· The present narrative review examined quantitative and qualitative research on family members who support survivors of trauma or abuse. Studies included in the present review were found in Narrative overviews of scientific literature contribute to the updating and critique of available medical knowledge. Indirectly, they help to formulate new research projects based on the synthesis and interpretation of the results of a non-systematic selection of published blogger.com by: 5 Narrative review: update on immunotherapy and pathological features in patients with bladder cancer Gaetano Aurilio, 1, # Alessia Cimadamore, 2, # Antonio Lopez-Beltran, 3 Marina Scarpelli, 2 Francesco Massari, 4 Elena Verri, 1 Liang Cheng, 5 Matteo Santoni, 6 and Rodolfo Montironi 2
Narrative Review | RESEARCH METHODOLOGY
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Over the last few years efficacy of immunotherapy using immune checkpoint inhibitors ICI has been investigated in patients with bladder cancer BC at all stages. The present article aims to assess new therapeutic options with emerging agents in BC patients, shedding light on ICI-based treatments encompassing all narrative review article stages, narrative review article, from non-muscle invasive NMIBC to muscle-invasive MIBC BC, concluding with metastatic MIBC.
In bacillus Calmette-Guerin BCG unresponsive patients with carcinoma in situ, pembrolizumab has been recently approved. In the neoadjuvant setting, results from two clinical trials seem to identify pathological and genomic features of highly responsive tumors.
A panel of biomarkers for patient selection is an actual need since the correlation between response and PD-L1 expression seem inconsistent across clinical trials, with some exceptions. Molecular characterization of BC, narrative review article, tumor mutation burden and immune-gene expression profiling might introduce new molecular biomarkers, hopefully transferable into the clinical-pathological practice.
Bladder cancer BC is the 11 th most commonly diagnosed cancer worldwide 12, narrative review article. However, after failure of platinum-based chemotherapy, effective therapeutic options are limited and prognosis is very poor for these patients. Over the last few years efficacy of immunotherapy using immune checkpoint inhibitors ICIs has been investigated in patients with BC at all stages. Indeed, anti-programmed cell-death protein 1 PD-1 pembrolizumab and nivolumab, as well as anti-programmed cell-death ligand 1 PD-L1 durvalumab, avelumab, and atezolizumab, have been labeled by the Food and Drug Administration FDA for metastatic urothelial BC patients who had disease progression after platinum-based chemotherapy.
Most relevant studies in terms of number of patients and clinical impact were selected. Early radical cystectomy RC is strongly recommended in patients narrative review article BCG unresponsive tumors 5. Bladder-sparing treatments are currently under investigation.
The rationale behind this is that PD-L1 expression has been associated with increased resistance to BCG immunotherapy. Moreover, granulomas induced by BCG in BCG-unresponsive patients show high levels of PD-L1 expression. The high expression of PD-L1 may suppress the T-cell narrative review article induced by BCG and be the cause of the BCG failure 6. A recent publication by Pierconti et al, narrative review article. examined the expression of PD-L1 both in tumor cells and in immune cells in patients with CIS primary responders and not responders to BCG therapy.
According to their results, PD-L1 positive expression performed using the 22C3 clone identify patients with BCG-unresponsive CIS 7. The KEYNOTE, phase II, is the first single-arm study enrolling patients with BCG unresponsive disease to receive pembrolizumab administered intravenously IV at a dose of mg every 3 weeks for 24 months or until disease progression or discontinuation due to toxicity. Phase I studies are now investigating the safety and preliminary antitumor activity of atezolizumab and pembrolizumab in combination with intravesical BCG NCT, NCT Five trials are currently investigating the use of ICI in BCG untreated patients but no results available yet, narrative review article.
Predictive narrative review article of response are needed in this setting. More advanced tumors express a lower burden of neoantigens that may explain the decreased response to BCG immunotherapy 9. Since the first molecular taxonomy published by Sjödahl et al. in 10several attempts have been made trying to classify the NMIBC in different narrative review article groups 11 The latest one, recently published by Robertson et al. Five consensus narrative review article of T1 tumors treated with BCG were identified.
The so-called T1-Myc and T1-early subtypes had the significantly worse recurrence-free survival than the other three subtypes grouped. Interestingly, both subtypes had elevated MYC expression and T1-early had a repressed immune response hallmarks for IFN-α and IFN-γ suggesting its tumor microenvironment may represent an immune desert.
