A Phase II Randomized Crossover Study of Liposomal Doxorubicin Versus Weekly Docetaxel in the First-line Treatment of Women With Metastatic Breast Cancer

PurposeWe aim to compare the efficacy and toxicity of liposomal doxorubicin and weekly docetaxel as first-line treatments for patients with metastatic breast cancer (MBC).Patients and MethodsPatients who had received no previous chemotherapy for MBC were eligible. Previous hormonal therapy, adjuvant chemotherapy, and radiation therapy were allowed. Patients were randomized to receive liposomal doxorubicin 40 mg/m² intravenously [I.V.] every 28 days or weekly docetaxel 36 mg/m² I.V. days 1, 8, and 15, repeated every 28 days. Patients with objective response or stable disease after 2 cycles continued treatment until tumor progression or unacceptable toxicity. At progression, patients were allowed to cross over to the other regimen. The trial was designed to detect a true difference of 10% in response rate with an 80% power.ResultsBetween March 2001 and July 2007, 102 patients were randomized. The 2 groups had similar demographics; 68% of patients had received previous adjuvant chemotherapy. Liposomal doxorubicin and weekly docetaxel produced similar objective response rates (28% vs. 31%), disease control rates (48% vs. 44%), and progression-free survival (6.5 months vs. 5.5 months). Both agents were well tolerated. Both agents produced crossover responses as second-line treatment (liposomal doxorubicin, 35%; weekly docetaxel, 14%).ConclusionLiposomal doxorubicin is well tolerated and has activity similar to weekly docetaxel in the first-line treatment of patients with MBC.     

Systemic steroid prophylaxis for cataract surgery in patients with posterior uveitis

Cataract remains difficult to manage in patients with uveitis affecting the posterior segment of the eye due to the high risk of postoperative complications, especially cystoid macular oedema, even in eyes in which inflammation has been completely suppressed preoperatively. A standard regimen of preoperative and perioperative systemic steroid prophylaxis was introduced into the uveitis clinic in order to prevent uveitis-related cystoid macular oedema in the postoperative period. The aim of this study was to assess if this policy resulted in an improvement in the visual recovery. Data from a single consecutive clinical series of 30 extracapsular cataract extraction procedures performed in 24 patients with posterior uveitis were collected retrospectively. Nineteen procedures were performed before and 11 after the introduction of the regimen of steroid prophylaxis. Success was graded according to the Snellen acuity at six months, the number of lines improvement in visual acuity by six months and the time from the operation date for acuity to recover to its best postoperative level. The median visual acuity after six months was 20/30 in the prophylaxis group compared with 20/80 in the controls (p = 0.052), representing a median improvement of five lines in the prophylaxis group and three lines in the controls (not significant). The eyes receiving prophylaxis achieved their best acuity in 1.8 months (median) compared with 5.9 months for the control group (p<0.01). This was not attributable to the longer period of follow-up in the control group and was independent of IOL implantation or the influence of any individual postoperative complication. When pseudophakic eyes were considered in isolation, the median acuity at six months was also better in the prophylaxis group (p = 0.023). The results suggest that preoperative systemic steroid prophylaxis may benefit the patient by hastening postoperative visual recovery independently of IOL implantation.     

Cost-savings analysis of an outpatient management program for women with pregnancy-related hypertensive conditions.

The aim of this study was to evaluate the cost savings of outpatient management services for women with pregnancy-related hypertensive conditions. The outpatient management program included verbal and written patient education related to the hypertensive disease process during pregnancy as well as self-care procedures. Biometric data (ie, automated blood pressure measurement, qualitative urine protein) were collected at least daily by the patient and transmitted telephonically to a nursing call center. Data were evaluated and subjective symptoms assessed daily. Electronic records were maintained and reports provided to the prescribing physician and case manager. Included for analysis were: patients with pregnancy-related hypertensive conditions receiving outpatient services between January 1999 and November 2003, singleton gestation, no history of chronic hypertension, and gestational age of 20.0-36.9 weeks at start of outpatient program (n = 1,140). Maternal characteristics, antenatal hospitalization and length of stay, progression of disease, and neonatal outcome were analyzed. To evaluate cost-effectiveness, a model was developed to compare the cost of the program plus adjunctive antenatal hospitalization, to control data. The mean gestational age at program start was 32.6 weeks. Antenatal hospital admission was required for 24.8% of patients, with a mean length of stay of 2.3 days per admission. Progression to severe preeclampsia occurred in 14.3% of patients. Mean gestational age at delivery was 37.0 weeks. Antepartum charges averaged 10,327 US dollars per control patient and 4,888 US dollars per program patient, a difference of 5,439 US dollars. For each dollar spent on outpatient management, an average of 2.50 US dollars was saved. Utilizing outpatient management services for women with pregnancy-related hypertension reduces the need for inpatient care and is cost-effective.     

