3 research outputs found
Oxidative stress in diffuse large B-cell lymphoma and follicular lymphoma, and TP53 mutations and translocations of MYC, Bcl-2 and Bcl-6 in diffuse large B-cell lymphoma
Abstract
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are two of the most common lymphomas in the Western world. DLBCL is an aggressive disease with a good response to treatment; about 75% of patients achieve permanent remission after first-line treatment. In patients with relapses or primary refractory disease, prognosis is dismal; only 10â20% of them can be cured, even with aggressive treatments. FL is an indolent lymphoma with a very good response to treatment and slow progression. Median survival with modern treatments is over 15 years. Nevertheless, some patients have short remissions and succumb to disease. Oxidative stress, TP53 mutations, and translocations of MYC, Bcl-2 and Bcl-6 have been linked in many neoplasms to aetiology and poor prognosis.
This thesis concerns oxidative stress and redox-state-regulating enzymes in DLBCL and FL, and TP53 mutations and translocations of MYC, Bcl-2 and Bcl-6 in DLBCL. High expression levels of the antioxidant enzyme thioredoxin and a marker of oxidative stress, nitrotyrosine, were related to poor prognosis in DLBCL. In FL, high-level expression of peroxiredoxin was associated with good prognosis. TP53 mutations in specific regions LSH and L3 and concurrent translocation of Bcl-2 were associated with poor prognosis in DLBCL. Not all TP53 mutations predicted survival. High expression levels of Bcl-2 and MYC were associated with poor prognosis in DLBCL.
Based on the results presented here, antioxidant function may have protective roles, but also may cause resistance to treatment. TP53 mutations have prognostic roles in DLBCL, but should be further defined. Novel therapies could be developed in connection with these mechanisms.TiivistelmÀ
Diffuusi suurisoluinen B-solulymfooma (DLBCL) ja follikulaarinen lymfooma (FL) ovat kaksi yleisintÀ lymfoomaa lÀnsimaissa. DLBCL on aggressiivinen syöpÀ, joka reagoi hyvin hoitoihin, jopa 75 % paranee. Kuitenkin potilailla, joilla syöpÀ uusiutuu hoitojen jÀlkeen tai etenee hoidon aikana, on erittÀin huono ennuste, noin 10-20 % nÀistÀ potilaista voidaan parantaa. FL on hyvÀennusteinen lymfooma, joka yleensÀ reagoi hyvin hoitoihin. Mediaani elossaoloaika kaikilla FL potilailla on yli 15 vuotta taudin toteamisesta. Osalla potilaista FL kuitenkin on aggressiivisempo. Oksidatiivinen stressin, TP53- mutaatioiden, MYC, Bcl-2 ja Bcl-6 -translokaatioiden on todettu olevan huonoon ennusteeseen yhteydessÀ olevia tekijöitÀ monissa syövissÀ, kuten lymfoomissa.
TĂ€mĂ€ vĂ€itöskirja tutki oksidatiivisen stressin ja hapetus-pelkistys reaktioon liittyvien entsyymien osuutta R-CHOP-hoidetuissa DLBCL:ssa ja FL:ssa immunohistokemian (IHC) avulla. DLBCL:ssa tutkittiin lisĂ€ksi TP53 mutaatioita, MYC, Bcl-2 ja Bcl-6 translokaatioiden roolia taudin kulussa. Korkea ekspressio oksidatiivisen stressin merkkiainetta nitrotyrosiinia ja antioksidantti thioredoksiinia olivat yhteydessĂ€ huonoon ennusteeseen DLBCL:ssa. FL:ssa runsas ilmentyminen antioksidativiisiin entsyymeihin kuuluvia peroksiredoksiineja olivat yhteydessĂ€ hyvÀÀn ennusteeseen. TP53 mutaatiot LSH ja L3 alueella ja Bcl-2 -translokaatiot yhdessĂ€ olivat yhteydessĂ€ huonoon ennusteeseen DLBCL:ssa. Kaikki TP53-mutaatiot eivĂ€t olleet assosioituneet huonoon ennusteeseen. DLBCL:ssa Bcl-2 ja MYC âproteiinien runsas ilmentyminen IHC:llĂ€ arvioituna liittyi huonoon ennusteeseen.
