Management Of Follicular Lymphoma Research Articles

Effectiveness of dose-intensified salvage regimens versus standard-dose chemotherapy on progression-free survival in early progressed follicular lymphoma before autologous stem cell transplantation: a systematic review protocol.

This review will evaluate the effectiveness of dose-intensified versus standard-dose salvage regimens on progression-free survival in early progressed follicular lymphoma before high-dose chemotherapy and autologous stem cell transplantation. Despite the substantial advances in the management of follicular lymphoma, approximately 20% of patients experience progression of the disease within 2 years of induction therapy. These patients have worse outcomes, and autologous stem cell transplantation is deemed to improve outcomes in this context. Little is known about the optimal salvage regimen. Studies must include patients ≥18 years old with early progressed follicular lymphoma who were submitted to autologous stem cell transplantation in subsequent remission. Clinical trials and observational studies will be included. The search strategy will be carried out in MEDLINE (PubMed), Embase (Periódicos CAPES), Scopus, Web of Science, LiLACS, and the Cochrane Library. No date or language restrictions will be imposed. The recommended JBI approach to critical appraisal, study selection, data extraction, and data synthesis will be used. Studies should score at least 50% in accordance with the critical appraisal tool. Data will be pooled whenever possible using the random effects model. Heterogeneity will be assessed using the standard χ2 and I2 tests. A funnel plot will be generated to assess publication bias if there are 10 or more studies included in the meta-analysis. The GRADE approach will be used to rate certainty of evidence. PROSPERO CRD42022373345.

Advancements in the Management of Follicular Lymphoma: A Comprehensive Review

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma in Western countries. While FL is generally incurable, standard initial therapies are associated with high response rates and durable remissions for most patients. In addition, novel targeted agents and immunotherapies are changing the treatment algorithm for patients with relapsed or refractory disease. This review discusses the initial staging, prognosis, and treatment options for newly diagnosed and relapsed/refractory FL. Initial treatment options for FL include active surveillance, radiotherapy, rituximab monotherapy, and chemoimmunotherapy. Staging with positron emission tomography/computed tomography and bone marrow biopsy is crucial for identifying early-stage patients. Most patients with FL will receive chemoimmunotherapy as the initial treatment with options including rituximab or obinutuzumab plus cyclophosphamide, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, and prednisone; bendamustine; or lenalidomide. No significant differences in overall survival have been observed in randomized studies comparing these regimens. Maintenance therapy with rituximab or obinutuzumab in responders to initial chemoimmunotherapy improves progression-free survival. For relapsed/refractory FL, treatment options include chemoimmunotherapy, lenalidomide-based regimens, tazemetostat, chimeric antigen receptor (CAR)-T cell therapy (axicabtagene ciloleucel and tisagenlecleucel), and CD3/CD20 bispecific antibodies (BsAbs). Given the encouraging outcomes obtained with CAR-T cell therapy and BsAbs, multiple trials are testing these highly active agents in earlier lines of therapy and among high-risk patients with early relapse after frontline chemoimmunotherapy. Additional studies and follow-up are needed to understand how these novel agents may further change treatment algorithms for FL.

Mixture Model to Predict the Cumulative Incidence of Relapses in Follicular Lymphoma : Need for Longer Follow-up or Alternative Outcomes

