 1:3. In general, median survival times had nearly linear relationships to increasing normoxic intervals with oxygen period held constant. Exceptions occurred at 4.0 and 2.0 ATA where a 5-min normoxic interval was too short for adequate recovery even with a 20-min oxygen period, and an oxygen period of 120 min was too long even with a normoxic interval of 30 min. These exceptions did not occur at 1.5 ATA. Survival time for many intermittent exposure patterns was equivalent to that for continuous exposure to an oxygen pressure definable as a time-weighted average of the alternating oxygen and normoxia periods. However, this predictive method underestimated the degree of protection achieved by several of the intermittent exposure patterns, especially those performed at 4.0 ATA. Results provided guidance for selection of intermittent exposure patterns for direct evaluation in humans breathing oxygen at 2.0 ATA. Definition of intermittent exposure patterns and conditions that produced prominent gains in oxygen tolerance can also facilitate the performance of future experiments designed to study potential mechanisms for oxygen tolerance extension by intermittent exposure. Heat shock and oxidation-specific stress proteins that are induced by exposure to oxidant injury are suggested for emphasis in such investigations.

Quality of life in advanced prostate cancer: results of a randomized therapeutic trial.

BACKGROUND: For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation. METHODS: Patients (n = 739) with stage M1 (bone or soft tissue metastasis) prostate cancer were enrolled in a QOL protocol that was a companion to Southwest Oncology Group INT-0105, a randomized double-blind trial comparing treatment with bilateral orchiectomy (surgical castration) plus either flutamide or placebo. Patients completed a comprehensive battery of QOL questionnaires at random assignment to treatment and at 1, 3, and 6 months later. Data were collected on three treatment-specific symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. All P values are two-sided. RESULTS: Questionnaire return rates for this study never dropped below 80%; only 2% of the patients did not submit baseline QOL assessments. Cross-sectional analyses (corrected for multiple testing) identified statistically significant differences that favored orchiectomy plus placebo for two of the five primary QOL parameters as follows: patients receiving flutamide reported more diarrhea at 3 months (P = .001) and worse emotional functioning at 3 and 6 months (both P<.003). Longitudinal analyses replicated these findings. Other analyzed QOL parameters favored the group receiving placebo but were not statistically significant after adjustment for multiple testing. CONCLUSIONS: We found a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for orchiectomized patients with metastatic prostate cancer who received placebo versus flutamide. Improvement over time was evident in both treatment groups but more so for patients receiving placebo.

Randomised controlled trial of alternative messages to increase enrolment in a healthy food programme among individuals with diabetes.

OBJECTIVES: We compared the effectiveness of diabetes-focused messaging strategies at increasing enrolment in a healthy food programme among adults with diabetes. METHODS: Vitality is a multifaceted wellness benefit available to members of Discovery Health, a South Africa-based health insurer. One of the largest Vitality programmes is HealthyFood (HF), an incentive-based programme designed to encourage healthier diets by providing up to 25% cashback on healthy food purchases. We randomised adults with type 2 diabetes to 1 of 5 arms: (1) control, (2) a diabetes-specific message, (3) a message with a recommendation of HF written from the perspective of a HF member with diabetes, (4) a message containing a physician's recommendation of HF, or (5) the diabetes-specific message from arm 2 paired with an 'enhanced active choice'(EAC). In an EAC, readers are asked to make an immediate choice (in this case, to enrol or not enrol); the pros and cons associated with the preferred and non-preferred options are highlighted. HF enrolment was assessed 1 month following the first emailed message. RESULTS: We randomised 3906 members. After excluding those who enrolled in HF or departed from the Vitality programme before the first intervention email, 3665 (94%) were included in a modified intent-to-treat analysis. All 4 experimental arms had significantly higher HF enrolment rates compared with control (p<0.0001 for all comparisons). When comparing experimental arms, the diabetes-specific message with the EAC had a significantly higher enrolment rate (12.6%) than the diabetes-specific message alone (7.6%, p=0.0016). CONCLUSIONS: Messages focused on diabetes were effective at increasing enrolment in a healthy food programme. The addition of a framed active choice to a message significantly raised enrolment rates in this population. These findings suggest that simple, low-cost interventions can enhance enrolment in health promoting programmes and also be pragmatically tested within those programmes. TRIAL REGISTRATION NUMBER: NCT02462057.

Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.

PURPOSE: To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE). PATIENTS AND METHODS: A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment. RESULTS: For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients. CONCLUSION: GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.

Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer.

PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

Therapy-related myelodysplastic syndrome after autologous stem cell transplantation for breast cancer.

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) are serious complications of chemotherapy and radiotherapy for cancer. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may be associated with an increased incidence of these complications. The frequency of t-MDS/AML after ASCT for breast cancer is uncertain. We reviewed our database of 379 consecutive breast cancer ASCT patients treated with alkylator-based chemotherapy, followed for a median of 1.52 years (range 0-8.97), with a median survival of 6.16 years. Three patients have developed tMDS/AML. The probability of developing this complication at 5 years is 0.032 in our series. We have used pathologic, cytogenetic and molecular methods to evaluate which portions of therapy may have predisposed to the development of this complication. Cytogenetic abnormalities were not found in the stem cell harvests of these patients by metaphase analysis or by fluorescence in situ hybridization (FISH). One patient demonstrated a clonal X chromosome inactivation pattern in her stem cell harvest, indicating pre-transplant chemotherapy may have been responsible for the development of her leukemia. As two of our patients developed this complication at greater than 4 years post-transplant, the number of cases may increase with longer follow-up. While the incidence appears to be low, further prospective and retrospective analysis will be necessary to determine which portions of therapy predispose to the development of t-MDS/AML in patients undergoing ASCT for treatment of breast cancer.

Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study.

AIMS: The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel. MATERIALS AND METHODS: In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment. RESULTS: Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups. CONCLUSIONS: In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.

Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.