Tulosten perusteella solujen hapetus-pelkistystilaa sÀÀtelevillÀ entsyymeillÀ voi olla dualistinen rooli, osittain suojeleva ja osittain vahingoittava lymfoomissa. TP53 -mutaatioilla voi olla ennusteellista merkitystÀ, mutta tÀmÀ vaatii lisÀÀ tutkimuksia
Treatment of diffuse large Bâcell lymphoma in elderly patients:replacing doxorubicin with either epirubicin or etoposide (VPâ16)
Abstract
Diffuse large Bâcell lymphoma (DLBCL) is the most common type of lymphoma. The standard therapy for DLBCL is RâCHOP. The current 5âyear overall survival is 60% to 70% using standard frontline therapy. However, the use of doxorubicin and its cardiotoxicity is a major clinical problem and preexisting cardiac disease may prevent the use of doxorubicin. Age greater than 65 years is a significant risk factor for anthracyclineâinduced cardiotoxicity, and therefore, the use of RâCHOP is often withheld from elderly patients. The feasibility of replacing doxorubicin with either epirubicin or etoposide in patients who have risk factors for heart complications is analyzed here. Clinical data of 223 DLBCL patients were retrospectively collected from hospital records. Fiftyâfive patients were treated with RâCHOP, 105 with RâCIOP (epirubicin instead of doxorubicin), 17 with RâCEOP (etoposide instead of doxorubicin), and 31 with RâCHOEP. Matchedâpair analysis was carried out between 30 patients treated with RâCEOP and RâCHOP. For all patients, the 2âyear progressionâfree survival (PFS) was 73.6%. In patients treated with RâCHOP, the 2âyear PFS was 84.2%, with RâCIOP 64.4%, with RâCEOP 87.7%, and with RâCHOEP 83.2%. In matchedâpair analysis, the 2âyear PFS was 92.3% with RâCHOP and 86.2% with RâCEOP. The 2âyear disease specific survival was 100% with RâCHOP and 86.2% with RâCEOP. In conclusion, RâCEOP offers reasonable PFS and disease specific survival in the treatment of DLBCL and good disease control can be achieved in elderly patients. Elderly patients with impaired cardiac function could benefit from the use of RâCEOP instead of RâCHOP. The results with RâCIOP were unsatisfactory, and we do not recommend using this protocol in elderly patients with cardiac disease
Evolution of pancreatic surgery over time and effects of centralization:a single-center retrospective cohort study
Abstract
Background: Short-term outcomes of pancreatic surgery have improved globally during the last two decades. Long-term survival of resectable pancreatic ductal adenocarcinoma (PDAC) has also shown slight improvement. We describe a cohort of 566 consecutive pancreatectomies performed at a Northern Finnish tertiary center. We analyze the trends in short-term outcomes of all-cause pancreatic surgery and long-term survival of PDAC patients.
Methods: All pancreatic resections performed at the Oulu University Hospital during years 2000â2020 were included. Patient data was analyzed in four time periods (2000â2005, 2006â2010, 2011â2015 and 2016â2020). Clinicopathological parameters of patients and tumors, complication data and short-term mortality were recorded for all patients and compared between time quartiles. Long-term survival and administration rates of neo-, and/or adjuvant therapy of PDAC patients were analyzed.
Results: A total of 566 pancreatectomies were performed during the study period: 359 (63%) pancreatoduodenectomies (PDs), 130 (23.0%) open left pancreatectomies (LPs), 45 (8.0%) laparoscopic LPs, 26 (5.1%) total pancreatectomies (TPs), and 6 (1.1%) enucleations. Median age of patients was 63 [57â71] years, and 49% [267] of patients were men. Number of pancreatectomies per time period increased from 67 in 2000â2005 to 266 in 2016â2020. American Society of Anesthesiologists (ASA) Physical Classification III patients and T3 tumors were more frequently operated on in later time periods. Complication rates remained at constant low levels throughout the study period, but reoperation rate increased from 9.4% in 2000â2010 to 16.2% in 2011â2020. Short-term (90-day) mortality after pancreatectomy decreased from 3.1% to 0.74%, while 5-year survival improved from 14.3% in 2006â2011 to 21.4% in 2011â2015. Resection rate of diagnosed PDAC cases, as reported by the Finnish Cancer Registry (FCR) for the catchment area, increased from 3.2% to 14.9% over the study period.
Conclusions: The hospital volume of pancreatectomies has increased substantially, while complications and postoperative mortality have remained at acceptable levels. Long-term survival and resection rate of PDAC patients showed notable improvement over two decades