Characterizing the impact of 25 years of DCIS treatment

The significant increase in the detection and treatment of ductal carcinoma in situ (DCIS) since the introduction of screening mammography has not been accompanied by the anticipated reduction in invasive breast cancer (IBC) incidence. The prevalence of DCIS requires a reexamination of the population level effects of detecting and treating DCIS. To further our understanding of the possible impact of DCIS diagnosis and treatment on IBC incidence in the U.S., we simulated breast cancer incidence over 25 years under various assumptions regarding the baseline incidence of IBC and the progression of DCIS to IBC. The simulations demonstrate a tradeoff between the expected increased incidence of IBC absent any DCIS detection and treatment and the rate of progression of DCIS to IBC. Our analyses indicate that a high progression of DCIS to IBC implies a significant increase in incidence of IBC over what is observed had we not detected and treated DCIS. Conversely, if we assume that there would not have been a significant increase over and above the observed incidence evident in SEER, then our model indicates that the rate of DCIS progression to clinically significant IBC is low. Given the tradeoff illustrated by our model, we must reevaluate the assumption that DCIS is a short-term obligate precursor of invasive cancer and instead focus on further exploration of the true natural history of DCIS.     

Anti-Mutagenic and Anti-Carcinogenic Potential of the Carotenoid Meso-Zeaxanthin

Meso-zeaxanthin was investigated for antimutagenic and anticarcinogenic activity, using the Ames test(Salmonella typhimurium strains TA 98, TA 100, TA 102 and TA 1535) with direct acting mutagens like sodiumazide (NaN3) (5 μg/ plate), nitro-o-phenylendiamin (NPD) (20 μg/ plate), N-methyl- N’-nitro-N-nitrosoguanidine(MNNG) (1μg/ plate) and tobacco extract 50 mg/ plate) and with a mutagen needing microsomal activation,acetamidofluorene (AAF) ( 20 μg/ plate). The carotenoid was found to inhibit the mutagenicity induced byNaN3, NPD and MNNG in a concentration dependent manner, as well as that with AAF and the tobacco extract.Concentrations needed for 50 % inhibiton was found to be 50 μg/ plate for the chemical mutagens and 100 μg/plate for tobacco extract. Using specific resorufin derivatives as substrates in vitro, the concentration of mesozeaxanthinneeded for 50 % inhibition of CYP1A2 (7-methoxyresorufin-O-demethylase) was 5 μg/ml, for CYP2B1/2 (7- pentoxyresorufin-O-depentylase) was 8 μg/ml and for CYP1A1 (7-ethoxyresorufin-O-deethylase) was 12μg/ml, while that of CYP 2E1 (aniline hydroxylase) was 7μg/ml and for CYP 1A, 2A, 2B, 2D and 3A (aminopyrene-N-demethylase) was 10.5 μg/ml. Evaluated using nitroso diethyl amine (NDEA) induced hepatocellular carcinomain rats, treatment with meso-zeaxanthin reduced the tumor incidence when compared to the control group. Theactivity of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase wasdrastically elevated in both serum and liver tissue of NDEA alone treated control animals and meso-Zeaxanthinpretreated animals showed significant decrease to normal levels, in line with histopathological findings.     

Clinical and Ultrasonographic Changes of the Breast after Use of Soy Isoflavones

Background: Phytoestrogens may be an alternative therapy in control of menopausal symptoms but theirdefinite effects on breast tissue must be determined. Our study aimed to define the clinical and ultrasonographicchanges of the breast after use of soy isoflavones in menopausal women. Materials and Methods: Menopausalwomen with hot flashes were randomly grouped as cases and controls and cases received soy isoflavones for12 weeks. Breast examination (BE) and ultrasonography (US) were done at 0, 6 and 12 weeks. Tenderness andnodularity on BE were graded 1-4 by breast surgeons. Results: There were 30 women in the case and 26 in thecontrol group. The mean age was 51.3 years and the mean age of menopause was 49.2 years. There was no changein the BE and US at 6 weeks in controls. In the case group, 10% had grade 1 tenderness and 13.3% grade 2tenderness and grade 1 nodularity in BE accompanied with diffuse small cysts in US. At 12 weeks, there was nochange in BE and US in the 2 groups. Conclusions: There was no statistically significant difference in the BE ofthe 2 groups at 6 and 12 weeks (p value=0.36 and 0.41 for nodularity and tenderness respectively) and in the USresults. Although the literature contains many facts concerning PEs and the breast, further prospective studiesare needed to identify structural breast changes produced by PEs in order to identify the appropriate dosageand indications of use.     

