Safety and efficacy of durvalumab with R-CHOP or R2-CHOP in untreated, high-risk DLBCL: a phase 2, open-label trial.

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R2-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2-8 cycles + R-CHOP (non-activated B-cell [ABC] subtype) or R2-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R2-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% [95% CI 50.2-82.0]) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP.

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Increasing incidence and survival of corpus uteri cancer in Estonia over the past two decades.

BACKGROUND: Corpus uteri cancer has become the fourth most common female cancer in Europe. In Estonia, the prevalence of obesity is increasing, and corpus uteri cancer survival has been relatively low. The aim of the study was to evaluate incidence, mortality and survival trends of corpus uteri cancer in Estonia by age, stage and histological subtypes with an emphasis on surgical treatment. METHODS: Estonian Cancer Registry data on incident cases of corpus uteri cancer were used to examine incidence trends (1995-2016) and calculate relative survival ratios (RSR) (1996-2016). Cases were classified by morphology and FIGO stage. Causes of Death Registry data were used to analyse corrected mortality (1995-2017). RESULTS: A total of 4281 cases were diagnosed in 1996-2016. A significant increase was seen in age-standardized incidence from 2009, while mortality remained stable throughout the study period. Significant increases were observed for type I cancers and age groups ≥65 years. Overall age-standardized 5-year RSR improved from 70% in 1996-2002 to 78% in 2010-2016. Survival increased for type I cancers, all age groups and all stages (significantly for stage IV). The proportion of surgically treated cases increased significantly from 85% to 89%, with the largest increases seen in older age groups and later stages. DISCUSSION: The rising corpus uteri cancer incidence in Estonia is driven by the type I cancer trend. Survival gain for later stages and older age groups likely reflected more frequent surgical treatment. To reduce mortality, further efforts are necessary to ensure appropriate care for all patients.

Trends in cervical cancer incidence and survival in Estonia from 1995 to 2014.

BACKGROUND: Cervical cancer (CC) incidence in Estonia is the third highest in Europe, even though an organised nation-wide screening program has been in place since 2006. The aim of the study was to analyse the incidence and survival of CC in Estonia, focusing on age, morphology and stage at diagnosis. METHODS: Data from Estonian Cancer Registry were used to analyse age-standardized (world) and age-specific incidence for 1968-2014 rates. Joinpoint regression was used to estimate the annual percentage change (APC) for incidence trends. Age-period-cohort model was used to summarise time trends in terms of cohort and period effects. Relative survival ratios (RSR) were calculated for cases diagnosed in 1995-2014. Union for International Cancer Control version 7 of the TNM classification for malignant tumours was used to categorise stage. RESULTS: The age-standardized incidence of CC increased since 1980s at a rate of 0.8% per year. A significant increase was seen for all age groups except for 70+. The incidence of squamous cell carcinoma mimicked the overall trend, while adenocarcinoma showed increase since mid-1990s (APC 6.7). Age-period-cohort modelling showed strong cohort effects with the lowest risk for birth-cohorts born around 1940 and significantly increasing risks for successive cohorts born thereafter. No period effects were seen. The proportion of stage IV cases increased from 13% in 2005-2009 to 18% in 2010-2014. A significant increase was seen in the overall 5-year RSR from 1995 to 1999 to 2010-2014 (58% vs 66%). In 2010-2014, the 5-year RSRs ranged from 89% in women aged 15-39 to 41% in age group 70+. For stages I to IV, the respective RSRs were 98, 74, 57 and 22%. CONCLUSIONS: The inadequate uptake and insufficient quality of the Pap-smear based screening program has not brought along a decline in the incidence of CC in Estonia. Stage distribution has shifted towards later stages. New approaches are needed to prevent CC in Estonia.

Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids.

Despite the extensive work on pathological mechanisms and some recent advances in the treatment of different hematological malignancies, leukemia continues to present a significant challenge being frequently considered as incurable disease. Therefore, the development of novel therapeutic agents with high efficacy and low toxicity is urgently needed to improve the overall survival rate of patients. In this comprehensive review article, the current knowledge about the anticancer activities of flavonoids as plant secondary polyphenolic metabolites in the most commonly used human established leukemia cell lines (HL-60, NB4, KG1a, U937, THP-1, K562, Jurkat, CCRF- CEM, MOLT-3, and MOLT-4) is compiled, revealing clear anti-proliferative, pro-apoptotic, cell cycle arresting, and differentiation inducing effects for certain compounds. Considering the low toxicity of these substances in normal blood cells, the presented data show a great potential of flavonoids to be developed into novel anti-leukemia agents applicable also in the malignant cells resistant to the current conventional chemotherapeutic drugs.

