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  • Nevala, Riikka; Tukiainen, Erkki; Tarkkanen, Maija; Böhling, Tom; Blomqvist, Carl; Sampo, Mika (2019)
    A single-institution series using a (neo)adjuvant chemotherapy and interdigitated hyperfractionated split-course radiation therapy (CRT) treatment protocol for soft tissue sarcoma was reviewed. Our specific aims were to study recurrence rates and long-term toxicity. Between 1998 and 2016, 89 patients with non-metastatic soft tissue sarcoma were treated with surgery combined with six courses of doxorubicin and ifosfamide and hyperfractionated radiation therapy (42-60 Gy/1.5 Gy twice daily). Patients were considered being at high risk if tumour malignancy grade was high and the tumour fulfilled at least two of the following criteria: size >8 cm, presence of necrosis or vascular invasion. The mean age of the patients was 50.7 years. With a median follow-up of 5.4 years for survivors, the local control rate was 81.4%. Six (7%) patients progressed during neoadjuvant CRT. Seven (8%) patients discontinued the treatment due to toxicity. Eighty-six patients were operated and three (3%) of these developed a long-term complication. The estimated metastasis-free survival was 47.6% and overall survival 53.0% at five years. The limb-salvage rate was 93%. The limb-salvage rate, local control and complication rates were good in these patients with high risk soft tissue sarcoma. Metastases-free survival and overall survival rates were less satisfactory, reflecting the aggressive nature of these tumours.
  • Heervä, Eetu; Väliaho, Vesa; Salminen, Tapio; Nieminen, Lasse; Carpelan, Anu; Kurki, Samu; Sundström, Jari; Huhtinen, Heikki; Rantala, Arto; Carpen, Olli; Minn, Heikki; Österlund, Pia; Ålgars, Annika; Ristamäki, Raija (2020)
  • Li, Xiaolei; Wu, Zhiqiang; An, Xiaojing; Mei, Qian; Bai, Miaomiao; Hanski, Leena; Li, Xiang; Ahola, Tero; Han, Weidong (2017)
    Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKK beta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.
  • Sonnenblick, Amir; Brohee, Sylvain; Fumagalli, Debora; Vincent, Delphine; Venet, David; Ignatiadis, Michail; Salgado, Roberto; Van den Eynden, Gert; Rothe, Francoise; Desmedt, Christine; Neven, Patrick; Loibl, Sibylle; Denkert, Carsten; Joensuu, Heikki; Loi, Sherene; Sirtaine, Nicolas; Kellokumpu-Lehtinen, Pirkko-Liisa; Piccart, Martine; Sotiriou, Christos (2015)
    Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.
  • Silk, Khadija; Kurki, Samu; Korpela, Taina; Carpen, Olli; Korkeila, Eija; Sundstrom, Jari (2017)
    Currently used factors predicting disease recurrence in stage II colorectal cancer patients are not optimal for risk stratification. Thus, new biomarkers are needed. In this study the applicability of ezrin protein expression together with MSI status and BRAF mutation status were tested in predicting disease outcome in stage II colorectal cancer. The study population consisted of 173 stage II colorectal cancer patients. Paraffin-embedded cancer tissue material from surgical specimens was used to construct tissue microarrays (TMAs) with next-generation technique. The TMA-slides were subjected to following immunohistochemical stainings: MLH1, MSH2, MSH6, PMS2, ezrin and anti-BRAF V600E antibody. The staining results were correlated with clinicopathological variables and survival. In categorical analysis, high ezrin protein expression correlated with poor disease-specific survival (p = 0.038). In univariate analysis patients having microsatellite instabile / low ezrin expression tumors had a significantly longer disease-specific survival than patients having microsatellite stable / high ezrin expression tumors (p = 0.007). In multivariate survival analysis, the presence of BRAF mutation was associated to poor overall survival (p = 0.028, HR 3.29, 95% CI1.14-9.54). High ezrin protein expression in patients with microsatellite stable tumors was linked to poor disease-specific survival (p = 0.01, HR 5.68, 95% CI 1.53-21.12). Ezrin protein expression is a promising biomarker in estimating the outcome of stage II colorectal cancer patients. When combined with microsatellite status its ability in predicting disease outcome is further improved.