Negative Impact of Chemotherapy on Breast Cancer Patients QOL - Utility of Antiemetic Treatment Guidelines and the Role of Race

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is one of the most important worries ofcancer patients. Although not life-threatening, it has a great negative impact on quality of life (QOL). Objective:The aim of this study was to determine the impact of CINV (i.e., acute and delayed) on breast cancer patientsQOL and to discern opinions related with antiemetic guidelines used dependent on the three main races inMalaysia (Malay, Chinese, Indian). Methods: In this longitudinal prospective observational study, 158 breastcancer patients treated with chemotherapy were interviewed and valid questionnaires (MANE and ONEM) wereused to report the impact of CINV on their QOL within the first 24 hours and after 3 to 5 days of chemotherapytreatment. Results: The main result was that delayed CINV has an impact on QOL greater than acute CINV. Theimpact of nausea was reportedly higher than that of vomiting. Also differences in race i.e., genetic polymorphisms(pharmacogenomics) influenced the utility of antiemetic treatments and patients opinions. Conclusion: Based onthe results of our study a new guideline for antiemetic treatment should be used to reduce the impact of CINVon QOL, taking into account variation in genetic polymorphisms among the three races in Malaysia.     

Progress in the Management of Malignant Pleural Mesothelioma in 2017

Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1–deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.     

10 Years of Preparedness by the Radiation Injury Treatment Network

The Radiation Injury Treatment Network (RITN) began in 2006 with the ambitious vision to provide a resource to help with the surge of casualties following a mass casualty incident with marrow toxic injuries. Through the efforts of the National Marrow Donor Program and American Society for Blood and Marrow Transplantation with the support of the Office of Naval Research, the initial 13 hospitals and cancer centers have grown to 76, training over 13,500 hospital staff and conducted, funded, and supported 580 disaster exercises testing preparedness. After a decade, there is more to do, but much laudatory work has been accomplished.     

Screening caused rising incidence rates of ductal carcinoma in situ of the breast

The purpose of this study was to examine trends in incidence and detection of ductal carcinoma in situ (DCIS) of the breast in southern Netherlands in the period 1984–2006 and assess the effect of mass screening. All patients with primary DCIS registered between 1984 and 2006 in the population-based Eindhoven Cancer Registry were included (n = 1,767). These data were linked to data from the population-based screening programme. The incidence of DCIS of the breast increased from 3/100,000 to almost 34/100,000 person-years in women aged 50–69 years in southern Netherlands since 1984. Mass screening was responsible for this increase. A stable 60% of DCIS was screen-detected. Over 11% of breast cancer patients have DCIS. In conclusion, the incidence of DCIS increased markedly in southern Netherlands with a clear effect of mammography screening since 1992.     

Epidemiology of Cancer of the Liver and Intrahepatic Bile Ducts in an Australian Population

The incidence of liver and intrahepatic bile duct cancer in Australia is low at about one third the world averagebut increases are evident. South Australian registry data have been used to describe: age-standardized incidenceand mortality trends; and disease-specific survivals, using Kaplan-Meier estimates and Cox proportional hazardsregression. The study included 1,220 incident cancers (901 hepatocellular carcinomas; 201 cholangiocarcinomas;118 other types) and 983 deaths. Incidence and mortality rates increased by 2-3 fold during 1977-2007. Incidenceincreases affected males, females and all ages. There was a strong: male predominance (3 to 1); and age gradient(70+ year old incidence >30 times under 50 year old incidence). Compared with hepatocellular carcinomas,cholangiocarcinomas and other histology types more often affected females and older ages and less often theAsian born. All histology types showed similar incidence increases. Apart from recognized risk factors (e.g.,hepatitis B/C infection and aflatoxins for hepatocellular carcinoma; liver-fluke infection for cholangiocarcinomas,etc.), common risk factors may include excess alcohol consumption and possibly obesity and diabetes mellitus.Five-year disease-specific survival in 1998-2007 was 16%, with higher fatalities applying for earlier periods,older patients, males, lower socio-economic groups, and cholangiocarcinomas. Aboriginal patients tended tohave higher case fatalities (p=0.054). Survival increases may be due to earlier diagnosis from alpha feta proteintesting and diagnostic imaging, plus more aggressive treatment of localized disease. Mortality increases require apreventive response, including hepatitis B vaccination, prevention of viral infection though contaminated bloodand other body fluids, early detection initiatives for high-risk patients, aggressive surgery for localized disease,and experimentation with new systemic therapies.     