Time Trends in Ovarian Cancer Survival in Estonia by Age and Stage.

OBJECTIVE: The objective of the study was to examine temporal trends in ovarian cancer (OC) survival in Estonia during 1995 to 2009 in relation to age and stage. MATERIALS AND METHODS: Estonian Cancer Registry data on all adult cases of primary OC diagnosed during 1995 to 2009 and followed up for vital status until 2014 were used to estimate relative survival ratios (RSRs). Cohort analysis was used to estimate 1-, 2-, and 5-year RSRs for patients diagnosed in 1995 to 1999, 2000 to 2004, and 2005 to 2009. Analysis was performed by age at diagnosis (<50; 50-59; 60-69; 70+ years) and stage (International Federation of Gynecology and Obstetrics 1988). RESULTS: Among 2296 women included in the study, the age-adjusted 5-year RSR improved from 27% in 1995 to 1999 to 38% in 2005 to 2009. Survival increase of 10% units from 1995 to 1999 to 2005 to 2009 was seen for women aged 50 to 59 and 60 to 69 years. Among younger and older women, the respective changes were smaller. In 1995 to 1999, the difference in survival between the youngest and oldest age groups was 41% units. This decreased over the study period to 37% units. From 1995 to 1999 to 2005 to 2009, the 5-year RSR increased from 82% to 91% for stage I patients; from 48% to 67% for stage II patients; from 25% to 35% for stage III patients; and from 11% to 16% for stage IV patients. CONCLUSIONS: The study showed an improvement of OC survival in Estonia in all age and stage groups, but particularly among younger women and those with early stage disease. Slower progress among older women is of great concern.

Acute de novo Leukemia in Estonia and Western Sweden 1982-2006: Positive Trend in the Survival of Acute Leukemia over 25 Years.

This study focuses on the incidence, treatment, and survival of de novo acute leukemia in a 25-year perspective in western Sweden and Estonia. At the beginning of our study, Estonia was a part of the Eastern bloc with planned economy, but since 1991 it is a member of the European Union and transforming into a market economy. Survival rates have steadily increased in both countries. However, a gap between their survival curves remains. Based on our data, it is difficult to explain the big difference in the 5-year relative survival in favor of western Sweden (55 vs. 22%). In Germany, there was a big difference in overall cancer survival between East and West Germany after the fall of the iron curtain, but today no difference is seen. Differences in survival are probably due to a higher proportion of intense chemotherapy regimens and a higher rate of hematopoietic stem cell transplantations in Sweden. Other important factors might be better supportive care and diagnostics as well as better adjuvant therapy. Better staff training and conditions in wards are also factors that might play an essential role.

Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines.

Despite numerous studies chronic lymphocytic leukemia (CLL) still remains an incurable disease. Therefore, all new compounds and novel strategies which are able to eradicate CLL cells should be considered as valuable clues for a potential future remedy against this malignancy. In the present study, the cytotoxic profiles of natural flavonoids were described in two human CLL cell lines, HG-3 and EHEB, indicating the flavone luteolin as the most potent flavonoid with half-maximal inhibitory constants (IC50) of 37 µM and 26 µM, respectively. Luteolin significantly increased the apoptotic cell population in both cell lines by increasing the activities of caspases-3 and -9 and triggering the intrinsic apoptotic pathway. Two flavonols, fisetin and quercetin, were somewhat less efficient in suppressing cellular viability, whereas baicalein, chrysin, (+)-catechin and hesperetin exerted only a small or no response at doses as high as 100 µM. Both fisetin and quercetin were able to augment the cytotoxic activity of luteolin in both cell lines by reducing the IC50 values up to four fold. As a result of this, luteolin displayed cytotoxicity activity already at low micromolar concentrations that could potentially be physiologically achievable through oral ingestion. No other tested flavonoids were capable of sensitizing CLL cells to luteolin pointing to a specific binding of fisetin and quercetin to the cellular targets which interfere with the signaling pathways induced by luteolin. Although further molecular studies to unravel this potentiating mechanism are certainly needed, this phenomenon could contribute to future remedies for prevention and treatment of chronic lymphocytic leukemia.

