Browsing by Subject "RADIOTHERAPY"

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  • Tuohinen, Suvi Sirkku; Skyttä, Tanja; Huhtala, Heini; Poutanen, Tuija; Virtanen, Vesa; Kellokumpu-Lehtinen, Pirkko-Liisa; Raatikainen, Pekka (2021)
    BACKGROUND Radiation therapy (RT) results in myocardial changes consisting of diffuse fibrosis, which may result in changes in diastolic function. OBJECTIVES The aim of this study was to explore RT-associated changes in left ventricular (LV) diastolic function. METHODS Sixty chemotherapy-naive patients with left-sided, early-stage breast cancer were studied with speckle tracking echocardiography at 3 time points: prior to, immediately after, and 3 years after RT. Global and regional early diastolic strain rate (SRe) were quantified, as were parameters of systolic function. RESULTS Regional changes in SRe, particularly the apical and anteroseptat segments, were observed over time and were more evident than global changes. The apical SRe declined from a median of 1.24 (interquartile range: 1.01 to 1.39) s(-1) at baseline to 1.02 (interquartile range: 0.79 to 1.15) s(-1) at 3 years of follow-up (p < 0.001). This decline was associated with the left ventricular maximal radiation dose (beta = 0.36, p = 0.007). The global SRe was CONCLUSIONS RT resulted in changes in the SRe in the apical and anteroseptat segments over 3 years of follow-up. Changes in SRe apical segments were present even in patients with preserved systolic function and were independently associated with RT dose and cardiovascular comorbidities. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
  • Seibold, Petra; Schmezer, Peter; Behrens, Sabine; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Flesch-Janys, Dieter; Nevanlinna, Heli; Fagerholm, Rainer; Aittomaki, Kristiina; Blomqvist, Carl; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Lambrechts, Diether; Wildiers, Hans; Kristensen, Vessela; Alnaes, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Hooning, Maartje J.; Hollestelle, Antoinette; Jager, Agnes; Seynaeve, Caroline; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Dunning, Alison M.; Rhenius, Valerie; Shah, Mitul; Kabisch, Maria; Torres, Diana; Ulmer, Hans-Ulrich; Hamann, Ute; Schildkraut, Joellen M.; Purrington, Kristen S.; Couch, Fergus J.; Hall, Per; Pharoah, Paul; Easton, Doug F.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Popanda, Odilia (2015)
    Background: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. Methods: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p <0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. Results: rs878156 in PARP2 showed a differential effect by chemotherapy (p = 0.093) and was replicated in BCAC studies (p = 0.009; combined analysis p = 0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency = 0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR) = 0.75, 95 % 0.53-1.07) and poorer survival when not treated with chemotherapy (HR = 1.42, 95 % 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR = 0.73, 95 % CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. Conclusions: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.