Fruit and vegetable intake: Few adolescent girls meet national guidelines

OBJECTIVE: To examine longitudinal changes in daily fruit and vegetable consumption among black and white adolescent girls and calculate the percent of girls who met the Healthy People 2010 recommendations. METHODS: Girls (1186 black and 1126 white) who participated in the National Heart, Lung, and Blood Institute Growth Health Study (NGHS) were included if they had completed a 3-day food diary for at least one of six annual assessments visits, beginning at ages 11 or 12. Mixed models estimated the association of visit and race with (a) average daily consumption of fruits and vegetables and (b) the probability of meeting intake recommendations on one or more out of 3 days. RESULTS: For girls of both races, fruit and vegetable consumption increased with age; white girls showed a greater increase in fruit and nutrient-rich vegetable intake than black girls. Across visits, girls consumed considerably fewer than the recommended daily servings of fruits (1.0-1.5), vegetables (1.7-2.5), or nutrient-rich vegetables (0.25). Most girls (95%) failed to meet Healthy People 2010 recommendations. CONCLUSIONS: Public health efforts are needed to meet Healthy People 2010 objectives.     

Are We Ready To Stratify Treatment for Diffuse Large B-Cell Lymphoma Using Molecular Hallmarks?

The division of the heterogeneous entity of diffuse large B-cell lymphoma (DLBCL) into the ontogenic phenotypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) is optimally determined by gene expression profiling (GEP), although simpler immunohistochemistry (IHC) algorithms are alternatively being used. The cell-of-origin (COO) classification assists in prognostication and may be predictive of response to therapy. Mounting data suggests that IHC methods of classifying COO may be inaccurate. GEP categorization of COO is superior in defining prognostically and biologically distinct DLBCL subtypes, but current barriers to its widescale use include inaccessibility, cost, and lack of methodological standardization and prospective validation. The poorer prognosis of ABC-DLBCL is frequently associated with constitutive activity in the NF-κB pathway and aberrations in upstream or downstream regulators of this pathway. The molecular mechanisms underlying lymphomagenesis in GCB-DLBCL are arguably less well defined, but C-REL amplification and mutations in BCL-2 and EZH2 are common. New technologies, such as next-generation sequencing, are rapidly revealing novel pathogenic genetic aberrations, and DLBCL treatment strategies are increasingly being designed focusing on distinctive pathogenic drivers within ontogenic phenotypes. This review examines emerging molecular targets and novel therapeutic agents in DLBCL, and discusses whether stratifying therapy for DLBCL using molecular features is merited by current preclinical and clinical evidence.     

Technology enhancements and changes in radiotherapy throughput in New South Wales