Background: The effectiveness of treatments in follicular lymphoma is evaluated by the reduction in the rate of recurrence. One of the methodological difficulties is related to the presence of competitive events such as death or second primary malignancies. The related cumulative incidence functions (CIF) are always estimated by using the non-parametric Aalen-Johansen estimator and the associated predictors by using the Fine and Gray approach or by considering a cause-specific Cox model. In the present study, we investigated if the use of a parametric mixture model would provide additional information on the interpretation of the impact of treatments in the management of follicular lymphoma. Methods: We used the RELEVANCE study database (Morschhauser et al.NEJM 2018, JCO 2022) because of the prolonged follow-up of patients treated for follicular lymphoma. RELEVANCE study is a multicenter, phase 3 randomized clinical trial that evaluates rituximab lenalidomide (R 2) as compared to rituximab plus chemotherapy (R-chemo), in patients with previously untreated follicular lymphoma. All 1030 patients received a rituximab maintenance. Results: With a median follow up of 72 months, median progression-free survival (PFS) was not reached in both groups (Kaplan-Meier estimator): the 6-years PFS was 60% and 59% for R 2 and R-chemo, respectively (Cox model, HR = 1.03 [IC95% CI, 0.84 to 1.27]). The CIF of relapse at 72 months was 41% and 39% in the R 2 and R-chemo, respectively (Aalen-Johansen estimator, Figure 1). We did not highlight any significant difference between the treatments in terms of the CIF of relapse (Fine and Gray model, HR = 0.938 [IC95% CI, 0.754 to 1.17], for the same prognostic time, the CIF of death was 2,5% and 2,9% in the R 2 and R-chemo, respectively). We then performed the test with the mixture model, and confirmed there was no significant differences across groups at 72 months. Indeed, 64% and 96% of patients have not relapsed and died respectively. However the mixture model approach allows for extrapolation, and thus we predicted the long-term CIF of relapse to be 67% if patients were followed-up 20 years across groups. The mixture model extrapolation calculated that 60% of relapse would occurr between 72 months and 240 months (20 years). Conclusion: There was no difference at 72 months for survival across tests; but the mixture model, that allow extrapolation, suggested that a difference could be revealed with a greater follow-up. We concluded that future studies of survival in FL will require longer follow-up. This comment appears of particular importance in the context of the forthcoming immunotherapies such as bispecific and CAR-T cells. We can also propose for hematologic malignancies with a chronic evolution, FL, alternative primary outcomes not based on survival, allowing a shorter read out, such as the disability-adjusted life years (DALYs) or quality-adjusted life years (QALYs).

A Predictive Model Based on Machine Learning for Early Progression/Relapse of Follicular Lymphoma

Introduction:Management of follicular lymphoma (FL) improved dramatically in the last decade, and progression/relapse of disease within 24 months (POD24) is now established as a predictor for poor survival. Risk prediction of early POD (E-POD) prior to the start of therapy may enhance clinical management and research strategies. We aimed to establish a comprehensive model based on machine learning (ML) that could predict the E-POD of FL patients for earlier identify such patients earlier. Methods: In this study, patients with a diagnosis of FL at the Shandong Provincial Hospital between January 1, 2010, to May 1, 2023, were identified retrospectively. All patients met the following criteria: pathologically confirmed with grades 1-3A FL and no previous treatment for FL. Model building was performed on a 70% split sample based on ML algorithms, and with 30% held for internal testing. Model performance was evaluated using the ROC curve, accuracy, precision, and f1-score. Furthermore, we compared the features of FL patients with early (<2 years) and late POD (relapsing after 5 years of starting treatment, L-POD). This study was in accordance with the Declaration of Helsinki and it was approved by the Medical Ethical Committee of the Shandong Provincial Hospital. All patients were obtained for the collection of informed consent at their first visit. Results: Of the included 224 patients, 45 (20.1%) had at least one POD. E-POD occurred in of the 29 (64.4%) evaluable patients and 6 (13.3%) had late POD (relapsing after 5 years of starting treatment, L-POD), In our center, the median age at the time of the FL diagnosis was 49 years (range 19-82), and the median length of follow-up was 28 months (range 3-120). Most patients were diagnosed with advanced disease (80.8%) and had grade 1-2 disease (75.9%). 75 cases (33.9%) had bone marrow participation and 63 cases (28.1%) with Ki-67≥30%. To establish a scoring system for predicting E-POD, we selected 34 variables for served as the input candidate features, including sociodemographic, clinical, and immunohistochemistry data, and used lymphoma E-POD (yes or no) as the output variable. In 14 models based on ML algorithms, the best models were RF Classifier (AUC: 0.83, Accuracy: 89.5%). To improve the performance, it was optimized after the complete construction of the model. Finally, the RF Classifier demonstrated AUC and accuracy as follows: 0.96, and 92.3% and we calculated the recall, precision, and F1 scores based on the confusion matrix as follows: 84.1%, 97.4%, and 90.3%, respectively. We evaluated the performance of prediction models built with data in a validation cohort and found the performance of the model was similar in both cohorts. Based on this RF Classifier, we selected relative variables important out of the multiple clinical and laboratory blood markers to predict E-POD ( Fig. 1A). Meanwhile, we analyzed the Pearson correlation coefficients (r) between 20 statistically meaningful biomarkers to reduce the complexity of the model ( Fig. 1B). To further screen for prognostic biomarkers, the top ten risk factors from the three best-performing models were integrated. The five biomarkers were completely involved in these three modules, including adenosine deaminase (ADA), β2-macroglobulin (β2-MG), C-reactive protein (CRP), aspartate transaminase (AST), and D-dimer. Additionally, we also found a significant difference in OS between the clusters among FL patients (p<0.05). Among 224 patients with FL, 45 (20.1%) patients experienced recurrence and progression. Besides 23 (60.5%) cases with E-POD, there are 6 (15.8%) patients who had L-POD. In comparison with those who experienced E-POD, L-POD patients showed a trend toward a better outcome, and a more favorable risk profile at presentation: lower pathological grade (1-2), anemia, and no mutation of the CARD11. Conclusion: We established a prognostic model to identify a subgroup of patients at high risk of E-POD based on AI analysis. This model utilizes objective variables easily and reliably measured at diagnosis which makes it easier for clinicians to predict the E-POD risk of FL and dynamically monitor changes during treatment. Further validation will hopefully facilitate the incorporation of these simple biomarkers into clinical decision-making tools to prevent adverse outcomes and promote personalized treatment options.

