Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, ...including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab.
To determine the safety and efficacy of atezolizumab in an international real-world setting.
Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406).
Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity.
The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).
The median treatment duration was 2.8mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval CI 7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8–11.9) and 6-mo OS was 65% (95% CI 61–69%).
SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options.
In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients.
SAUL confirms the tolerability of atezolizumab in real-world patients with urinary tract carcinoma. Efficacy in the IMvigor211-like subgroup and the broader unselected population was consistent with previous anti-PD-L1/PD-1 pivotal trials, supporting the use of atezolizumab in these patients.
This manuscript reviewes recent knowledge regarding first line therapy of metastatic urothelial bladder cancer. Bladder cancer is on the 10th place in the world by its incidence, and more prevalent ...in men. Patients with metastatic urothelial cancer should be classified into one of the two groups: cisplatin eligible and cisplatin-ineligible. Cisplatin-eligible can be treated with cisplatin based regimens and have better outcome. Cisplatin-ineligible patients (40-50%) are cisplatin-ineligible patients are primarily those with creatinine clirence les than 50 ml/min, the ones with certain comorbities and/or poor ECOG performance status, and, as an alternative, can be treated with carboplatin which is less effective. After the diagnosis of metastatic bladder cancer has been confirmed, it is necessary to choose one of the cisplatin based chemotherapy regimens. However, one should have in mind that cisplatin can cause certain side effects such as nephrotoxic, neurotoxic and ototoxic effects. A minority of patients are not eligible for any platinum-containing chemotherapy regimen. Besides chemotherapy regimens, checkpoint inhibitors (CPIs)-PD-1 and PD-L1 inhibitors play an important role in first-line therapy of metastatic urothelial cancer. NCCN guidelines have included avelumab, pembrolizumab and atezolizumab in a first-line systemic therapy. Recently, Javelin Bladder 100 study has confirmed a positive impact of avelumab as a maitenance therapy in cisplatin-eligible and cisplatin-ineligible patients, which is why the combination of chemotherapy and avelumab is nowadays deemed to be the best therapeutic option.
Intracranial germ cell tumors are rare brain tumors that are distinguished based on their histology and selected tumor markers. Non-germinomatous germ cell tumors are a diverse group of such tumors ...having the poorest prognosis. Most commonly, they are located in the suprasellar and pineal regions. Since the exact treatment protocol has not yet been established, there is currently no standardized modality of management. We present a case of intracranial multifocal non-germinomatous germ cell tumor in an 18-year-old male, along with relevant literature review. We describe initial diagnostic and treatment procedures in a young adult presented with diplopia and ataxic gait. Neuroradiological findings and elevated alpha fetoprotein and beta chain of the human chorionic gonadotropin tumor markers indicated the possible mixed germ cell tumor. Chemotherapy regimen was adjusted accordingly, biopsy was not performed. The patient's clinical condition improved significantly and his alpha fetoprotein values decreased remarkably after initiation of chemotherapy. In conclusion, initial evaluation with neuroimaging, tumor markers, and cytology from cerebrospinal fluid is important as guidance to further treatment and prognosis. In selected cases, biopsy may not be indicated to start adjuvant chemotherapy. We emphasize the importance of specific treatment modality selection based mainly on tumor markers, regardless of the precise histologic classification.
Germline pathogenic and likely pathogenic (P/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men ...and to evaluate the clinical characteristics of P/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P/LP variant in CHEK2 (4/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa.
The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of ...reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies.
We studied the potential role of exposure to various metal(oid)s (As, Cd, Cr, Hg, Ni, and Pb) in prostate cancer. Two cohorts were established: the Croatian cohort, consisting of 62 cases and 30 ...controls, and the Serbian cohort, consisting of 41 cases and 61 controls. Blood/serum samples were collected. Levels of investigated metal(oid)s, various parameters of oxidative stress, and prostate-specific antigen (PSA) were determined in collected samples. A comparison of the measured parameters between 103 prostate cancer patients and 91 control men from both Croatian and Serbian cohorts showed significantly higher blood Hg, SOD, and GPx levels and significantly lower serum SH levels in prostate cancer patients than in controls. Correlation analyses revealed the significant relationship between certain parameters of oxidative stress and the concentrations of the measured metal(loid)s, pointing to the possible role of metal(oid)-induced oxidative stress imbalance. Furthermore, a significant inverse relationship was found between the blood Pb and the serum PSA in prostate cancer patients, but when the model was adjusted for the impacts of remaining parameters, no significant association between the serum PSA and the measured parameters was found. The results of the overall study indicate a substantial contribution of the measured metal(loid)s to the imbalance of the oxidant/antioxidant system. Although somewhat conflicting, the results of the present study point to the possible role of investigated metal(oid)s in prostate cancer, especially for Hg, since the obtained relationship was observed for both cohorts, followed by the disturbances in oxidative stress status, which were found to be correlated with Hg levels. Nevertheless, further studies in larger cohorts are warranted to explain and confirm the obtained results.