Sulfotransferase 1A1 as a Biomarker for Susceptibility to Carcinogenesis: From Molecular Genetics to the Role of Dietary Flavonoids.

BACKGROUND: Sulfotransferase (SULT) 1A1 is a phase II metabolic enzyme that catalyzes sulfate conjugation of various phenolic compounds, including endogenous substances, such as estrogens and thyroid hormones, but also different xenobiotics. Although sulfation is classically considered as a detoxification event facilitating the excretion of more water soluble metabolites from the body, in some cases such bioconversion may also lead to bioactivation of promutagens, producing highly reactive intermediates which are capable of damaging DNA and promoting carcinogenesis. The most common polymorphism in SULT1A1 (Arg213His) has an important functional impact by affecting the capacity to sulfate diverse substrates and numerous case-control studies have shown associations between SULT1A1 variants and susceptibility to different malignancies. Several factors may significantly influence such relationships, including ethnicity, gender, parity, menopausal status, use of estrogen replacement therapy, exposure to tobacco smoke or occupational chemicals. RESULTS AND CONCLUSION: In this review article, we show that one more important determinant should be considered as a stratifying factor in studies of possible associations between SULT1A1 variants and cancer risk, i.e., the dietary intake of different flavonoids. As sulfation of bioactive plant polyphenols can change their potential anticancer activities and, on the other hand, these phytochemicals are capable to behave also as potent SULT1A1 inhibitors, the regular dietary exposure of humans to these compounds can make a great contribution to the impact of sulfation capacity on individual susceptibility to carcinogenesis. The effect of specific flavonoids as well as their interactions with other factors on associations between SULT1A1 alleles and cancer risk certainly needs further thorough studies.

Multi-Target Cytotoxic Actions of Flavonoids in Blood Cancer Cells.

To date, cytotoxic effects of flavonoids in various cancer cells are well accepted. However, the intracellular signaling cascades triggered by these natural compounds remain largely unknown and elusive. In this mini- review, the multiplicity of molecular targets of flavonoids in blood cancer cells is discussed by demonstrating the involvement of various signaling pathways in induction of apoptotic responses. Although these data reveal a great potential of flavonoids for the development of novel agents against different types of hematological malignancies, the pleiotropic nature of these compounds in modulation of cellular processes and their interactions certainly need unraveling and further investigation.

Chemomodulating Effects of Flavonoids in Human Leukemia Cells.

Flavonoids, a diverse class of polyphenolic compounds, are well known for their anticancer properties. Moreover, it is generally accepted that these plant secondary metabolites can also sensitize malignant cells to conventional chemotherapeutic drugs and could thus be considered as potential adjunctive agents in cancer treatment. In this review article we show that besides potentiating the anticancer activity of standard chemotherapeutics by modifying the molecular events that are involved in cell growth, differentiation and apoptosis, flavonoids might also act as inhibitory modulators in human leukemia cells. The specific behavior of a certain flavonoid in such combination treatments is multifactorial being dependent on various aspects, including cellular context, molecular mechanisms of clinical drugs, temporal regimen of administration, as well as doses of agents. Based on the highly complex nature of leukemogenesis it is feasible that a multifaceted therapeutic approach is also required to cure this disease and therefore, combined chemotherapeutic schemes incorporating natural plant metabolites as chemosensitizing agents can represent a new attractive strategy for more successful treatment of leukemia patients in the future. However, as highlighted in this review, caution should be taken when affecting malignant cells concurrently with chemotherapeutic drugs and flavonoids as unwisely chosen combinations can lead to inadvisable results and sometimes even deteriorate the clinical outcomes.

Role of flavonoids in future anticancer therapy by eliminating the cancer stem cells.