Axicabtagene Ciloleucel in the Management of Follicular Lymphoma: Current Perspectives on Clinical Utility, Patient Selection and Reported Outcomes.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) that has shown efficacy in B-cell non-Hodgkin's lymphoma. It has shown high efficacy in relapsed/refractory follicular lymphoma (FL) even in the presence of high risk features (early relapse, heavily pretreated patients and bulky disease). Treatment options for R/R follicular lymphoma do not offer long-term remissions, especially in the third-line setting. Axi-cel was studied in R/R FL in the ZUMA-5 study, which showed high response rates with durable remissions. Axi-cel was associated with anticipated but manageable toxicities. Long-term follow up may be able to inform the potential for cure of FL. Axi-cel should be part of the standard of care options for R/R FL beyond second line.

Small volume biopsy diagnostic yield at initial diagnosis versus recurrence/transformation of follicular lymphoma: Aretrospective Cyto-Heme Interinstitutional Collaborative study.

Few studies have evaluated diagnostic yield of small volume biopsies (SVB) for the diagnosis and management of follicular lymphoma (FL). The authors performed a multi-institutional retrospective analysis of SVBs including fine-needle aspiration (FNA) and needle core biopsy (NCB) for initial FL diagnosis and suspected recurrence or transformation of FL. A total of 676 workups beginning with SVB were assessed for the mean number of biopsies per workup, the proportion of workups requiring multiple biopsies, and the proportion with a complete diagnosis including grade, on initial biopsy. Compared to workups performed for question transformation/recurrence, those done for initial FL diagnosis were significantly more likely to require multiple biopsies (p<.01), had a higher mean number of biopsies per workup (1.7 vs. 1.1, absolute standardized difference=1.1), and a lower complete diagnosis rate at initial biopsy (39% vs. 56%). At initial FL diagnosis, NCB +/- FNA was associated with fewer biopsies per workup compared to FNA +/- CB (1.2 vs. 1.9), fewer workups requiring multiple biopsies (23% vs. 83%), and a higher complete diagnosis rate (71% vs. 18%). In contrast, during assessment for transformation/recurrence, NCB and FNA showed a similar mean number of biopsies per workup (1.2 vs. 1.2) and few workups required multiple biopsies (6% vs. 19%). SVB at initial FL diagnosis often required additional biopsies to establish a complete diagnosis. In contrast, when assessing for transformed/recurrent FL, additional biopsies were generally not obtained regardless of SVB type, suggesting that in these clinical settings SVB may be sufficient for clinical decision-making.

