Morphological and pathological response in primary systemic therapy of patients with breast cancer and the prediction of disease free survival

AIM: To identify breast cancer subtypes likely to respond to primary systemic therapy (PST or neoadjuvant therapy) and to assess the accuracy of physical examination (PE) and breast ultrasonography (US) in evaluating and predicting residual size of breast carcinoma following PST. METHODS: 116 patients who received at least two cycles of PST between 1998 and 2009 were selected from a prospectively collected clinical database. Radiological assessment was done by mammography and US. Prior to PST, tumors were subclassified according to core biopsy (NCB) and/or fine-needle aspiration-based immunohistochemical profiles of NCB. Pathological response rates were assessed following the surgeries by using Chevallier classification. Tumor measurements by PE and US were obtained before and after PST. Different clinical measurements were compared with histological findings. Disease-free survival (DFS) was assessed. RESULTS: Pathological complete remission (pCR=Chevallier I/II) was observed in 25 patients (21.5%), 44% of whom had triple negative histology, 28% Her2 positive and 76% had high-grade tumor. Of 116 patients, 24 received taxane-based PST, 48 combined taxane + anthracycline treatment, 8 trastuzumab combinations, 21 anthracycline-based treatments, and 15 other treatments. In the taxane treated group, the pCR rate was 30%, in the taxane + anthracycline group 25%, in the anthracycline group 9.5%, and in trastuzumab group 37.5%. After PST, PE and US were both significantly associated with pathology (P<0.001 and P=0.004, respectively). Concerning OS, significant difference was observed between the Chevallier III and IV group (P=0.031) in favor of Chevallier III group. In the pCR group, fewer events were observed during the follow-up period. CONCLUSIONS: Our results show that even limited, routinely used immunohistochemical profiling of tumors can predict the likelihood of pCR to PST: patients with triple negative and Her2-positive cancers are more likely to achieve pCR to PST. Also, PE is better correlated with pathological findings than US

