A propensity score-weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer.

PURPOSE: A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. METHODS: Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. RESULTS: Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0 months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2 months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1 months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. CONCLUSION: PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients.

PURPOSE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). CONCLUSION: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort.

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), alcohol intake and MTHFR polymorphisms (677C > T and 1298A > C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4-Q1 = 1.26; 95% CI 1.00-1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4-Q1 = 1.29; 95% CI 1.02-1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation.

Factors associated with oxidative stress and cancer risk in the Breast and Prostate Cancer Cohort Consortium.

Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880-rs1050450, and alcohol consumption-rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79-0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49-0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation.

Photodynamic therapy provides local control of cholangiocarcinoma in patients awaiting liver transplantation.

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)-directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol-driven neoadjuvant chemoradiation and ERCP-directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP-directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention-to-treat disease-free survival was 75% at mean follow-up of 28.1 months. In summary, ERCP-directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.

Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3).

CONTEXT: Sex steroids play a central role in breast cancer development. OBJECTIVE: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG. DESIGN: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC). SETTING AND PARTICIPANTS: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC. MAIN OUTCOME MEASURES: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk. RESULTS: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk. CONCLUSIONS: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype.

BACKGROUND: Dicer, a ribonuclease, is the key enzyme required for the biogenesis of microRNAs and small interfering RNAs and is essential for both mammalian development and cell differentiation. Recent evidence indicates that Dicer may also be involved in tumourigenesis. However, no studies have examined the clinical significance of Dicer at both the RNA and the protein levels in breast cancer. METHODS: In this study, the biological and prognostic value of Dicer expression was assessed in breast cancer cell lines, breast cancer progression cellular models, and in two well-characterised sets of breast carcinoma samples obtained from patients with long-term follow-up using tissue microarrays and quantitative reverse transcription-PCR. RESULTS: We have found that Dicer protein expression is significantly associated with hormone receptor status and cancer subtype in breast tumours (ER P=0.008; PR P=0.019; cancer subtype P=0.023, luminal A P=0.0174). Dicer mRNA expression appeared to have an independent prognostic impact in metastatic disease (hazard ratio=3.36, P=0.0032). In the breast cancer cell lines, lower Dicer expression was found in cells harbouring a mesenchymal phenotype and in metastatic bone derivatives of a breast cancer cell line. These findings suggest that the downregulation of Dicer expression may be related to the metastatic spread of tumours. CONCLUSION: Assessment of Dicer expression may facilitate prediction of distant metastases for patients suffering from breast cancer.

A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer.

Inflammation plays a key role in the development of colorectal cancers. We have investigated the relationship between PTGS2 (COX2) polymorphisms and colorectal cancer risk in a hospital based case-control study. We recruited 292 patients with colorectal cancer and 274 controls from new patients admitted to Bellvitge Hospital, Barcelona, Spain, from 1996 to 1998. Subjects responded to a questionnaire on risk factors. Genotypes of the eight more frequent polymorphisms of PTGS2 were determined. Two polymorphisms are located in the promoter sequence, one in the untranslated region of exon 1, one in exon 3, one in intron 5, two in the untranslated region of exon 10, and one downstream of the last polyadenylation (poly-A) signal. Associations were analysed with logistic regression models assuming a dominant effect for rare variants to increase statistical power. An association was detected between colorectal cancer and a polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01. A nearby polymorphism downstream of the last poly-A signal also showed a nonsignificant increase in risk (OR 2.17, 95% CI 0.99-4.78, P=0.05). Analysis of haplotypes confirmed that individuals with these variants were at increased risk of colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97-4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti-inflammatory drugs and risk of colorectal cancer were also explored.

Genotype transposer: automated genotype manipulation for linkage disequilibrium analysis.

UNLABELLED: The purpose of this work is to provide the modern molecular geneticist with tools to perform more efficient and more accurate analysis of the genotype data they produce. By using Microsoft Excel macros written in Visual Basic, we can translate genotype data into a form readable by the versatile software 'Arlequin', read the Arlequin output, calculate statistics of linkage disequilibrium, and put the results in a format for viewing with the software 'GOLD'. AVAILABILITY: The software is available by FTP at: ftp://xcsg.iarc.fr/cox/Genotype_Transposer/. SUPPLEMENTARY INFORMATION: Detailed instruction and examples are available at: ftp://xcsg.iarc.fr/cox/Genotype&_Transposer/. Arlequin is available at: http://lgb.unige.ch/arlequin/. GOLD is available at: http://www.well.ox.ac.uk/asthma/GOLD/.

Chronic lateral ankle instability: assessment of subjective outcomes following delayed primary repair and a new secondary reconstruction.