Moving beyond chemotherapy in the management of follicular lymphoma

Follicular lymphoma (FL) is the most common indolent lymphoma. It is estimated that approximately 2,000 Canadians are newly diagnosed with FL each year; however, this is an underestimation of the disease burden due to the indolent nature of FL. Indeed, the life expectancy for most patients can be measured in decades, with slow but constant improvement in survival estimates having been achieved over time.&#x0D; Traditionally, FL has been considered a chemo-sensitive disease and, for the last 15 years, antibodies targeting the CD20 surface epitope on B cells have become a compelling adjunct to induce long-lasting remission in the frontline setting. Outcomes are favourable for most patients; a long-term follow-up from the seminal PRIMA trial showed that the median progression-free survival (PFS) was 10.5 years in patients treated with immunochemotherapy as part of an initial induction regimen followed by rituximab maintenance, as compared with just over 4 years in the control arm (initial induction regimen followed by observation). In terms of chemotherapy backbone, bendamustine has established itself as the preferred standard in Canada and induces durable response in the majority of patients.&#x0D; This article will focus on patients with high-tumour burden disease in need of treatment, as opposed to patients with limited-stage disease who may benefit from localized radiation or patients with advanced-stage with low-tumour burden disease who may benefit from observation or single agent rituximab.

Management of follicular lymphoma at first relapse

Follicular lymphoma (FL) is the most common subtype of indolent B-cell non-Hodgkin’s lymphoma (NHL). Histologically, it is subcategorized as grade 1, 2, 3A or 3B. FL, grade 3B is considered an aggressive form of the disease and is managed similar to diffuse large B-cell lymphoma (DLBCL). The intent of this article is to discuss the management of FL at first relapse. However, the knowledge of upfront management strategy is crucial in planning treatment in the event of a relapse.

Targeted Therapy for Relapsed/Refractory Follicular Lymphoma: Focus on Clinical Utility of Tazemetostat.

The management of follicular lymphoma (FL) in the relapsed and refractory setting is challenging and an area of ongoing investigation. Epigenetic dysregulation has recently been shown to be a hallmark of FL. Mutations in histone-modifying genes are likely early, driver events in FL pathogenesis, and so are attractive targets to drug. Gain-of-function mutations in the histone methyltransferase EZH2 are common in FL and maintained through disease evolution. With mounting data supporting a critical role for EZH2 as an oncogenic driver for FL, the small molecule inhibitor, tazemetostat, was developed. Tazemetostat has shown promising activity in preclinical models and early phase trials. Importantly, responses were seen in patients with high-risk features. Based on these data, tazemetostat was approved in the US in 2020 for EZH2mut patients with FL who had received at least two prior lines of systemic therapy, or for EZH2wt patients without alternative treatment options. Here, we will review the biology of FL as it pertains to tazemetostat, the available clinical trial data, and future directions for this new therapy.

IV. Pathogenesis, Diagnosis, and Therapeutic Management of Follicular Lymphoma

IV. Pathogenesis, Diagnosis, and Therapeutic Management of Follicular Lymphoma

Age and comorbidity are determining factors in the overall and relative survival of patients with follicular lymphoma.

Frailty and concurrent medical conditions are crucial factors in the management of follicular lymphoma (FL). We evaluated the impact of age and comorbidity on survival, causes of death, histological transformation (HT), and second malignancies (SM) in a large single-center series of grade 1-3A FL. We studied 414 patients diagnosed in the rituximab era, categorized into three age groups (≤60, 61-70, >70 years) and two comorbidity groups (Charlson Comorbidity Index, CCI, 0-1 and ≥2). Despite a similar cumulative incidence of relapse, older and comorbid patients had a lower 10-year overall survival (OS, 88, 65, and 41% for patients ≤60 years, 61-70 years, and >70 years, P<0.0001; and 76 vs. 51% for CCI 0-1 and ≥2, P<0.0001). In a multivariate analysis for OS, comorbidity retained its prognostic impact (HR=2.5, P=0.0003). The proportion of patients dying due to FL was higher among those ≤60 years (74%) and those with a CCI 0-1 (67%). Furthermore, 10-year excess mortality (survival reduction) was more prominent for patients >70 years (30%) and those with a CCI ≥2 (32%). Patients with a CCI ≥2 also had a higher incidence of SM. These data encourage a comprehensive pre-treatment evaluation and a tailored therapeutic approach for all FL patients.