Germ-cell testicular cancer (GCTC) is a malignant neoplasm derived from the primordial germ cell. Although it accounts for approximately 1% of all malignancies in men, it is the most common cancer of ...younger male population, with the highest incidence between ages 15 and 35. Testicular cancer incidence rate has risen globally over the past several decades, with the average increase in the incidence of testicular cancer in Croatia of 7%
per annum
from the year 1983 to 2007. Two main groups are seminomas and non-seminomas, each accounting for 50% of cases, and they differ in treatment modalities and response to therapy. Despite increase in the incidence rate, a promising circumstance is that GCTC has become a model of curable cancer. Because of advances in diagnostic procedures, sophisticated radiation techniques and especially the introduction of cisplatin based chemotherapy protocols together with advanced postchemotherapy surgical techniques, curability is expected in about 95% of all patients diagnosed with testicular cancer and over 70% of patients with advanced disease. In this review, we will focus on treatment strategies of primary GCTC.
Previous studies have shown that different alcoholic beverage types impact prostate cancer (PCa) clinical outcomes differently. However, intake patterns of specific alcoholic beverages for PCa status ...are understudied. The study's objective is to evaluate intake patterns of total alcohol and the three types of beverage (beer, wine, and spirits) by the PCa risk and aggressiveness status.
This is a cross-sectional study using 10,029 men (4676 non-PCa men and 5353 PCa patients) with European ancestry from the PCa consortium. Associations between PCa status and alcohol intake patterns (infrequent, light/moderate, and heavy) were tested using multinomial logistic regressions.
Intake frequency patterns of total alcohol were similar for non-PCa men and PCa patients after adjusting for demographic and other factors. However, PCa patients were more likely to drink wine (light/moderate, OR = 1.11,
= 0.018) and spirits (light/moderate, OR = 1.14,
= 0.003; and heavy, OR = 1.34,
= 0.04) than non-PCa men. Patients with aggressive PCa drank more beer than patients with non-aggressive PCa (heavy, OR = 1.48,
= 0.013). Interestingly, heavy wine intake was inversely associated with PCa aggressiveness (OR = 0.56,
= 0.009).
The intake patterns of some alcoholic beverage types differed by PCa status. Our findings can provide valuable information for developing custom alcohol interventions for PCa patients.
Tremendous work of civil and environmental engineering has been focused on development of sustainable buildings. From economical and ecological viewpoint, this approach is a significant step forward, ...but the microenvironment created in such living surroundings may present a complex radiochemical setting, which could be a threat to the health of its occupants. This paper gives overview about levels of indoor radon, insight in risks related with radioactivity of fly ash and zircon, current application of nanoparticles and concrete additives in buildings and their possible impact on human health. As construction engineering is current producer of almost 50% of waste encouragement of incorporation of toxic and radioactive agents in buildings could in future demand redefinition of building construction waste as hazardous and special waste disposals. Collaboration between governmental and non-governmental bodies, manufacturers, scientific institutions, and chartered engineers is needed in order to find balance between quality of indoor air, and to enable maintaining of high health standards by application of non-toxic or non-carcinogenic building materials that meet energy efficiency, building structure stability and security requirements.
► Study gives insight in health risks related with radiochemical exposure in buildings. ► Building has to meet energy efficiency, structure stability and health standards. ► Need for re-evaluation of occupational exposure in building industry is shown.
Development of graphical/visual presentations of cancer etiology caused by environmental stressors is a process that requires combining the complex biological interactions between xenobiotics in ...living and occupational environment with genes (gene-environment interaction) and genomic and non-genomic based disease specific mechanisms in living organisms. Traditionally, presentation of causal relationships includes the statistical association between exposure to one xenobiotic and the disease corrected for the effect of potential confounders.
Within the FP6 project HENVINET, we aimed at considering together all known agents and mechanisms involved in development of selected cancer types. Selection of cancer types for causal diagrams was based on the corpus of available data and reported relative risk (RR). In constructing causal diagrams the complexity of the interactions between xenobiotics was considered a priority in the interpretation of cancer risk. Additionally, gene-environment interactions were incorporated such as polymorphisms in genes for repair and for phase I and II enzymes involved in metabolism of xenobiotics and their elimination. Information on possible age or gender susceptibility is also included. Diagrams are user friendly thanks to multistep access to information packages and the possibility of referring to related literature and a glossary of terms. Diagrams cover both chemical and physical agents (ionizing and non-ionizing radiation) and provide basic information on the strength of the association between type of exposure and cancer risk reported by human studies and supported by mechanistic studies. Causal diagrams developed within HENVINET project represent a valuable source of information for professionals working in the field of environmental health and epidemiology, and as educational material for students.
Cancer risk results from a complex interaction of environmental exposures with inherited gene polymorphisms, genetic burden collected during development and non genomic capacity of response to environmental insults. In order to adopt effective preventive measures and the associated regulatory actions, a comprehensive investigation of cancer etiology is crucial. Variations and fluctuations of cancer incidence in human populations do not necessarily reflect environmental pollution policies or population distribution of polymorphisms of genes known to be associated with increased cancer risk. Tools which may be used in such a comprehensive research, including molecular biology applied to field studies, require a methodological shift from the reductionism that has been used until recently as a basic axiom in interpretation of data. The complexity of the interactions between cells, genes and the environment, i.e. the resonance of the living matter with the environment, can be synthesized by systems biology. Within the HENVINET project such philosophy was followed in order to develop interactive causal diagrams for the investigation of cancers with possible etiology in environmental exposure.
Causal diagrams represent integrated knowledge and seed tool for their future development and development of similar diagrams for other environmentally related diseases such as asthma or sterility. In this paper development and application of causal diagrams for cancer are presented and discussed.
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