Search

Background: Toxicity data from cancer trials are summarized into a single outcome, dose-limiting toxicity (DLT), which does not account for multiple lower grade toxic effects nor differentiates between toxicity types and gradations within DLT. Methods: Toxicity data were summarized into a toxicity burden score (TBS) using a weighted sum. The severity weights were estimated via regression using historical data. We demonstrated the method using historical data from a bortezomib trial and illustrated the advantages of defining DLT based on TBS in a simulated dose-finding trial. Results: The estimated weights were 0.17, 0.40 and 0.85 for grade 1/2, grade 3 and grade 4 platelets, respectively; 0.19, 0.64, 1.03 and 2.53 for grade 1, 2, 3 and 4 neuropathy, respectively and 0.17 for each grade 3 or higher nonhematologic toxic effects unrelated to treatment. In the simulated trial, the probability of selecting doses above the maximum tolerated dose decreased when using the DLT defined based on TBS. Conclusions: TBS is a feasible approach to summarize toxicity. It includes information from the grades and types of multiple toxic effects and can be applied in all phases of drug development. Further efforts should focus on validating the method in a large prospective study before applying it in practice. [ABSTRACT FROM PUBLISHER]

Studies suggest improved survival following resection of colorectal cancer liver metastases (CLMs). We investigated predictors of survival among patients with CLM who underwent hepatic resection using the SEER-Medicare database to identify patients >/=65 years diagnosed with CLM, 1991-2003, who underwent hepatectomy. Cox proportional hazards models were used to identify factors associated with survival after hepatectomy. Of 923 patients with CLM who underwent hepatectomy, 514 were stages I-III and developed CLM>6 months after diagnosis (metachronous), and 409 were stage IV with CLM at diagnosis (synchronous). From the date of hepatectomy, 5 year survival was 22%; younger age, being married, female gender, surgery in an NCI-designated cancer centre, fewer comorbidities, fewer positive lymph nodes, and lower grade were associated with improved survival. Both 5-fluorouracil (5FU)-based chemotherapy and hepatic arterial infusion (HAI) of floxuridine-based chemotherapy following hepatectomy improved survival (HR=0.62, 95% CI: 0.50-0.78; HR=0.51, 95% CI: 0.28-0.97, respectively) in the synchronous, but not metachronous, group. The HR for overall mortality was higher in hospitals with a high vs low procedure volume (0.75, 95% CI: 0.58-0.94). A substantial subgroup of patients with CLM who undergo hepatectomy experiences long-term survival. High hospital procedure volume and use of 5FU-based or HAI-based chemotherapy after resection were associated with improved prognosis. [ABSTRACT FROM AUTHOR]

Background: In 2005, the Institute of Medicine released a report citing the importance of comprehensive treatment summaries or "survivorship plans" for cancer patients completing adjuvant therapy. However, little is known about the best approach or the impact of these interventions on patient well-being. We compared quality of life, treatment satisfaction and cancer impact measures between a minimal or more intensive intervention. Methods: The study was conducted at a single-institution academic breast cancer practice. Women with non-metastatic breast cancer were randomized within six weeks of completing adjuvant therapy (chemotherapy/radiation therapy) to a minimal intervention group (MG) or intensive intervention group (IG). The MG group was given the NCI publication, "Facing Forward: Life after Cancer Treatment" by lay research staff. The intensive group received the same NCI publication; met in person for 1 hour with a nurse practitioner who provided a treatment summary, surveillance and screening recommendations, and information on risk for late effects; and met in person for 1 hour with a nutritionist to review lifestyle recommendations. Subjects were informed that they were in a study of cancer survivors but unaware they were being randomized. The randomization was stratified by ethnicity (Hispanic/non-Hispanic). Both groups completed the 81 -item impact of cancer instrument (IOC), functional assessment of chronic illness therapy-treatment satisfaction-patient satisfaction questionnaire (FACIT-TS-PS) and assessment of survivor concerns (AOC) at baseline, 3 and 6 months. Group t-tests and between group linear regression analyses were performed controlling for ethnicity. Results: Of 140 patients who signed consent, 126 women (66 non-Hispanic, 60 Hispanic) completed baseline questionnaires, 109 completed 3 month, and 109 completed 6 month assessments. The groups were well balanced with regard to age (mean = 54), race, marital status, income and employment status. There were no statistically significant differences between the MG and IG on the 8 domains that comprise the FACIT-TS-PS at 3 and 6 months. The health worry scale of the AOC was lower in the IG (p = 0.006) compared to MG, indicating less health worry and the negative outlook score of the IOC was higher in the MG (p = 0.043) compared to IG at 3 months. At baseline, 3 and 6 months, Hispanic women compared to non-Hispanic women had significantly higher (worse) ACS and IOC health worry (p < 0.001), social life interference (p = 0.01) and meaning of cancer scales (p = 0.0004), but also had greater trust in medical professionals (p = 0.029). Conclusions: We did not observe a difference in most of the IOC or treatment satisfaction scores between the MG and IG interventions at 3 or 6 months, nor did we find any significant change from baseline in either group. However, less health worry and less negative outlook were seen in the IG compared to the MG. At baseline and follow-up, Hispanic women in both interventions compared to non-Hispanic women had more extreme scores on most measures. Despite minimal difference between the interventions, the intensive intervention was more time-consuming and used more health care resources. [ABSTRACT FROM AUTHOR]