  • Hirvonen, Outi M.; Leskelä, Riikka-Leena; Gronholm, Lotta; Haltia, Olli; Rissanen, Antti; Tyynela-Korhonen, Kristiina; Rahko, Eeva K.; Lehto, Juho T.; Saarto, Tiina (2019)
    Background: To avoid aggressive treatments at the end-of-life and to provide palliative care (PC), physicians need to terminate futile anti-cancer treatments and define the palliative goal of the treatment in time. This single center study assesses the practices used to make the decision that leads to treatment with a palliative goal, i.e., the PC decision and its effect on anti-cancer treatments at the end of life. Material and methods: Patients with a cancer diagnosis treated in tertiary hospital during 1st January 2013 - 31st December 2014 and deceased by the end of 2014 were identified in the hospital database (N = 2737). Of these patients, 992 were randomly selected for this study. The PC decision was screened from patient records, i.e., termination of cancer-specific treatments and a focus on symptom-centered PC. Results: The PC decision was defined in 82% of the patients during the last year of life (49% >30 days and 33%
  • Kallio, Pauliina; Jokinen, Elina; Högström, Jenny; Das, Suvendu; Heino, Sarika; Lähde, Marianne; Brodkin, Jefim; Korhonen, Emilia A.; Alitalo, Kari (2020)
    Abnormal vasculature in tumors leads to poor tissue perfusion and cytostatic drug delivery. Although drugs inducing vascular normalization, for example, angiopoietin-2 (Ang2)-blocking antibodies, have shown promising results in preclinical tumor models, clinical studies have so far shown only little efficacy. Because Ang2 is known to play a protective role in stressed endothelial cells, we tested here whether Ang2 blocking could enhance radiation-induced tumor vascular damage. Tumor-bearing mice were treated with anti-Ang2 antibodies every 3 or 4 days starting 3 days before 3 x 2 Gy or 4 x 0.5 Gy whole-body or tumor-focused radiation. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal tumors. Single-cell RNA-sequencing revealed that Ang2 blocking rescued radiation-induced decreases inT cells and cells of the monocyte/macrophage lineage. In addition, anti-Ang2 enhanced radiation-induced apoptosis in cultured endothelial cells. In vivo, combination treatment decreased tumor vasculature and increased tumor necrosis in comparison with tumors treated with monotherapies. These results suggest that a combination of Ang2-blocking antibodies with radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice. Significance: These findings offer a preclinical rationale for further testing of the use of radiation in combination with Ang2-blocking antibodies to improve the overall outcome of cancer treatment.
  • Koivunoro, Hanna; Kankaanranta, Leena; Seppälä, Tiina; Haapaniemi, Aaro; Mäkitie, Antti; Joensuu, Heikki (2019)
    Background and purpose: Head and neck squamous cell carcinoma (HNSCC) that recurs locally is a therapeutic challenge. We investigated the efficacy of boron neutron capture therapy (BNCT) in the treatment of such patients and the factors associated with treatment response and survival. Methods and materials: Seventy-nine patients with inoperable, locally recurred HNSCC were treated with L-boronophenylalanine-mediated BNCT in Espoo, Finland, between February, 2003 and January, 2012. Prior treatments consisted of surgery and conventionally fractionated radiotherapy to a median cumulative dose of 66 Gy (interquartile range [IQR], 59-70 Gy) administered with or without concomitant chemotherapy. Tumor response was assessed using the RECISTv. 1.0 criteria. Results: Forty patients received BNCT once (on 1 day), and 39 twice. The median time between the 2 treatments was 6 weeks. Forty-seven (68%; 95% confidence interval [CI], 57-79%) of the 69 evaluable patients responded; 25 (36%) had a complete response, 22 (32%) a partial response, 17 (25%) a stable disease lasting for a median of 4.2 months, and 5 (7%) progressed. The patients treated with BNCT twice responded more often than those treated once. The median follow-up time after BNCT was 7.8 years. The 2-year locoregional progression-free survival rate was 38% and the overall survival rate 21%. A high minimum tumor dose and a small volume were independently associated with long survival in a multi-variable analysis. Conclusions: Most patients responded to BNCT. A high minimum tumor dose from BNCT was predictive for response and survival. (C) 2019 The Authors. Published by Elsevier B.V.
  • Nieminen, M.; Aro, K.; Jouhi, L.; Bäck, L.; Mäkitie, A.; Atula, T. (2018)
    Background: Head and neck cancers are often diagnosed at a late stage, thus resulting in a generally poor prognosis. This is partly attributable to patients' hesitancy in seeking treatment. However, the length and causes of these patient delays remain relatively unknown. Material and methods: We included all new head and neck cancer patients treated at our tertiary care center between 2016 and 2017. Using a patient questionnaire, we collected data on patients' symptoms and other factors related to seeking medical care, and recorded both patient- and primary health care-related delays. We then compared the data collected from these patients to patient and tumor characteristics collected from hospital records, and analyzed various causes for delay before a specialist consultation to the Department of Otorhinolaryngology - Head and Neck Surgery. Results: Among the patients (n = 142) in our study, the median patient delay was 35 d with 73% of patients seeking medical care within 3 months. In comparison, the median primary health-care delay was 20 d. Certain symptoms influenced patient delay. Hoarseness and breathing difficulties correlated with longer patient delay while patients with a lump on the neck had a shorter delay. Patient delay was associated with certain tumor-related factors such as the tumor site and the presence of regional metastases, which resulted in shorter patient delay. None of the patient-related factors appeared to impact delay. Important factors influencing primary health-care delay included the initial location visited and whether any follow-up visit was scheduled or not. Conclusions: Although most patients sought medical advice without a major delay and were adequately referred, we found that long delays existed. Raising awareness of the symptoms of head and neck cancer among general population and health-care providers is probably the best way to get patients to curative treatment without delay.