The investigation and management of follicular lymphoma.

The investigation and management of follicular lymphoma.

Clinical Significance of Uptake Value on F18-FDG PET/CT and Histological Grade in 164 Patients with Follicular Lymphoma Including Transformation - a Single Center Retrospective Study

Introduction: Follicular lymphoma is the most common indolent non-Hodgkin lymphoma, but has heterogeneous clinical behavior. PET-CT scan has the central role of determining of clinical staging and its five-point Deauville scale to grade response has been widely accepted in the management of follicular lymphoma. PET-CT scan also plays a significant role of predicting transformation of follicular lymphoma by considering high uptake of standardized uptake value (SUV). Recently, the total metabolic tumor volume (TMTV) measured by PET-CT scan and histological grades are prognostic factors of FL. But TMTV is not easily measured as everyday medical care, more simplified marker such as SUV value is desired. Methods: We retrospectively analyzed 275 patients who were diagnosed as follicular lymphoma including transformed form in our hospital between January 2008 and November 2018. One patient had also been diagnosed as rectal cancer as well as follicular lymphoma, aso we excluded this patient from our study. Results: We first investigated the relationship between histological grade and SUV value on FDG PET/CT. One hundred and ninety-eight biopsies were conducted at the same time of PET-CT. The median SUVmax value was 6.6 (range, 0-34.1) in FL grade 1 patients (n=89), 7.4 (0-23.9) in FL grade 2 patients (n=59), 12.1 (4.6-26.5) in FL grade 3a patients (n=33), and 14.8 (6.5-34.4) in FL grade 3b (n=17) (p&amp;lt;0.01). We then analyzed clinical impact of SUVmax value on follicular lymphoma grade 1-3a. Patients with follicular lymphoma grade 3b, or lack of information were excluded, so we finally analyzed 164 patients. Median follow-up of survivors was 47.5 (0.4-10989) months. The median age at diagnosis was 62 (31-90) years. Ninety patients were male. Thirty-two patients were diagnosed as duodenum follicular lymphoma. Ninety-four patients were advanced clinical stage (III/IV). Using FLIPI2 score, 32 patients (20%) were in the low risk group, 105 (64%) in the intermediate group, and 27 (16%) in the high risk group. Thirty-six patients had high tumor burdens defined by GELF criteria. The median SUVmax value was 7.5 (range, 0-34.1). As first line treatment strategy, 83 patients (51%) received watch and wait strategy, 38 (23%) received R-CHOP, 3 patients (2%) received R-CVP, 14 (9%) received R-Benda, 20 (12%) received RIT, and 6 (4%) received others. High uptake value (SUV max ≧ 10 vs. SUV max &amp;lt; 10) correlated with high tumor burden and sIL2-R (p&amp;lt;0.01), but did not affect OS and time to next treatment (TNT) (97.3% vs. 98.9% in 5-year OS (p=0.82), 54.6% vs. 72.3% in 5-year TNT (p=0.09)), regarless of first line treatment. Conclusion: Uptake value of SUVmax correlated with histological grade of FL and high tumor burden, but did not affect OS and TNT. Disclosures No relevant conflicts of interest to declare.

The role of obinutuzumab in the management of follicular lymphoma.

The outcomes for follicular lymphoma (FL) have improved significantly in recent years. This has been driven by an improved understanding of the pathobiology of FL and the development of therapeutic anti-CD20 antibodies. Combining rituximab with chemotherapy, coupled with its use as maintenance therapy, has contributed to significant improvements in disease control and progression-free survival. However, FL remains incurable and almost all patients invariably relapse. Therefore, there remains a need to develop novel therapeutic options and optimize existing regimens. Obinutuzumab (a first-in-class, glycoengineered, humanized type 2 anti-CD20 antibody) has been evaluated in a number of clinical trials. In this review, we will summarize the evaluable results of clinical trials investigating the efficacy of obinutuzumab in the treatment of FL.