  • Xia, Guanggai; Zhang, Hongbo; Cheng, Ruoyu; Wang, Hongcheng; Song, Ziliang; Deng, Lianfu; Huang, Xinyu; Santos, Helder A.; Cui, Wenguo (2018)
    The low radical surgery rate of pancreatic cancer leads to increased local recurrence and poor prognosis. Gemcitabine (GEM) is the preferred chemotherapeutic for pancreatic cancer. However, systemic chemotherapy with GEM has reached a bottleneck due to its serious side effects after frequent injections. In this study, GEM is successfully enwrapped into electrospun fibers via microsol electrospinning technology to form a stable core-shell fibrous structure. The GEM release rate can be adjusted by altering the thickness of the hyaluronan-sol inner fiber and the quantity of loaded GEM, and the release can be sustained for as long as three weeks. In vitro assays show that these electrospun fibers effectively inhibit pancreatic cancer cells and promote apoptosis. In vivo studies show that the fibrous membranes are better for inhibiting the growth of residual tumors than that of integrated tumors. Furthermore, immunohistochemistry results show that GEM-loaded fibers promote a higher cell apoptosis rate than does systemically injected GEM in residual tumors. In addition, the local delivery of GEM with fibers significantly reduces liver toxicity. In summary, a core-shell electrospun fiber for the controlled and localized delivery of GEM, which greatly improves the treatment of residual tumors and prevents pancreatic tumor recurrence, is developed.
  • Normann, Lisa Svartdal; Aure, Miriam Ragle; Leivonen, Suvi-Katri; Haugen, Mads Haugland; Hongisto, Vesa; Kristensen, Vessela N.; Maelandsmo, Gunhild Mari; Sahlberg, Kristine Kleivi (2021)
    HER2-positive (HER2+) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2+breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2+cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2+breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2+breast cancer (OS: p=0.039; BCSS: p=0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2+breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2+breast cancers.
  • Korpela, Taija; Ristimäki, Ari; Udd, Marianne; Vuorela, Tiina; Mustonen, Harri; Haglund, Caj; Kylänpää, Leena; Seppänen, Hanna (2022)
    Background Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS). Methods Between 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and histological findings were evaluated applying international guidelines. Results DSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0-57.6 vs. 20.6 months, 95% CI 10.3-30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19-9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02-2.16], lymph node metastases N1-2 (HR 1.71, 95% CI 1.16-2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04-2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27-2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03-2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453). Conclusions Our results indicate that the pancreatic stroma is associated with PDAC patients' DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.
  • Ojala, Kaisu; Meretoja, Tuomo J.; Mattson, Johanna; Salminen-Peltola, Paivi; Leutola, Suvi; Berggren, Marianne; Leidenius, Marjut H. K. (2016)
    Background and objectives: This study aims to clarify quality of breast cancer surgery in population-based setting. We aim to elucidate factors influencing waiting periods, and to evaluate the effect of hospital volume on surgical treatment policies. Special interest was given to diagnostic and surgical processes and their impact on waiting times. Methods: All 1307 patients having primary breast cancer surgery at the Helsinki and Uusimaa Hospital District during 2010 were included in this retrospective study. Results: Median waiting time for primary surgery was 24 days and significantly affected by additional imaging and diagnostic biopsies as well as hospital volume. Final rate of breast conserving surgery was surprisingly low, 51%, not affected by hospital volume, p = 0.781. Oncoplastic resection and immediate breast reconstruction (IBR) were performed more often in high volume units, p <0.001. Quality of axillary surgery varied with unit size. Multiple operations, IBR and high volume unit were factors prolonging initiation of adjuvant treatment. Conclusion: Quality of preoperative diagnostics play a crucial role in minimizing the need of repeated imaging and biopsies as well as multiple operations. Positive impact of high-volume hospitals becomes evident when analyzing procedures requiring advanced surgical techniques. High-volume hospitals achieved better quality in axillary surgery. (C) 2016 Elsevier Ltd. All rights reserved.