  • Vento, Seija Inkeri; Vähämurto, Pauli; Silventoinen, Kaija; Karjalainen-Lindsberg, Marja-Liisa; Mannisto, Susanna; Leppa, Sirpa; Makitie, Antti Aarni (2017)
    Objectives: Extramedullary plasmacytoma in the sinonasal tract or nasopharynx is rare. The aim of the study was to review data on symptoms, clinical findings, treatment and follow-up of plasmacytomas in the sinonasal and nasopharyngeal regions in order to delineate the main clinical characteristics and the optimal management. Method: Twenty-five patients with sinonasal or nasopharyngeal plasmacytoma, diagnosed and treated at the Helsinki University Hospital during a 39-year period from 1975 to 2013 were retrospectively reviewed. Results: There were 18 males and 7 females with a median age of 66 years (range, 36-80). Sixty-eight percent received only radiotherapy or (chemo)radiotherapy. Forty-seven percent of them had a complete response to primary radiotherapy and one patient had a complete response after receiving additional brachytherapy. Four patients were treated primarily with surgery only. Two of them had a local recurrence, but were then successfully treated with radiotherapy. Altogether, four patients received a combination of surgery and (chemo)radiotherapy. Forty-four percent were alive with no evidence of disease after a median follow-up time of 78 months. Forty percent died of their disease and 16% died of other causes. Conclusions: Our study supports radiotherapy as a treatment of choice, but for small tumours surgery alone or in combination with radiotherapy may also be considered. Chinese abstract
  • Gregoire, Vincent; Evans, Mererid; Quynh-Thu Le,; Bourhis, Jean; Budach, Volker; Chen, Amy; Eisbruch, Abraham; Feng, Mei; Giralt, Jordi; Gupta, Tejpal; Hamoir, Marc; Helito, Juliana K.; Hu, Chaosu; Hunter, Keith; Johansen, Jorgen; Kaanders, Johannes; Laskar, Sarbani Ghosh; Lee, Anne; Maingon, Philippe; Mäkitie, Antti; Micciche, Francesco; Nicolai, Piero; O'Sullivan, Brian; Poitevin, Adela; Porceddu, Sandro; Skiadowski, Krzysztof; Tribius, Silke; Waldron, John; Wee, Joseph; Yao, Min; Yom, Sue S.; Zimmermann, Frank; Grau, Cai (2018)
    Purpose: Few studies have reported large inter-observer variations in target volume selection and delineation in patients treated with radiotherapy for head and neck squamous cell carcinoma. Consensus guidelines have been published for the neck nodes (see Gregoire et al., 2003, 2014), but such recommendations are lacking for primary tumour delineation. For the latter, two main schools of thoughts are prevailing, one based on geometric expansion of the Gross Tumour Volume (GTV) as promoted by DAHANCA, and the other one based on anatomical expansion of the GTV using compartmentalization of head and neck anatomy. Method: For each anatomic location within the larynx, hypopharynx, oropharynx and oral cavity, and for each T-stage, the DAHANCA proposal has been comprehensively reviewed and edited to include anatomic knowledge into the geometric Clinical Target Volume (CTV) delineation concept. A first proposal was put forward by the leading authors of this publication (VG and CG) and discussed with opinion leaders in head and neck radiation oncology from Europe, Asia, Australia/New Zealand, North America and South America to reach a worldwide consensus. Results: This consensus proposes two CTVs for the primary tumour, the so called CTV-P1 and CVT-P2, corresponding to a high and lower tumour burden, and which should be associated with a high and a lower dose prescription, respectively. Conclusion: Implementation of these guidelines in the daily practice of radiation oncology should contribute to reduce treatment variations from clinicians to clinicians, facilitate the conduct of multi institutional clinical trials, and contribute to improved care of patients with head and neck carcinoma. (C) 2017 Elsevier B.V. All rights reserved.