Despite the numerous recent advances made in conventional anticancer therapies, metastasis and recurrence still remain the major problems in cancer management. The current treatment modalities kill the bulk of the tumor, leaving cancer stem cells behind and therefore, the agents specifically targeting this cancer initiating cell population may have important clinical implications. In this review article, the data about the inhibitory action of flavonoids, both natural as well as their synthetic derivatives, on the self-renewal capacity and survival of cancer stem cells of different origins are compiled and analyzed. These data indicate that several plant secondary metabolites, including soy isoflavone genistein, green tea catechins and a widely distributed flavonol quercetin, have the potential to suppress the stemness markers and properties, traits of the epithelial-to-mesenchymal transition and migratory characteristics, being also able to sensitize these cells to the standard chemotherapeutic drugs. These polyphenolic compounds act through multiple signal transduction pathways, providing thus the maximal therapeutic response and offering some promise to be included in the future cancer treatment schemes in combination with the conventional therapies. Such approach may give an important contribution to the shift of cancer management from palliative to curative mode, likely leading to the disease-free survival. Thus, flavonoids can serve as attractive candidates for novel anticancer agents by eliminating the roots of cancer.

A mathematical model of natural killer cell activity.

Natural killer (NK) cells are capable of lysing their target cells with the help of perforin. The application of these cells for immunotherapy requires the estimation of their potency for the purpose of validation and batch-to-batch comparison. Cytotoxicity measurements have been carried out at only a few effector target ratios, therefore, allowing only semiquantitative assessment at best. By using a novel approach of varying the effector target ratio continuously and careful analysis of the experimental data after the reactions, we have achieved a precision necessary for constructing a mathematical model of cytotoxic reaction. Curve-fitting to experimental data indicates that NK cell cytotoxicity follows the law of mass action and fits the model of a single ligand-receptor interaction. The method allows to use the value of half-maximal lysis to describe the potency of cytotoxic NK cells numerically.

Sequential population-based studies over 25 years on the incidence and survival of acute de novo leukemias in Estonia and in a well-defined region of western Sweden during 1982-2006: a survey of patients aged ≥65 years.

Estonia regained independence in 1991 after five decades of occupation by the Soviet Union. The present population-based survey was carried out over five consecutive 5-year study periods (1982-2006) on the incidence and survival of de novo acute leukemia patients aged ≥65 years at diagnosis in Estonia and in a well-defined area in western Sweden. During the study period of retrospective work (1982-1996), the first 10 years were carried out while Estonia was still under the mentorship of the Soviet Union. Over these years, Estonian hematologists did not have access to therapeutic measures readily available to Swedish hematologists, and the results for survival for western Swedish patients with acute myeloid leukemia (AML) far exceeded those of their Estonian counterparts. However, the results for acute lymphoblastic leukemia were equally dismal in the two countries. Subsequent prospective population-based studies were carried out during the years 1997-2006. A gradual improvement as to long-term relative survival of the Estonian AML patients was observed. When studying 2002-2006, no difference as regards relative survival at 5 years was anymore present between the two countries. Over the first 20 years of our population-based studies, it was repeatedly observed that the age-standardized incidence rate particularly for de novo AML was considerably higher for the western Swedish as compared to the Estonian cohorts. During the last 5-year study period (2002-2006), no such difference between the two countries was present, indicating that some true changes in the reporting procedure in Estonia had occurred.

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this project was to review the literature and define clinical practice guidelines for the use of cytokines and growth factor agents for the prevention or treatment of oral mucositis induced by cancer chemotherapy or radiotherapy. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible. RESULTS: Sixty-four clinical studies across 11 interventions were evaluated. A recommendation was made for the use of recombinant human KGF-1 (palifermin) at a dose of 60 µg/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplant for prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. A suggestion was made against using granulocyte macrophage colony-stimulating factor mouthwash for the prevention of oral mucositis in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. No guideline was possible for any other cytokine or growth factor agents due to inconclusive evidence. CONCLUSIONS: Of the cytokine and growth factor agents studied for oral mucositis, the evidence only supports use of palifermin in the specific population listed above. Additional well-designed research is needed on other cytokine and growth factor interventions and in other cancer treatment settings.

The incidence and survival of acute de novo leukemias in Estonia and in a well-defined region of western Sweden during 1997-2001: a survey of patients aged 16-64 years.