The MINDVIEW project: First results

[EN] We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from C-11-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that C-11-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naive, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia. (c) 2018 Elsevier Masson SAS. All rights reserved.This project is funded by EU grant FP7-HEALTH-F2-2013-603002.Benlloch Baviera, JM.; González Martínez, AJ.; Pani, R.; Preziosi, E.; Jackson, C.; Murphy, J.; Barbera Ballester, J.... (2018). The MINDVIEW project: First results. European Psychiatry. 50:21-27. https://doi.org/10.1016/j.eurpsy.2018.01.002S212750Gonzalez, A. J., Gonzalez-Montoro, A., Aguilar, A., Conde, P., Canizares, G., Hernandez, L., … Benlloch, J. M. (2016). A brain PET insert MR compatible: Final design and first results. 2016 IEEE Nuclear Science Symposium, Medical Imaging Conference and Room-Temperature Semiconductor Detector Workshop (NSS/MIC/RTSD). doi:10.1109/nssmic.2016.8069619Dahl, K., Schou, M., Ulin, J., Sjöberg, C.-O., Farde, L., & Halldin, C. (2015). 11C-carbonylation reactions using gas–liquid segmented microfluidics. RSC Advances, 5(108), 88886-88889. doi:10.1039/c5ra20646d[26] Långström B and Sjöberg CO, System for controlling environment in reaction box, From PCT Int. Appl. (2013), WO 2013103312 A1 20130711.Autret, A., Bert, J., Strauss, O., & Visvikis, D. (2012). Projector with realistic detector scatter modelling for PET list-mode reconstruction. 2012 IEEE Nuclear Science Symposium and Medical Imaging Conference Record (NSS/MIC). doi:10.1109/nssmic.2012.6551759[10] Young JW Head and Face Antropometry of Adult U.S. Citizens, Civil Aeromedical Institute, Federal Aviation Administration, U.S. Department of Transportation, Report number DOT/FAA/AM-93/10, July 1993.Braff, D. L. (1990). Sensorimotor Gating and Schizophrenia. Archives of General Psychiatry, 47(2), 181. doi:10.1001/archpsyc.1990.01810140081011Preziosi, E., Sánchez, S., González, A. J., Pani, R., Borrazzo, C., Bettiol, M., … Benlloch, J. M. (2016). Performance study of a PET scanner based on monolithic scintillators for different DoI-dependent methods. Journal of Instrumentation, 11(12), C12076-C12076. doi:10.1088/1748-0221/11/12/c12076Howes, O., McCutcheon, R., & Stone, J. (2015). Glutamate and dopamine in schizophrenia: An update for the 21st century. Journal of Psychopharmacology, 29(2), 97-115. doi:10.1177/0269881114563634Moliner, L., Correcher, C., González, A. J., Conde, P., Hernández, L., Orero, A., … Benlloch, J. M. (2013). Implementation and analysis of list mode algorithm using tubes of response on a dedicated brain and breast PET. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 702, 129-132. doi:10.1016/j.nima.2012.08.029Zelano, J., Mikulovic, S., Patra, K., Kühnemund, M., Larhammar, M., Emilsson, L., … Kullander, K. (2013). The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. Experimental Neurology, 239, 73-81. doi:10.1016/j.expneurol.2012.09.006Antich, P., Malakhov, N., Parkey, R., Slavin, N., & Tsyganov, E. (2002). 3D position readout from thick scintillators. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 480(2-3), 782-787. doi:10.1016/s0168-9002(01)01214-1Gonzalez-Montoro, A., Benlloch, J. M., Gonzalez, A. J., Aguilar, A., Canizares, G., Conde, P., … Sanchez, F. (2017). Performance Study of a Large Monolithic LYSO PET Detector With Accurate Photon DOI Using Retroreflector Layers. IEEE Transactions on Radiation and Plasma Medical Sciences, 1(3), 229-237. doi:10.1109/trpms.2017.2692819Rahman, O., Takano, A., Amini, N., Dahl, K., Kanegawa, N., Långström, B., … Halldin, C. (2015). Synthesis of ([11C]carbonyl)raclopride and a comparison with ([11C]methyl)raclopride in a monkey PET study. Nuclear Medicine and Biology, 42(11), 893-898. doi:10.1016/j.nucmedbio.2015.07.003Howes, O. D., Kambeitz, J., Kim, E., Stahl, D., Slifstein, M., Abi-Dargham, A., & Kapur, S. (2012). The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment. Archives of General Psychiatry, 69(8). doi:10.1001/archgenpsychiatry.2012.169Ling, T., Lewellen, T. K., & Miyaoka, R. S. (2007). Depth of interaction decoding of a continuous crystal detector module. Physics in Medicine and Biology, 52(8), 2213-2228. doi:10.1088/0031-9155/52/8/012González, A. J., Majewski, S., Sánchez, F., Aussenhofer, S., Aguilar, A., Conde, P., … Benlloch, J. M. (2016). The MINDView brain PET detector, feasibility study based on SiPM arrays. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 818, 82-90. doi:10.1016/j.nima.2016.02.046Wong, D. F., Waterhouse, R., Kuwabara, H., Kim, J., Brasic, J. R., Chamroonrat, W., … Mozley, P. D. (2013). 18F-FPEB, a PET Radiopharmaceutical for Quantifying Metabotropic Glutamate 5 Receptors: A First-in-Human Study of Radiochemical Safety, Biokinetics, and Radiation Dosimetry. Journal of Nuclear Medicine, 54(3), 388-396. doi:10.2967/jnumed.112.107995Jackson, C., O’Neill, K., Wall, L., & McGarvey, B. (2014). High-volume silicon photomultiplier production, performance, and reliability. Optical Engineering, 53(8), 081909. doi:10.1117/1.oe.53.8.081909Rahman, O., Långström, B., & Halldin, C. (2016). Alkyl Iodides and [11 C]CO in Nickel-Mediated Cross-Coupling Reactions: Successful Use of Alkyl Electrophiles containing a β Hydrogen Atom in Metal-Mediated [11 C]Carbonylation. ChemistrySelect, 1(10), 2498-2501. doi:10.1002/slct.201600643Sullivan, J. M., Lim, K., Labaree, D., Lin, S., McCarthy, T. J., Seibyl, J. P., … Morris, E. D. (2012). Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans. Journal of Cerebral Blood Flow & Metabolism, 33(4), 532-541. doi:10.1038/jcbfm.2012.195Levin, C. S. (2003). Detector design issues for compact nuclear emission cameras dedicated to breast imaging. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 497(1), 60-74. doi:10.1016/s0168-9002(02)01893-4Larhammar, M., Patra, K., Blunder, M., Emilsson, L., Peuckert, C., Arvidsson, E., … Kullander, K. (2015). SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis. Biological Psychiatry, 77(6), 526-536. doi:10.1016/j.biopsych.2014.07.017Kaul, M., Surti, S., & Karp, J. S. (2013). Combining Surface Treatments With Shallow Slots to Improve the Spatial Resolution Performance of Continuous, Thick LYSO Detectors for PET. IEEE Transactions on Nuclear Science, 60(1), 44-52. doi:10.1109/tns.2013.2240315Bleich, A., Brown, S.-L., Kahn, R., & van Praag, H. M. (1988). The Role of Serotonin in Schizophrenia. Schizophrenia Bulletin, 14(2), 297-315. doi:10.1093/schbul/14.2.29