  • Andritsch, Elisabeth; Beishon, Marc; Bielack, Stefan; Bonvalot, Sylvie; Casali, Paolo; Crul, Mirjam; Delgado-Bolton, Roberto; Donatih, Davide Maria; Douis, Hassan; Haas, Rick; Hogendoorn, Pancras; Kozhaeva, Olga; Lavender, Verna; Lovey, Jozsef; Negrouk, Anastassia; Pereira, Philippe; Roca, Pierre; de Lempdes, Godelieve Rochette; Saarto, Tiina; van Berck, Bert; Vassal, Gilles; Wartenberg, Markus; Yared, Wendy; Costa, Alberto; Naredi, Peter (2017)
    Background: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care Sarcomas - which can be classified into soft tissue and bone sarcomas - are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients. Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
  • Nieminen, Markus; Atula, Timo; Bäck, Leif; Mäkitie, Antti; Jouhi, Lauri; Aro, Katri (2020)
    The incidence of human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Patients with HPV-associated and HPV-unassociated OPSCC differ in many aspects, which may also impact their diagnostic and management timelines. This study aims at studying the patient, primary health care (PHC) and specialist-care (SC) delays and possible differences between these two patient groups in seeking medical care.
  • Korja, Miikka; Raj, Rahul; Seppä, Karri; Luostarinen, Tapio; Malila, Nea; Seppälä, Matti; Mäenpää, Hanna; Pitkäniemi, Janne (2019)
    We assessed population-level changes in glioblastoma survival between 2000 and 2013 in Finland, with focus on elderly patients (> 70 y) in order to assess if changes in treatment of glioblastoma are reflected also in population-based survival rates. We identified all patients (age 18 y) from the Finnish Cancer Registry (FCR) with a histopathological diagnosis of primary glioblastoma in 20002013. Patients were followed up until December 2015. The accuracy of register-based search of glioblastoma patients was internally validated. We report age-standardized relative survival ratios and relative excess risks (RERs) of death in 20002006 (pre-period) and 20072013 (post-period). We identified 2045 glioblastoma patients from the FCR. The accuracy of the FCR-based search was 97%. Median age was 63.3 years, and 42% were women. Incidence increased on average by 1.6% (P = 0.004) and median age by 0.4 years per calendar year. Between the pre- and post-periods, the proportion of patients > 70 years increased from 24% to 27%. In > 70-year-old patients, the median survival time increased from 3.6 months in 20002006 to 4.5 months in 20072013 (RER 0.82, 95% CI: 0.680.98). In 70-year-old patients, the median survival time increased from 9.3 months in 20002006 to 11.7 months in 20072013 (RER 0.74, 95% CI: 0.670.82). Despite the increased proportion of elderly glioblastoma patients, population-level survival of glioblastoma patients has improved since the year 2000. However, increasing incidence, increasing age of patients, and poor survival in elderly are alarming, and future studies should perhaps focus more on elderly.