Background: Selective estrogen receptor modulators (SERMs) have been shown to decrease breast cancer incidence among high-risk women, but uptake for prevention has been poor. Observational studies have demonstrated that serum 25-hydroxyvitamin D (25-OHD) is inversely related to breast cancer risk, such that levels >40 ng/ml are associated with about a 40% reduction in breast cancer risk compared to women who are vitamin D deficient (25-OHD <20 ng/ml). Uncertainty remains about whether vitamin D supplementation will reduce breast cancer risk, the optimal dose of vitamin D, and the target level of serum 25-OHD. We examined the safety of high dose vitamin D and the effects on serum 25-OHD in women at high risk for breast cancer. Methods: Forty high-risk women (defined as a 5-year Gail risk ³1.67%, lobular or ductal carcinoma in situ [LCIS/DCIS], BRCA1/BRCA2 mutation carrier, or stage I/II invasive breast cancer in remission for >5 years) were assigned to a 1-year intervention of vitamin D3 20,000 or 30,000 IU weekly. Other eligibility criteria included baseline mammographic density (MD) ≥25%, serum 25-OHD ≤ 32 ng/ml, no current SERM use and no history of kidney stones. Women underwent a digital mammogram at baseline and 12 months, and serial blood draws every 3 months. In addition, random core breast biopsies were conducted in premenopausal women, whereas postmenopausal women underwent a breast MRI at baseline and 12 months. Participants were monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months. The primary objective is to determine the safety and feasibility of high-dose vitamin D in this study population. Secondary objectives are to determine changes in breast density and blood-based biomarkers (25-OHD, 1,25(OH)D, PTH, IGF-I, IGFBP-3). Serum 25-OHD was measured by Diasorin radioimmunoassay. Results: From November 2007 to January 2011, 292 women were screened and 142 were ineligible. Main reasons for ineligibility (%) included 25-OHD >32 ng/ml (27), opted for SERM (23), prior kidney stones (11), and MD <25% (9). Of the 40 enrolled participants: median age 50 years (range, 37-73); pre/postmenopausal: 20/20; white/hispanic/black/asian: 19/14/6/1; median body mass index 26.6 kg/m² (20-39.6); elevated Gail risk/LCIS/DCIS/stage I or II breast cancer: 20/10/8/2; mean baseline serum 25-OHD 20.2 ng/ml (9-31). Currently, 1 participant is on-study, 31 completed the intervention, 6 were lost to follow-up, 1 withdrew due to hypercalciuria (spot urine Ca/Cr >0.37) and 1 withdrew due to dyspepsia. Mean serum 25- OHD rose to 47 ng/ml at 3 months, 49.1 ng/ml at 6 months, and 53.7 ng/ml (range, 26-77) at 12 months. No significant hypercalcemia (serum Ca >10.5 mg/dl) occurred at either dose level. Imaging and biomarker analyses are ongoing. Discussion: We have demonstrated that a 1-year intervention of high-dose vitamin D3 is well tolerated and can increase serum 25-OHD above a target level of 40 ng/ml. This preliminary data has informed an ongoing phase IIb randomized placebo-controlled trial (SWOG 0812) of high-dose vitamin D in 200 high-risk premenopausal women and highlights the importance of early phase breast cancer chemoprevention trials with intermediate biomarker endpoints to test novel agents. [ABSTRACT FROM AUTHOR]