BACKGROUND: In a recent retrospective study, we investigated the incidence and survival of de novo acute leukemia (AL) patients aged 16-64 years over three 5-year periods (1982-1996) in Estonia and in the Western Swedish Health Care Region. The incidence rates were similar in the two countries, but the survival data were highly different. Thus, relative survival at 5 years for de novo AL patients in Estonia was virtually negligible, whereas the corresponding figures for the Swedish patients increased from 20.3 to 38.9% during the study period. AIM: To prospectively compare the results for incidence and outcome of de novo AL between the two countries during 1997-2001. RESULTS: Incidence rates for de novo AL were lower in Estonia than in western Sweden but not significantly so. However, the survival for de novo AL patients in Estonia had improved considerably, with the relative survival at 5 years being 16.4%; such improvement was particularly seen in acute myeloid leukemia patients. For the Swedish patients, no change in survival was recorded. CONCLUSION: In Estonia, a remarkable improvement in outcome for young de novo AL patients was seen after 1996. Nevertheless, relative survival for the Estonian patients had still not reached the levels found in the Swedish cohort.

The incidence and survival of acute de novo leukemias in Estonia and in a well-defined region of western Sweden during 1997-2001: a survey of patients aged >or=65 years.

BACKGROUND: In a recently published retrospective population-based study over three 5-year periods (1982-1996) we investigated the outcome for de novo acute leukemia (AL) patients aged >or=65 years at diagnosis in Estonia (a country that had been occupied by the Soviet Union over 5 decades) and in the so-called Western Swedish Health Care Region. The age-standardized yearly incidence rates regarding the total number of de novo AL was 5.3/100000 inhabitant for Estonia and 8.0 for Sweden, this difference being statistically significant merely as regards acute myeloid leukemia (AML). The relative survival for the total cohort of de novo AL as well as for de novo AML was significantly longer (p<0.001) for Swedish as compared to Estonian patients. METHODS: In view of the miserable outcome for the Estonian patients we decided to prospectively compare the results for incidence and outcome of de novo AL between the two countries. RESULTS: The present report covers the first 5-year period comprising 1997-2001 and deals only with patients aged >or=65 years at diagnosis. The age-adjusted annual incidence rates for de novo AML were lower in Estonia (6.4/100000) than in Sweden (9.2/100000) but not significantly so. The present results also show that the outcome for the Estonian AML patients had improved considerably over the study period; thus, at no time point, i.e., at 1, 3 and 5 years did relative survival between the two countries differ significantly. CONCLUSION: Yet, as compared to the Swedish cohort relative survival for the Estonian patients did still not reach an acceptable level.

Changes in the natural history of renal cancer: comparison of Estonian data from the periods 1986-1988 and 1996-1998.

To explain considerable increase in survival of renal cancer patients in Estonia during last decades, we compared the stage distribution, diagnostic and treatment methods for the patient groups diagnosed in the periods 1986-1988 and 1996-1998. A significant difference in stage distribution was detected with an increase for stages I-II and a decrease for stages III-IV in 1996-1998. There was a shift in primary diagnostic methods from intravenous urography and angiography to ultrasonography and computed tomography. In multivariate analysis the independent prognostic factors for overall survival were age, stage, and operation status. In conclusion, the increase in the survival of renal cancer patients has been due to the larger number of cases with the earlier stage, which is associated with the application of ultrasonography and computed tomography. Another factor for better survival was the higher operation rate among patients with stage IV disease, a possible factor was the change in operation techniques.

The effect of allogeneic stem cell transplantation on outcome in younger acute myeloid leukemia patients with minimal residual disease detected by flow cytometry at the end of post-remission chemotherapy.

Minimal residual disease (MRD) levels were determined by multi-parameter flow cytometry in 45 younger adult patients ( pound60 years old) with acute myeloid leukemia (AML) in complete remission. Data were collected after induction (MRD1; n=43) and/or at the end of post-remission chemotherapy or before stem cell transplantation (SCT)(MRD2; n=31). Patients with detectable MRD2 who underwent allogeneic or autologous SCT had significantly better 5-year relapse-free survival than patients not transplanted (80%, 53% and 0%, respectively p=0.003). Therefore allogeneic SCT should be considered in younger adult AML patients with detectable MRD at the end of post-remission chemotherapy. Autologous SCT may be an alternative for patients not eligible for allogeneic SCT.