  • Utriainen, Pauliina; Suominen, Anu; Mäkitie, Outi; Jahnukainen, Kirsi (2019)
    Background: Neuroblastoma is the most common extra-cranial solid tumor in children. Intensive therapy including autologous stem-cell transplantation (HSCT) has improved the poor prognosis of high-risk neuroblastoma (HR-NBL) but may impair gonadal function. Objectives: To investigate the gonadal function and fertility in long-term survivors of childhood HR-NBL. Design: A cohort including all Finnish (n = 20; 11 females) long-term (> 10 years) survivors of HR-NBL and an age-and sex-matched control group (n = 20) was examined at a median age of 22 (16-30) years. Oncologic treatments, pubertal timing, hormonal therapies and the number of off-spring were recorded, and pituitary and gonadal hormones were measured. Results: Altogether 16/20 of the long-term survivors of HR-NBL entered puberty spontaneously; puberty was hormonally induced in four survivors (three females). Among the 8/11 female survivors with spontaneous puberty, seven had spontaneous menarche, but 5/8 developed ovarian failure soon after puberty. Nine females currently needed estrogen substitution. AMH, a marker of ovarian reserve, was lower in the female survivors than controls (median 0.02 vs. 1.7 mu g/l, p <0.001). As a group, male survivors had smaller testicular size (8.5 vs. 39ml, p <0.001) and lower inhibin B ( Conclusion: Gonadal failure is common in long-term survivors of HR-NBL treated with HSCT. Fertility may be preserved in some survivors treated without total-body irradiation.
  • Santti, Kirsi; Ihalainen, Hanna; Ronty, Mikko; Boehling, Tom; Karlsson, Christina; Haglund, Caj; Tarkkanen, Maija; Blomqvist, Carl (2018)
    Background and Objectives: Desmoid tumors are soft-tissue tumors originating from myofibroblasts with a tendency to recur after surgery. High expression of proliferation markers is associated with shortened progression-free and/or overall survival in many neoplasms, including soft-tissue sarcomas. We investigated the prognostic role of cyclin A and Ki67 in desmoid tumors by immunohistochemistry. Methods: The study included 76 patients with desmoid tumor operated at Helsinki University Hospital between 1987 and 2011. A tissue micro array (TMA) was constructed and the TMA sections were immunostained with cyclin A and Ki67 antibodies. A computer-assisted image analysis was performed. Results: Cyclin A expression was evaluable in 74 and Ki67 in 70 patients. Cyclin A immunopositivity varied from 0% to 9.9%, with a mean of 1.9%. Cyclin A expression correlated significantly with Ki67. Cyclin A expression was associated with recurrence-free survival (HR 1.9, 95% CI = 1.1-3.2, P = .02), as were positive margin (HR 6.0, 95% CI = 1.6-22.5, P = .008) and extremity location (HR 5.3, 95% CI = 1.7-16.8, P = 0.005). Ki67 immunopositivity varied from 0.33% to 13.8%, with a mean of 4.6%, but had no significant prognostic impact (HR 1.1, P = .2). Conclusions: Our study indicates that cyclin A may be a new prognostic biomarker in surgically treated desmoid tumors.
  • Skaga, Erlend; Kulesskiy, Evgeny; Fayzullin, Artem; Sandberg, Cecilie J.; Potdar, Swapnil; Kyttälä, Aija; Langmoen, Iver A.; Laakso, Aki; Gaal-Paavola, Emilia; Perola, Markus; Wennerberg, Krister; Vik-Mo, Einar O. (2019)
    BackgroundA major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naive glioblastoma stem cells (GSC) is unclear.MethodsWe cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation.ResultsAlthough tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p
  • Nicoli, Taija K.; Sinkkonen, Saku T.; Anttila, Turkka; Makitie, Antti; Jero, Jussi (2017)
    Treatment of jugulotympanic paragangliomas (JTPGLs) remains challenging with no clear guidelines for management or follow-up. The aim of this retrospective case-note study was to assess long-term results of operatively and conservatively managed JTPGLs between years 1974-2013. A total of 36 patients with JTPGLs were identified. Clinical characteristics and management outcomes of patients were reviewed. Data were extracted on demographics, symptoms, timing of diagnosis, tumor location and size, embolization, and management, including pre- and post-operative imaging, analysis of operative techniques, and follow-up. Pulsatile tinnitus and hearing loss were the most common presenting symptoms. Thirty-four (94 %) patients were treated with primary surgical therapy and two (6 %) with radiotherapy. The surgical approaches included endaural approach for Fisch Class A tumors and a variety of approaches for Fisch Class B-D tumors with an increasing predilection for function-preserving surgery. Eight (24 %) patients received subtotal resection. Five (15 %) patients had a local recurrence within 10 years after primary surgery. Two (6 %) patients suffered a permanent cranial nerve (CN) deficit after primary surgery. We advocate radical surgery when tumor resection is possible without compromising CNs. Function-preserving surgery with at least a 10-year follow-up for Fisch Class B-D tumors should be considered if CNs are in danger.