Background Observational and experimental data support a potential breast cancer chemopreventive effect of green tea. Methods We conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I- III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg ( n = 16), 600 mg ( n = 11) and 800 mg ( n = 3) twice daily or matching placebo ( n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor ( HGF), vascular endothelial growth factor ( VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers. Results From July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (−12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months ( P = 0.02) and 13.9% at 4 months ( P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E ( P = 0.08). No significant differences were observed for other biomarkers. Conclusions Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism. [ABSTRACT FROM AUTHOR]

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

Background Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. Patients and methods Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). Results In phase I (n = 12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. Conclusion Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030. [ABSTRACT FROM PUBLISHER]

Background: Fulvestrant produces a clinical benefit rate (CBR) of ∼45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib–fulvestrant combination in HR-positive MBC. [ABSTRACT FROM PUBLISHER]

Given the survival benefits of adjuvant chemotherapy for advanced ovarian cancer (OC), we examined the associations of survival with the time interval from debulking surgery to initiation of chemotherapy and with the duration of chemotherapy. Among patients > or =65 years with stages III/IV OC diagnosed between 1991 and 2002 in the Surveillance, Epidemiology, and End Results-Medicare database, we developed regression models of predictors of the time interval from surgery to initiation of chemotherapy and of the total duration of chemotherapy. Survival was examined with Cox proportional hazards models. Among 2558 patients, 1712 (67%) initiated chemotherapy within 6 weeks of debulking surgery, while 846 (33%) began treatment >6 weeks. Older age, black race, being unmarried, and increased comorbidities were associated with delayed initiation of chemotherapy. Delay of chemotherapy was associated with an increase in mortality (hazard ratio (HR)=1.11; 95% CI, 1.0-1.2). Among 1932 patients in the duration of treatment analysis, the 1218 (63%) treated for 3-7 months had better survival than the 714 (37%) treated for < or =3 months (HR=0.84; 95% CI, 0.75-0.94). This analysis represents one of the few studies describing treatment delivery and outcome in women with advanced OC. Delayed initiation and early discontinuation of chemotherapy were common and associated with increased mortality. [ABSTRACT FROM AUTHOR]

Background: Overweight or obese women with breast cancer (BC) have a higher risk of distant recurrence and death compared to normal weight women. There is increasing evidence that insulin significantly mediates these adverse clinical outcomes. Laboratory and population studies demonstrate that metformin offers a protective BC effect through reduction of serum insulin levels and direct modulation of cellular protein synthesis and growth through AMPK pathway signaling. Our aim is to assess the biologic impact of metformin on blood- and tumor- based markers on insulin, IGF and AMPK/mTOR pathway signaling, and/or proliferation in operable BC patients with a body mass index (BMI) ≥ 25 kg/m². Methods: The study was an open-label pre-surgical trial with metformin 1500 mg PO per day (500 mg am/1000 mg pm) for 2-4 weeks prior to surgical resection in 35 overweight or obese patients with invasive BC (n = 25) or ductal carcinoma in situ (n = 10) and no history of diabetes. The primary endpoint was to assess a reduction in tumor proliferation. We have 80% power to detect a 30% decrease in Ki-67 in invasive BCs from baseline to post-metformin values (two-sample t-test, 0.05). Secondary endpoints include changes in BMI and insulin resistance markers, such as fasting serum insulin, lipid panel, glucose, leptin, and adiponectin. Tumor markers will be compared to untreated historical controls matched by age, BMI, and tumor characteristics. Results: Between Oct 2009 to Aug 2011, we screened 116 patients, enrolling 35 with newly diagnosed BC: 18/34 overweight (27.6: 25.1-29.7) and 16/34 obese (35.9: 30.5-46.4). Hispanic women made up 80% of the population (28/35). The median metformin duration was 22 days (1-64). All took metformin until the evening prior to surgery, except 2 (1 withdrew and 1 stopped early after surgery delay). More than half had a prior diagnosis of hypertension and a third had hypercholesterolemia. In the invasive BC cohort (n = 25), 19/25 (76%) were HR+/HER2-. The most common grade I-II included self-limiting diarrhea, flatulence, abdominal pain, fatigue, and anorexia. Grade III events included abdominal pain (n = 1) and diarrhea (n = 3). The change in blood markers are described in the table. Tumor Ki-67 (immunohistochemistry) and pathway signaling analyses (reverse protein microarray) are ongoing. Conclusions: Our study is unique to other pre-surgical metformin trials due to the enrichment of overweight/obese BC patients and the ethnically diverse population. We observed a significant decrease in serum cholesterol and leptin with metformin, and a trend toward lower insulin, HOMA, and adiponectin. No significant changes in glucose or IGFP-3 levels are noted. We are awaiting tumor-based biomarker evaluation. Pre-surgical trials can assess an agent's biological effect prior to long-term intervention trials. [ABSTRACT FROM AUTHOR]