Chronic lateral ankle instability is a condition commonly encountered by the podiatric physician. Chronic instability usually occurs after injuries to the lateral collateral ligamentous complex. The purpose of this article is to report subjective results of a retrospective study comparing delayed primary ligamentous repair and a new secondary ligamentous reconstruction. Our patient population includes 23 patients who responded to a detailed questionnaire. Three patients had bilateral ligamentous repair for a total of 26 ankles. Sixteen ankles underwent delayed primary ligamentous repair, while 10 ankles had a secondary reconstruction utilizing the authors' technique. The overall postoperative improvement was 90% in those with a delayed primary repair and 82% in those with the new secondary reconstruction. The average return to full activity for both groups was 10 weeks. Average follow-up for both groups was 12 months. The authors feel these results demonstrate that delayed primary repair and the authors' new secondary reconstruction both provide favorable clinical and surgical outcomes.

Identification of a species specific regulatory site in human pancreatic cholesterol esterase.

All mammalian pancreatic cholesterol esterases (CEase) bind to membrane-associated heparin at a single site on the intestinal brush border membrane with a dissociation constant of 100 nM. While the enzyme is bound to the membrane, the activity of the human and bovine enzymes is enhanced 2-fold when compared to the activity of the enzyme in solution. On the other hand, soluble heparin potently inhibits the human CEase-catalyzed hydrolysis of cholesterol oleate with an IC50 of 2 x 10(-4) mg/mL, a value that is about 10(4) times more potent than that found with the bovine enzyme. The C-terminal portion of the human enzyme contains 16 proline-rich repeats of 11 amino acids each, while that from other species contains only a few of these repeat units. To determine if the unique human C-terminus is responsible for this inhibition, two chimeras containing either the human N-terminus (residues 1-445) and the bovine C-terminus (residues 446-557), HB, or the bovine N-terminus (residues 1-445) and the human C-terminus (residues 446-722), BH, were prepared. The cholesterol oleate hydrolytic activity of these chimeras was similar to that for the recombinant human and bovine enzymes. Importantly, each chimera was inhibited by heparin with IC50 values of 0.03 and 0.1 mg/mL for HB and BH, respectively. These intermediate IC50 values indicate that human CEase has two structural regions that contribute to is unique inhibition by this sulfated glycosaminoglycan, and these could regulate cholesterol uptake in humans.

Treatment of Kawasaki syndrome: a comparison of two dosage regimens of intravenously administered immune globulin.

Because intravenously administered immune globulin (IVIG) is effective in reducing the incidence of coronary artery aneurysms in Kawasaki syndrome when given at a dose of 400 mg/kg daily for 4 days, we undertook a multicenter clinical trial comparing two dosage regimens of IVIG. Patients were randomly assigned to receive IVIG at either 400 mg/kg daily for 4 days (22 patients) or 1 gm/kg as a single dose (22 patients). All patients received aspirin therapy, and all were enrolled within 7 days of onset of fever. The presence of coronary artery aneurysms was evaluated by means of two-dimensional echocardiography before infusion; at days 4 to 6, 14 to 21, and 42 to 49 after infusion; and at 1 year. Coronary artery aneurysms were detected in 3 of the 44 patients, including one patient receiving 400 mg/kg and two patients receiving 1 gm/kg (p value not significant). No giant aneurysms were detected. No major side effects occurred with either dosage regimen. Patients receiving the 1 gm/kg dose had a faster resolution of fever and were discharged from the hospital approximately 1 day sooner than the 400 mg/kg group (p = 0.01). Although the relatively small sample size in this trial does not allow for a more definitive statement regarding the occurrence of coronary artery aneurysms, it appears that the 1 gm/kg dose is associated with a more rapid clinical improvement and a shorter hospital stay.

Pancreatic cholesterol esterases. 1. Pancreatic cholesterol esterase induction during maturation.

The activities of pancreatic cholesterol esterase from calf and cow pancreas were examined in detail. A 1300-fold enhancement of enzymatic activity was found after maturation, even though cholesterol esterase activity levels in other organs did not change from the juvenile to the adult species. Radioimmunoassays also showed that the calf pancreas contained at least 100-fold less cholesterol esterase protein. Decreased amounts of protein were not due to enhanced proteolysis, since cytosol from cow pancreas degrades exogenously added cholesterol esterase faster than that from calf pancreas. Rather, enhancement of pancreatic cholesterol esterase activity associated with bovine maturation was the result of specific, increased synthesis of a 72-kDa enzyme. This labile 72-kDa cholesterol esterase species was purified to homogeneity by a two-step process in 75% yield and is the major form of bovine pancreatic cholesterol esterase (99%). A much less abundant 67-kDa species, accounting for less than 1% of total pancreatic cholesterol esterase activity, was also purified to homogeneity in a similar two-step process. These results demonstrate that a specific form of pancreatic cholesterol esterase is induced during maturation, and they bear importantly on understanding juvenile cholesterol metabolism as related to dietary absorption of this sterol.