Therapeutic effects of the Sp1 inhibitor mithramycin A in glioblastoma

Mithramycin A (MitA) is a chemotherapeutic compound which has been used in the therapy of several types of cancer. For experimental cancer it has been shown that MitA mediates the expression of genes involved in tumor progression such as genes involved in immunosurveillance, cell motility or cell death. MitA works synergistically with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and with antiangiogenic agents. We were therefore interested in analyzing whether MitA might be a suitable agent for glioma therapy. We demonstrate herein that the cell death sensitizing effects of MitA are cell line specific, independent of the endogenous status of the tumor suppressor p53 as well as of the endogenous expression of X-linked inhibitor of apoptosis (XIAP) or basal sensitivity towards death ligand-induced cell death. In glioma cells, MitA reduced the secretion and activity of the migration-involved matrix metalloproteinases (MMP), diminished vascular endothelial growth factor (VEGF), and increased recepteur d’origine nantais (RON) kinase messenger RNA (mRNA), paralleled by a significant reduction of glioma cell migration. In contrast to other cancer types, in glioma cells MitA did not alter the expression of the immunorelevant genes major histocompatibility complex I class related (MIC)-A, MIC-B or UL16 binding proteins (ULBP). We conclude that, whereas MitA-mediated reduction of XIAP expression and sensitization to Apo2L/TRAIL are cell line specific, its antimigratory effects are more general and might be the result of altered expression of MMP, VEGF, and/or RON kinase. Therefore, MitA might be a potential agent to reduce glioma cell migration.     

Differences in the longevity of topo IIα and topo IIβ drug-stabilized cleavable complexes and the relationship to drug sensitivity

Purpose DNA topoisomerase II (topo II) is an important cellular target for chemotherapeutic agents. Human cells have two isoforms of topo II ( and ), and both are inhibited by the chemotherapeutic agents etoposide, amsacrine (mAMSA) and mitoxantrone. It is known that the cytotoxic importance of topo II or topo II drug-induced complexes differs depending on which drug is present. This study was designed to (a) assess isoform-specific formation and reversal of topo II and cleavable complexes, and (b) determine whether the cytotoxic importance of either isoform was related to differences in the longevity of the complexes.Methods Mouse embryonic fibroblasts (MEFs) were used to study the cellular response to the topo II poisons etoposide, mitoxantrone and mAMSA. The longevity of topo II and complexes was determined using the TARDIS assay. This immunofluorescence assay can differentiate between the topo II isoforms and thus allowed us to investigate the persistence and importance of topo II and complexes for the first time.Results In MEFs treated with etoposide, 50% of topo II complexes dissociated within 40 min whereas dissociation of topo II complexes took only 20 min. Disappearance of complexes was a slower process for mitoxantrone-treated cells. The time taken to reduce topo II and topo II cleavable complexes by 50% was 10 and 6 h, respectively. In contrast, mAMSA-stabilized topo II and topo II cleavable complexes were equally stable (dissociation within 15 min for both isoforms). These stability data were confirmed using an in vitro assay.Conclusions We previously demonstrated that topo II is the major target for etoposide and mitoxantrone but that both topo II and topo II are important for mAMSA cytotoxicity. The longevity of the topo II and cleavable complexes shown here is therefore an important factor in determining the cytotoxic sensitivity of either isoform to these drugs.Abbreviations FITC Fluorescein isothiocyanate - mAMSA Amsacrine - PBS Phosphate-buffered saline - TARDIS Trapped in agarose DNA immunostaining - topo Topoisomerase     

Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non–Small Cell Lung Cancer in the Global Phase III ALEX Study

IntroductionAt the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months’ follow-up (cutoff December 1, 2017).MethodsPatients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant.ResultsBaseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib.ConclusionAlectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.     

Does the site of the orthotopic neobladder outlet matter? A prospective randomized comparative study

Background

To compare the results of urethral anastomosis to a button hole and to the lowest part of the anterior suture line during orthotopic neobladder substitution.

Improving the quality of radiation oncology: 10 years’ experience of QUATRO audits in the IAEA Europe Region

Background and purpose

The IAEA has developed a methodology for comprehensive quality audits of radiotherapy practices called Quality Assurance Team for Radiation Oncology (QUATRO). This study explores the factors that impacted quality of care among QUATRO audited centres in the IAEA Europe Region.

Prospective Feasibility Trial of Sentinel Lymph Node Biopsy in the Setting of Inflammatory Breast Cancer

Background

Most inflammatory breast cancer (IBC) patients have axillary disease at presentation. Current standard is axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NACT). Advances in NACT have improved pathologic complete response (pCR) rates increasing interest in performing sentinel lymph node (SLN) biopsy (SLNB). Previous studies on SLNB for IBC patients did not assess nodal response with imaging or use dual tracer mapping. We sought to prospectively determine false negative rates of SLNB in IBC patients using dual tracer mapping, and to correlate pathology with preoperative axillary imaging.

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in?vitro and in?vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in?vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in?vitro as well as in?vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in?vivo growth of xenotransplants.