Evidence-based hydro- and balneotherapy in Hungary-a systematic review and meta-analysis

Balneotherapy is appreciated as a traditional treatment modality in medicine. Hungary is rich in thermal mineral waters. Balneotherapy has been in extensive use for centuries and its effects have been studied in detail. Here, we present a systematic review and meta-analysis of clinical trials conducted with Hungarian thermal mineral waters, the findings of which have been published by Hungarian authors in English. The 122 studies identified in different databases include 18 clinical trials. Five of these evaluated the effect of hydro- and balneotherapy on chronic low back pain, four on osteoarthritis of the knee, and two on osteoarthritis of the hand. One of the remaining seven trials evaluated balneotherapy in chronic inflammatory pelvic diseases, while six studies explored its effect on various laboratory parameters. Out of the 18 studies, 9 met the predefined criteria for meta-analysis. The results confirmed the beneficial effect of balneotherapy on pain with weight bearing and at rest in patients with degenerative joint and spinal diseases. A similar effect has been found in chronic pelvic inflammatory disease. The review also revealed that balneotherapy has some beneficial effects on antioxidant status, and on metabolic and inflammatory parameters. Based on the results, we conclude that balneotherapy with Hungarian thermal-mineral waters is an effective remedy for lower back pain, as well as for knee and hand osteoarthritis. © 2013 The Author(s)

HIV risk behaviors among female IDUs in developing and transitional countries

Abstract Background A number of studies suggest females may be more likely to engage in injection and sex risk behavior than males. Most data on gender differences come from industrialized countries, so data are needed in developing countries to determine how well gender differences generalize to these understudied regions. Methods Between 1999 and 2003, 2512 male and 672 female current injection drug users (IDUs) were surveyed in ten sites in developing countries around the world (Nairobi, Beijing, Hanoi, Kharkiv, Minsk, St. Petersburg, Bogotá, Gran Rosario, Rio, and Santos). The survey included a variety of questions about demographics, injecting practices and sexual behavior. Results Females were more likely to engage in risk behaviors in the context of a sexual relationship with a primary partner while males were more likely to engage in risk behaviors in the context of close friendships and casual sexual relationships. After controlling for injection frequency, and years injecting, these gender differences were fairly consistent across sites. Conclusion Gender differences in risk depend on the relational contexts in which risk behaviors occur. The fact that female and male risk behavior often occurs in different relational contexts suggests that different kinds of prevention interventions which are sensitive to these contexts may be necessary.</p

Advances in Understanding Environmental Risks of Red Mud After the Ajka Spill, Hungary

In the 5 years since the 2010 Ajka red mud spill (Hungary), there have been 46 scientific studies assessing the key risks and impacts associated with the largest single release of bauxite-processing residue (red mud) to the environment. These studies have provided insight into the main environmental concerns, as well as the effectiveness of remedial efforts that can inform future management of red mud elsewhere. The key immediate risks after the spill were associated with the highly caustic nature of the red mud slurry and fine particle size, which once desiccated, could generate fugitive dust. Studies on affected populations showed no major hazards identified beyond caustic exposure, while red mud dust risks were considered equal to or lesser than those provided by urban dusts of similar particle size distribution. The longer-term environmental risks were related to the saline nature of the spill material (salinization of inundated soils) and the release and the potential cycling of oxyanion-forming metals and metalloids (e.g., Al, As, Cr, Mo, and V) in the soil–water environment. Of these, those that are soluble at high pH, inefficiently removed from solution during dilution and likely to be exchangeable at ambient pH are of chief concern (e.g., Mo and V). Various ecotoxicological studies have identified negative impacts of red mud-amended soils and sediments at high volumes (typically [5 %) on different test organisms, with some evidence of molecularlevel impacts at high dose (e.g., genotoxic effects on plants and mice). These data provide a valuable database to inform future toxicological studies for red mud. However, extensive management efforts in the aftermath of the spill greatly limited these exposure risks through leachate neutralization and red mud recovery from the affected land. Monitoring of affected soils, stream sediments, waters and aquatic biota (fungi, invertebrates and fish) have all shown a very rapid recovery toward prespill conditions. The accident also prompted research that has also highlighted potential benefits of red mud use for critical raw material recovery (e.g., Ga, Co, V, rare earths, inform), carbon sequestration, biofuel crop production, and use as a soil ameliorant