Background: Randomized studies investigating adjuvant bisphosphonates in women with breast cancer are ongoing. While bisphosphonates would be expected to prevent the deterioration of bone microarchitecture that accompanies hormone or chemotherapy, complete suppression of osteoclast activity for prolonged periods of time can decrease repair of micro-cracks, and possibly lead to decreased bone strength. While bone strength is governed by the amount of bone present, trabecular and cortical components of bone microarchitecture also contribute independently to bone strength. We aimed to characterize the effects of long-term bisphosphonates on bone microarchitecture in women with breast cancer using high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius and tibia. Methods: We conducted a cross-sectional study involving early stage breast cancer patients treated with bisphosphonates on the S0307 clinical trial. Women were randomized to receive zoledronic acid, oral clodronate or oral ibandronate in doses far higher than those used in osteoporosis treatment as per protocol. After 18-36 months of bisphosphonate therapy, participates underwent a one-time evaluation of areal bone mineral density (aBMD) of the 1/3 radius, lumbar spine, and hip by dual energy x-ray absorptiometry (DXA), and cortical and trabecular volumetric BMD (vBMD) and trabecular microarchitecture of the radius and tibia by HR-pQCT. HR-pQCT measurements were compared to healthy young premenopausal women and age-matched Caucasian women. Results: Baseline characteristics of the 12 enrolled patients: median age of 53 (range 40- 67); white/Hispanics 7/5; pre/postmenopausal 4/8; mean body mass index 28.7 kg/m2 (20.9-34.8); average time on bisphosphonates 20 months (18-30); zoledronic acid/clodronate/ibandronate 5/6/1. The median aBMD DXA T-score of the 1/3 radius, lumbar spine and total hip were normal at +0.3, +0.1, and +0.2, respectively. Mean total, cortical, and trabecular vBMD of the radius as measured by HR-pQCT were 330±71, 905±55, and 146±35 mg hydroxyapatite/cm3, respectively. Mean cortical thickness was 0.803±0.170 mm, and mean trabecular number was 1.9±0.2. Mean total, cortical, and trabecular vBMD of the tibia were 285±54, 880±54, and 150±38 mg hydroxyapatite/cm3, respectively. Mean cortical thickness was 1.135±0.264 mm, and mean trabecular number was 1.7±0.3. There were no statistically significant differences between study group and each control. However, results were more similar to healthy young premenopausal control than the age-matched control. Conclusion: Women on long-term bisphosphonate therapy for breast cancer had normal aBMD by DXA and normal cortical and trabecular vBMD, cortical thickness and trabecular number at the peripheral skeleton compared to healthy young women and age-matched women. This preliminary data is reassuring for cancer survivors if benefits from this therapy are established in the adjuvant setting. [ABSTRACT FROM AUTHOR]