Several immunotherapy-based trials are in clinical development in patients with localized MIBC, narrative review article, either as immuno-based combination strategies or as Narrative review article single-agent, though data are available just for two neoadjuvant phase II trials testing atezolizumab 14 narrative review article pembrolizumab 15respectively.
The ABACUS is a phase II study in MIBC cisplatin-unfit patients with clinical T2—T4aN0 stage tumor, narrative review article, planned to assess the efficacy of atezolizumab as neoadjuvant treatment. A total of 95 participants have received three-weekly atezolizumab IV at a dose of 1, mg for 2 cycles, prior to RC.
Fifty patients were planned to receive three-weekly pembrolizumab Narrative review article at a dose of mg for 3 cycles. Only one patient interrupted the study drug for grade 3 transaminitis No significant correlation between PD-L1 expression and outcome, narrative review article, on either immune cells or tumor cells was found 14 Notably, preexisting T cell activation correlated with response.
A higher percentage of inflamed tumors compared to metastatic setting was reported; among inflamed tumors, responding tumors had an inflammatory infiltrate composed by T cells double positive for CD8 and granzyme B a surrogate marker for CD8 activated cells unlike relapsing inflamed tumors, narrative review article, which showed low levels of activated T cells. TMB, on the contrary, did not correlate with response.
Of interest, in the PURE trial, patients with squamous-cell carcinoma or a lymphoepithelioma-like variant of BC had major, although preliminary, pathological responses compared with those with other narrative review article variant histologies, narrative review article. PD-L1 expression was evaluated with 22C3 antibody using CPS.
IMvigor is a single-arm, multicentre, phase 2 trial of atezolizumab as front-line therapy in untreated cisplatin-ineligible MIBC patients. A narrative review article of patients were enrolled and of whom received atezolizumab IV at a dose of 1, mg every 3 weeks until disease progression occurred. Clinical responses there were both early 2 months than late after 6 months during atezolizumab treatment, and were observed across all PD-L1 subgroups according to tumour-infiltrating immune cells status and by baseline prognostic subgroups.
In all patient population, median progression-free survival PFS was 2. Atezolizumab toxicity was well-tolerated with manageable immune-mediated events that required steroid therapy alone, only one toxic death for sepsis occurred IMvigor is a multicentre, placebo-controlled, narrative review article, phase 3 trial of atezolizumab with or without chemotherapy as first-line treatment in patients with locally advanced or metastatic urothelial MIBC.
The trial allowed the inclusion of patients with or without a cisplatin-eligibility condition. At a median follow-up of Interim median OS findings showed an improvement of 16 months for cohort A versus The meaningful PFS benefit of adding atezolizumab to conventional platinum-based chemotherapy favored its potential introduction as a treatment front-line option DANUBE is an open-label, phase 3 trial to assess durvalumab with or without tremelimumab monoclonal antibody against CTLA-4 versus IV chemotherapy as a front-line therapy in previously untreated locally advanced or metastatic urothelial MIBC patients.
In patients with PD-L1 overexpressed, median OS was In all randomized patients, median OS was The primary endpoint was OS both in the overall population and in the PD-L1 biomarker positive population. Median OS in the overall population was Adverse events led to discontinuation of avelumab in There were no immune-related deaths. The study met its primary endpoint demonstrating longer overall patient survival with first-line avelumab maintenance both in the overall population and PD-L1 positive patients In all patient population, median OS was Overall, narrative review article, PFS did not differ between the two-study group.
Pembrolizumab had a favorable toxicity profile compared with the chemotherapy agents and was associated with significantly longer OS of approximately 3 months The CheckMate was a single arm, phase 2, multicenter trial testing nivolumab in narrative review article with metastatic or unresectable urothelial cancer who have progressed or recurred following platinum-based chemotherapy 24 Table 1.
Confirmed objective response was achieved in 52 Responses were seen irrespective of tumour PD-L1 expression. In this trial, gene expression profile has been performed with unexpected results. Tumors classified as basal according to the TCGA classification had highest response to nivolumab.
Moreover, narrative review article, the responders had high interferon-γ gene expression, the highest CXCL9 or CXCL10 expression and the highest CD8 expression BCG, bacillus Narrative review article BSC, best supportive care; c-DDP unfit, cisplatin-ineligible; chemo.
Medical treatment for urothelial BC patients has rapidly been evolving from a platinum-based chemotherapy to immunotherapy-oriented approach at any disease stage. This finding maintains open the debate on which is the optimal biomarker to improve decision making by physicians across daily clinical practice. A possible explanation of this finding might be that TURBT specimens are more representative of the tumor tissue at the time of immunotherapy compared to primary tumors either in RC specimens or TURBT removed from patients many years narrative review article they become metastatic.