The effect of dopamine agonists on adaptive and aberrant salience in Parkinson's disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinson's disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus-reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus-reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus-reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward

Simultaneous Recruitment of Drug Users and Men Who Have Sex with Men in the United States and Russia Using Respondent-Driven Sampling: Sampling Methods and Implications

The Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP) examined the role of drug use in the sexual transmission of the human immunodeficiency virus (HIV) from traditional high-risk groups, such as men who have sex with men (MSM) and drug users (DU), to lower risk groups in three US cities and in St. Petersburg, Russia. SATHCAP employed respondent-driven sampling (RDS) and a dual high-risk group sampling approach that relied on peer recruitment for a combined, overlapping sample of MSM and DU. The goal of the sampling approach was to recruit an RDS sample of MSM, DU, and individuals who were both MSM and DU (MSM/DU), as well as a sample of sex partners of MSM, DU, and MSM/DU and sex partners of sex partners. The approach efficiently yielded a sample of 8,355 participants, including sex partners, across all four sites. At the US sites—Los Angeles, Chicago, and Raleigh–Durham—the sample consisted of older (mean age = 41 years), primarily black MSM and DU (both injecting and non-injecting); in St. Petersburg, the sample consisted of primarily younger (mean age = 28 years) MSM and DU (injecting). The US sites recruited a large proportion of men who have sex with men and with women, an important group with high potential for establishing a generalized HIV epidemic involving women. The advantage of using the dual high-risk group approach and RDS was, for the most part, the large, efficiently recruited samples of MSM, DU, and MSM/DU. The disadvantages were a recruitment bias by race/ethnicity and income status (at the US sites) and under-enrollment of MSM samples because of short recruitment chains (at the Russian site)

Izloženost genotoksičnim agensima iz životnog okoliša tijekom prenatalnog razvoja i djetinjstva

Health disorders and diseases related to environmental exposure in children such as cancer and immunologic disturbances (asthma, allergies) are on the rise. However, complex transplacental and prepubertal genotoxicology is given very limited consideration, even though intrauterine development and early childhood may be critical for elucidating the cancer aetiology. The foetus is transplacentally exposed to contaminants in food and environment such as various chemicals, drugs, radiochemically contaminated water and air. Target organs of xenobiotic action may differ between the mother and the foetus due to specific stage of developmental physiology and enzyme distribution. This in turn may lead to different levels of clastogenic and aneugenic metabolites of the same xenobiotic in the mother and the foetus. Adult’s protective behaviour is not sufficient to isolate children from radioisotopes, pesticides, toxic metals and metalloids, environmental tobacco smoke, endocrine disrupting chemicals, and various food contaminants, which are just a part of the stressors present in a polluted environment. In order to improve legislation related to foetus and child exposure to genotoxic and possibly carcinogenic agents, oncologists, paediatricians, environmental health specialists, and genotoxicologists should work together much more closely to make a more effective use of accumulated scientific data, with the final aim to lower cancer incidence and mortality.Unatoč velikim naporima da se smanji okolišna izloženost u djece se dalje bilježi trend porasta pojavnosti karcinoma i imunosnih poremećaja (astma, alergije). Premda su intrauterini razvoj i rano djetinjstvo kritično razdoblje za tumačenje etiologije nastanka karcinoma, transplacentalna i prepubertetna genotoksikologija do danas su slabo istražene. Fetus je transplacentalno izložen brojnim fizikalnim i kemijskim čimbenicima: kontaminantima iz hrane i okoliša, radiokemijski kontaminiranoj vodi, zraku te lijekovima. Ciljna tkiva za djelovanje ksenobiotika mogu biti različita u majke i fetusa zbog različitosti u razvojnoj fiziologiji i distribuciji enzima. Zbog toga u organizmu majke i fetusa mogu nastati različite razine klastogenih i aneugenih metabolita istog ksenobiotika. Zaštitna uloga odraslih u namjeri da spriječe negativne utjecaje onečišćenog okoliša na djetetovo zdravlje često je ograničena jer su radioizotopi, olovo, PCB, pasivno pušenje, živa, endokrino aktivne tvari, pesticidi i kontaminanti prisutni u svim životnim područjima tijekom razvoja i rasta djeteta. Kako bi se poboljšalo zakonodavstvo vezano uz izloženost djece genotoksičnim i vjerojatno kancerogenim tvarima, tijekom razvoja potrebna je bolja suradnja onkologa, pedijatara, stručnjaka zdravstvene ekologije i genotoksikologa. Na taj način ostvarilo bi se uspješnije iskorištavanje postojećih znanstvenih podataka u cilju smanjenja incidencije karcinoma i mortaliteta