Background: Pathologic complete response (pCR) or a low Residual Cancer Burden (RCB) score following neoadjuvant chemotherapy (NACT) predicts a superior survival in breast cancer (BC) patients. An early predictive marker of tumor response during NACT would provide a way to optimize treatment for non-responders; however, no ideal technology currently exists. Diffuse optical tomography (DOT) is a novel, fast, safe, and low-cost technique that uses near infrared light to provide 3D data on tissue vascularity without the use of radiation, making it a promising technology for assessing early tumor response to NACT. We hypothesized that a 2-week change in DOT parameters would predict response to NACT as measured by the RCB score. Methods: Women with stage II-IIIc invasive BC scheduled to undergo NACT with 12 cycles of a weekly taxane followed by 4 cycles of doxorubicin with cyclophosphamide (AC) were enrolled. Treatment with additional biologic therapies was allowed. DOT measurements were made before starting NACT, 2 weeks into treatment, and before surgery. Concentrations of oxyhemoglobin [HbO2], deoxyhemoglobin [Hb], total hemoglobin [HbT], and tissue scattering (SC) were measured by DOT. Final pathology specimens were scored for the RCB index (continuous measure), RCB class (0, 1, 2, 3), and a dichotomized RCB score (RCB class 0 or 1: responders to NACT; RCB class 2 or 3: non-responders). Correlation analysis, ANOVA testing, and two sample t-tests were used to evaluate the relationship between the two-week changes in DOT parameters and the RCB score. Results: Since July 2011, we have recruited 11 pts, of whom 7 have undergone surgery. Complete data is available for 6 pts. Two of 7 pts had a pCR (RCB 0), 1 had RCB 1, 3 had RCB 2, and 1 had RCB 3. The Pearson correlation between the 2-week change in [Hb] and the continuous RCB index was 0.94 (p = 0.0047), and that between the 2-week change in SC and the RCB index was 0.93 (p = 0.0073). At 2 weeks, the [Hb] decreased by 6.7% for pts whose pathology demonstrated an RCB 0 (pCR), 1.8% for RCB 1, 0.6% for RCB 2, and increased 0.7% for RCB 3. ANOVA and Tukey testing demonstrated a significant difference in the [Hb] change for pts with RCB 0 compared to pts with RCB 1, 2, or 3 (p <0.05). At 2 weeks, SC decreased by 26.5% for pts with RCB 0, 19.3% for RCB 1, 3.7% for RCB 2, and increased by 25.1% for RCB 3. There was a significant difference in the SC change for pts with RCB 0 compared to pts with RCB 3 (p <0.05). Responders (RCB 0/1) had a 5% decrease in [Hb] at 2 weeks compared to non-responders (RCB 2/3) who had a decrease in 0.18% in [Hb] (p = 0.0045), and responders had a 24% decrease in SC compared to non-responders who had an increase in 6% (p = 0.044). Conclusions: DOT change is an early predictor of response to NACT as measured by the RCB score. We found a significant linear association between the RCB index and the 2-week change in [Hb] and SC. Significantly different changes in DOT parameters were associated with the other RCB classifications. Additional recruitment is ongoing and differences by tumor subtype will be evaluated. [ABSTRACT FROM AUTHOR]

Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer (BC). However, musculoskeletal complaints can lead to nonadherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome and determine predictors of worsening symptoms. Methods: Postmenopausal women with stage I-III BC initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worse symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES). Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline. Linear Regression was performed to evaluate the association between baseline symptoms and change in symptoms. Results: A total of 169 patients have been consented, 3-month data is available on 102; 6-month data on 85. Median age: 63 (42-89); White/Black/Asian/Hispanic: 61.48/30.33/3.28/25.6; median BMI (kg/m2): 28 (12-50). Compared to baseline, there was a statistically significant increase in BPI pain severity and endocrine related symptoms on the FACT-ES at 3 and 6 months. Significant changes in the BPI pain interference, M-SACRAH pain and stiffness, WOMAC function, physical well-being on the FACT-ES, trial outcome index and pinch grip strength were seen at 3 months; however these changes did not remain significant at 6 months. Logistic regression models evaluating predictors of patient reported outcome measures and grip strength were performed. Baseline score was the strongest predictor of worsening symptoms (p < 0.01) after correcting for age, prior chemotherapy and baseline joint conditions. Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which is most prominent at the 3 months evaluation. Patients with baseline joint symptoms are at greatest risk for worsening symptoms on AIs. [ABSTRACT FROM AUTHOR]