  • Medina, Tuula Penate; Gerle, Mirko; Humbert, Jana; Chu, Hanwen; Koepnick, Anna-Lena; Barkmann, Reinhard; Garamus, Vasil M.; Sanz, Beatriz; Purcz, Nicolai; Will, Olga; Appold, Lia; Damm, Timo; Suojanen, Juho; Arnold, Philipp; Lucius, Ralph; Willumeit-Roemer, Regina; Acil, Yahya; Wiltfang, Joerg; Goya, Gerardo F.; Glueer, Claus C.; Medina, Oula Penate (2020)
    Simple Summary A novel active release system magnetic sphingomyelin-containing liposome encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin was evaluated. The liposomal sphingomyelin is a target for the sphingomyelinase enzyme, which is released by stressed cells. Thus, sphingomyelin containing liposomes behave as a sensitizer for biological stress situations. In addition, the liposomes were engineered by adding paramagnetic beads to act as a receiver of outside given magnetic energy. The enzymatic activity towards liposomes and destruction caused by the applied magnetic field caused the release of the content from the liposomes. By using these novel liposomes, we could improve the drug release feature of liposomes. The improved targeting and drug-release were shown in vitro and the orthotopic tongue cancer model in mice optical imaging. The increased delivery of cisplatin prolonged the survival of the targeted delivery group versus free cisplatin. Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.
  • Alberro, J. A.; Ballester, B.; Deulofeu, P.; Fabregas, R.; Fraile, M.; Gubern, J. M.; Janer, J.; Moral, A.; de Pablo, J. L.; Penalva, G.; Puig, P.; Ramos, M.; Rojo, R.; Santesteban, P.; Serra, C.; Sola, M.; Solarnau, L.; Solsona, J.; Veloso, E.; Vidal, S.; Abe, O.; Abe, R.; Enomoto, K.; Kikuchi, K.; Koyama, H.; Masuda, H.; Nomura, Y.; Ohashi, Y.; Sakai, K.; Sugimachi, K.; Toi, M.; Tominaga, T.; Uchino, J.; Yoshida, M.; Coles, C. E.; Haybittle, J. L.; Moebus, V.; Leonard, C. F.; Calais, G.; Garaud, P.; Collett, V.; Davies, C.; Delmestri, A.; Sayer, J.; Harvey, V. J.; Holdaway, I. M.; Kay, R. G.; Mason, B. H.; Blomqvist, C.; Saarto, T.; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG); GROCTA Trialists (2018)
    Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.
  • Sahi, Helka; Their, Jenny; Gissler, Mika; Koljonen, Virve (2020)
    Merkel cell carcinoma (MCC) is a rare cutaneous carcinoma that has gained enormous interest since the discovery of Merkel cell polyoma virus, which is a causative oncogenic agent in the majority of MCC tumours. Increased research has focused on effective treatment options with immuno-oncology. In this study, we reviewed the real-world data on different treatments given to MCC patients in Finland in 1986-2016. We used the Finnish Cancer Registry database to find MCC patients and the Hospital Discharge Register and the Cause-of-Death Register to obtain treatment data. We identified 376 MCC patients and 33 different treatment entities and/or combinations of treatment. An increase was noted in the incidence of MCC since 2005. Therefore, the cohort was divided into two groups: the "early" group with time of diagnosis between years 1986 and 2004 and the "late" group with time of diagnosis between 2005 and 2016. The multitude of different treatment combinations is a relatively new phenomenon; before the year 2005, only 11 treatments or treatment combinations were used for MCC patients. Our data show that combining radiation therapy with simple excision provided a survival advantage, which was, however, lost after adjustment for stage or age. Our registry study serves as a baseline treatment efficacy comparison as we move into the age of immunotherapy in MCC. Standardizing the treatment of MCC patients in Finland requires more work on awareness and multidisciplinary co-operation.