Indeed, not only the different assays and cut-off should be taken into account when comparing different narrative review article, but also the tissue samples used in each trial. The majority of tissue samples tested in immunotherapy trial in the metastatic setting are primary tumor and not metastatic sites. In addition, neoadjuvant ICI therapy demonstrated to do not compromise the safety of the subsequent RC. In such context, when considering treatments combination, a phase II randomized clinical trial is evaluating neoadjuvant nivolumab plus urelumab agonist antibody to CD versus nivolumab alone in MIBC patients considered as cisplatin-unfit or in those who refuse chemotherapy.
The trial is currently recruiting patients NCT Narrative review article this line, another phase 2 neoadjuvant study, currently recruiting, is testing the safety of nivolumab with or without ipilimumab monoclonal antibody against CTLA-4 before surgery in MIBC patients not eligible for cisplatin-based chemotherapy NCT In the adjuvant setting there is interest in clinical research as well.
A phase 3 study of neo-adjuvant nivolumab and NKTR a PEGylated interleukin-2 CDbiased agonist or nivolumab alone or standard of care in cisplatin-unfit MIBC patients is enrolling patients. A total of patients are estimated to be enrolled into the study, narrative review article, and randomly assigned to receive neoadjuvant nivolumab plus NKTR narrative review article by RC and subsequent adjuvant nivolumab plus NKTR experimental combination armneoadjuvant nivolumab followed by RC and continuation of adjuvant nivolumab experimental monotherapy armor RC alone without neo-adjuvant therapy standard of care NCT Moving towards the therapeutic scenario of metastatic BC patients, we would like to underline that the advantage of As for the median PFS of 2.
Accordingly, the PFS estimation should not be considered as a reliable surrogate endpoint of clinical benefit under immune-based treatments. On the other hand, the 2-month immunotherapy advantage as PFS cohort A versus cohort C in the IMvigor trial seems a weak point for supporting the potential use of atezolizumab plus platinum-based chemotherapy as a front-line therapy option.
When considering treatment combinations as first-line therapy, it is worthy of mention that no benefit was reported in the phase 3 DANUBE trial with combined or single-agent immune-based regimens versus a narrative review article regimen PD-L1 expression in metastatic settings has been evaluated with different assays, cut-offs, cellular compartments, which makes the comparison among different trials challenging Figure 1.
However, to perform PD-L1 assays for both drugs, pathology laboratories need two different platforms Dako and Ventanaoften not available in the same institution 26 - Recently IFN-γ has been proposed as biomarker of response for ICI treatment.
Levels of IFN-γ release were investigated in non-small narrative review article lung cancer and melanoma patients receiving immunotherapy with promising results 29 The IFN-γ gene expression signature has been evaluated in clinical trials on atezolizumab, nivolumab, durvalumab and pembrolizumab and demonstrated to be associated with higher ORR, PFS and OS 192431 Illustrations of PD-L1 scoring algorithms applied in UC. PD-L1, programmed cell-death ligand 1; UC, urothelial cancer, narrative review article.
Likewise, the findings by the phase 3 KEYNOTE trial of pembrolizumab versus a chemotherapy-based regimen taxanes or vinflunine as second-line narrative review article are of paramount importance. The significant 3-month OS advantage obtained from this study overcomes the 2-month OS advantage of vinflunine approved by EMA over BSC 10 ; this result is further supported by the fact that pembrolizumab has a better safety profile than that of chemotherapy agents.
Writing Narrative Review - Full Webinar
, time: 2:07:27[How to write a narrative literature review article ?]
reducing bias in the selection of articles for review and employing an effective bibliographic research strategy. The dynamics of narrative review writing, the organizational pattern of the text, the analysis, and the synthesis processes are also discussed. Keywords: Narrative review, Systematic review, Search methodology, Review writing Introduction A periodic synthesis of knowledge is Cited by: Systematic literature review X narrative review Scientific literature review articles are methodological studies which use database searches to retrieve results of research, and have as their mail goal the objective and theoretical discussion of a specific topic or theme In an extensive narrative review, Vestergren, Drury, and Chiriac () summarized the outcomes for participants after they had taken part in protest and activism. The authors categorized the changes they found in published research articles into two domains, the behavioral or objective and the psychological or subjective changes
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