AimsTo assess the effect that the age of linear accelerators and recent changes in technology have had on linear accelerator throughput in New South Wales, Australia.Materials and methodsDuration was measured (time of patient entry into the treatment room to time of exit) of each radiotherapy treatment fraction delivered on each linear accelerator over a 5-day period. Patient-, treatment- and equipment-based variables were collected for all treatment fractions, and assessed for their effect on fraction duration. Comparisons were made between these data and similar productivity data collected from a study carried out in 1996. Since the sample sizes for both the study periods were large enough, the distributions of the means were assumed normal (Central Limit Theorem). Specific analyses were carried out to assess the affect that new technologies, such as automatic field-sequencing (AFS) and multi-leaf collimator (MLC), have had on fraction duration.ResultsA total of 12 892 treatment fields and 4316 treatment fractions were delivered on 27 linear accelerators over 135 days. Comparison between the 2003 and 1996 productivity data showed an increase in the mean number of patients treated per hour by 11% and fields treated per hour by 31%. The mean number of fields treated per fraction increased by 15%. The mean fraction duration was reduced by 13% for linear accelerators of less than the median age of 7 years that were equipped with MLC/AFS, or both, compared with older linear accelerators without AFS and MLC. This reduction was more obvious for complex techniques, such as four-field breast treatments (27% decrease in fraction duration). The mean number of fields treated per hour was 43% more on the newer machines equipped with AFS and MLC.ConclusionsAn increase in productivity has been observed between the 1996 and 2003 study periods, as measured by patients or fields per hour, despite an increase in treatment complexity as measured by fields per fraction. The application of AFS and MLC, and the use of newer linear accelerators, significantly shortened the mean duration per fraction for the common treatment techniques.     

Involvement of both intrinsic and extrinsic pathways in IFN-gamma-induced apoptosis that are enhanced with cisplatin

IFN-gamma has direct anti-proliferative effects on ovarian cancer cell lines and tumour cells isolated from ovarian cancer ascites. The aim of this study was to further elucidate the mechanisms involved. An IFN-gamma-mediated cell cycle blockade was detectable in synchronised cell populations. Apoptosis, which was caspase dependent, was also induced. When caspase activity was blocked, the anti-proliferative effect of IFN-gamma was only partially reduced indicating independent roles for both growth inhibition and apoptosis in its actions. We have demonstrated involvement of the intrinsic apoptotic pathway; IFN-gamma treatment resulted in mitochondrial membrane depolarisation, cytochrome c release into the cytosol and activation of caspase 9. Cytochrome c release was blocked by the presence of a general caspase inhibitor, suggesting a role for caspases upstream of the mitochondria. One candidate is caspase 8, which was also activated in cells treated with IFN-gamma. Levels of Bid, a pro-apoptotic molecule that can mediate mitochondrial membrane permeabilisation when cleaved by caspase 8, were also decreased and indicated a potential link between these two pathways in IFN-gamma-induced apoptosis. Furthermore, together with cisplatin, IFN-gamma exerted a more powerful anti-proliferative effect.     

Complications following bilateral prophylactic mastectomy

BACKGROUND: Bilateral prophylactic mastectomy significantly decreases breast cancer risk, but complications of the procedure have only been described in single-site studies. We describe the frequency and type of complications in women who underwent bilateral prophylactic mastectomy in a multisite community-based cohort. METHODS: Women aged 18-80 years undergoing bilateral prophylactic mastectomy without a personal history of breast cancer at one of six health plans were eligible. We identified women from automated data sources, then reviewed hospital data, ambulatory notes, and other chart elements to confirm eligibility and obtain all charted information about complications and surgeries performed after prophylactic mastectomy, including reconstructive procedures. Reconstructions were characterized by type (implant vs. tissue graft). Complications were noted for a 1-year period after any surgical procedure. RESULTS: We identified 269 women with prophylactic mastectomy who were followed for a mean of 7.4 years. Their mean age was 44.9 years. Nearly 80% undertook reconstruction, most with prosthetic implants. One or more complications occurred in 64%. The most common complications were pain (35% of women), infection (17%), and seroma (17%). Women with no reconstruction had fewer complications (mean of .93) than women who had implant (2.0) or tissue graft (2.4) reconstruction procedures (differences from no reconstruction: 1.07 [95% confidence interval = 0.36 to 1.77] and 1.50 [95% confidence interval = 0.44 to 2.56] respectively). Delay of reconstruction after mastectomy was associated with a borderline-significant higher risk of complications (80.6%) compared to simultaneous reconstruction (64.0%, P = .055). CONCLUSION: We found that almost two-thirds of women undergoing bilateral prophylactic mastectomy had at least one complication following surgery. Further work should be done to minimize and to understand the effect of complications of bilateral prophylactic mastectomy.     

Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.

PURPOSE: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. EXPERIMENTAL DESIGN: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro. RESULTS: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. CONCLUSIONS: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.