  • Mroueh, R.; Haapaniemi, A.; Saarto, T.; Grönholm, L.; Grénman, R.; Salo, T.; Mäkitie, A. A. (2019)
    PurposeLate-stage OTSCC is associated with poor overall survival (OS). Non-curative treatment approach aims to improve quality of life and prolong survival of patients deemed incurable. The purpose of this study was to investigate the used non-curative treatment modalities for OTSSC and patient survival.MethodsAll patients diagnosed with OTSCC and treated with non-curative intent at the HUS Helsinki University Hospital (Helsinki, Finland) during the 12-year period of 2005-2016 were included. Survival analysis after the non-curative treatment decision was conducted using the Kaplan-Meier method in this population-based study.ResultsEighty-two patients were identified. A non-curative treatment decision was made at presentation without any previous treatment in 26 patients (7% of all patients diagnosed with OTSCC during the study period). Palliative radiotherapy was administered to 24% of all patients. The average survival time after the non-curative treatment decision was 3.7months (median 2 and range 0-26).ConclusionsDue to the short mean survival time after decision for treatment with non-curative intent, and the notable symptom burden in this patient population, a prompt initiation of all non-curative measures is warranted.
  • Gomes-Silva, Wagner; Prado-Ribeiro, Ana Carolina; Brandao, Thais Bianca; Morais-Faria, Karina; de Castro Junior, Gilberto; Mak, Milena Perez; Lopes, Marcio Ajudarte; Rocha, Marcelo Marques; Salo, Tuula; Tjaderhane, Leo; de Goes, Mario Fernando; Santos-Silva, Alan Roger (2017)
    Recent evidence suggests that head-and-neck radiotherapy (HNRT) increases active forms of matrix metalloproteinase-20 (MMP-20) in human tooth crowns, degrading the dentin-enamel junction (DEJ) and leading to enamel delamination, which is a pivotal step in the formation of radiation-related caries (RRC). Additional participation of enzymatic degradation of organic matrix components in caries progression was attributed to MMP-20 in dentin. Therefore, the current study tested the hypothesis that MMP-20 is overexpressed in the DEJ, dentin-pulp complex components, and carious dentin of post-HNRT patients, leading to detectable micromorphological changes to the enamel and dentin. Thirty-six teeth were studied, including 19 post-HNRT specimens and 17 nonirradiated controls. Optical light microscopy was used to investigate the micromorphological components of the DEJ, dentin-pulp complex components, and carious dentin. The samples were divided into 2 subgroups: nondemineralized ground sections (n = 20) and demineralized histological sections (n = 16). In addition, immunohistochemical analysis using the immunoperoxidase technique was conducted to semiquantitatively assess MMP-20 expression in the DEJ, dentin-pulp complex components, and carious dentin. No apparent damage to the DEJ microstructure or other dentin-pulp complex components was observed and no statistically significant differences were detected in MMP-20 expression (p > 0.05) between the irradiated and control groups. This study rejected the hypothesis that MMP-20 is overexpressed in the DEJ, dentin-pulp complex components, and carious dentin of post-HNRT patients, leading to detectable micromorphological changes. Hence, direct effects of radiation may not be regarded as an independent factor to explain aggressive clinical patterns of RRC. (C) 2017 S. Karger AG, Basel