Back Cover

The back cover image is based on the Review Article* Diagnosis and Management of follicular lymphoma: A comprehensive review by Reyad Dada** https://doi.org/10.1111/ejh.13271

Diagnosis and management of follicular lymphoma: A comprehensive review.

Follicular Lymphoma (FL) is an indolent lymphoma and may have various clinical courses. Worldwide, FL is the second most common non-Hodgkin lymphoma (NHL) type after diffuse large B-cell lymphoma. In this review article, the author is discussing relevant diagnostic tools, prognostic factors, and updated study results on the management of patients withnewly diagnosed and relapsed/refractory FL. Controversies in the treatment, maintenance therapy, stem cell transplantation, and novel treatment approaches will be comprehensively discussed.

CLINICAL SIGNIFICANCE OF UPTAKE VALUE ON F18‐FDG PET/CT AND HISTOLOGICAL GRADE IN 164 PATIENTS WITH FOLLICULAR LYMPHOMA INCLUDING TRANSFORMATION – A SINGLE CENTER RETROSPECTIVE STUDY

Introduction: Follicular lymphoma is the most common indolent non-Hodgkin lymphoma, but has heterogeneous clinical behavior. PET-CT scan has the central role of determining of clinical staging and its five-point Deauville scale to grade response has been widely accepted in the management of follicular lymphoma. PET-CT scan also plays a significant role of predicting transformation of follicular lymphoma by considering high uptake of standardized uptake value (SUV). However, the SUV cut-off values distinguishing transformation are not determined and are different in each study, and clinical significance of SUV value on FDG PET/CT is not considered in detail yet. Methods: We retrospectively analyzed 275 patients who were diagnosed as follicular lymphoma including transformed form in our hospital between January 2008 and November 2018. One patient had also been diagnosed as rectal cancer as well as follicular lymphoma, aso we excluded this patient from our study. Results: We first investigated the relationship between histological grade and SUV value on FDG PET/CT. One hundred and ninety-eight biopsies were conducted at the same time of PET-CT. The median SUVmax value was 6.6 (range, 0-34.1) in FL grade 1 patients (n=89), 7.4 (0-23.9) in FL grade 2 patients (n=59), 12.1 (4.6-26.5) in FL grade 3a patients (n=33), and 14.8 (6.5-34.4) in FL grade 3b (n=17) (p<0.01). We then analyzed clinical impact of SUVmax value on follicular lymphoma grade 1-3a. Patients with follicular lymphoma grade 3b, or lack of information were excluded, so we finally analyzed 164 patients. Median follow-up of survivors was 47.5 (0.4-10989) months. The median age at diagnosis was 62 (31-90) years. Ninety patients were male. Thirty-two patients were diagnosed as duodenum follicular lymphoma. Ninety-four patients were advanced clinical stage (III/IV). Using FLIPI2 score, 32 patients (20%) were in the low risk group, 105 (64%) in the intermediate group, and 27 (16%) in the high risk group. Thirty-six patients had high tumor burdens defined by GELF criteria. The median SUVmax value was 7.5 (range, 0-34.1). As first line treatment strategy, 83 patients (51%) received watch and wait strategy, 38 (23%) received R-CHOP, 3 patients (2%) received R-CVP, 14 (9%) received R-Benda, 20 (12%) received RIT, and 6 (4%) received others. High uptake value (SUV max ≧ 10 vs. SUV max < 10) correlated with high tumor burden (p<0.01), but did not affect OS and time to next treatment (97.3% vs. 98.9% in 5-year OS (p=0.79), 54.6% vs. 72.3% in time to next treatment (p=0.07)). Conclusion: Uptake value of SUVmax correlated with histological grade of follicular lymphoma and high tumor burden, but did not affect OS and TTT after first line treatment therapy. Keywords: F-18-fluorodeoxyglucose (FDG); follicular lymphoma (FL); positron emission tomography (PET).

Management of Follicular Lymphoma: Assessment of Practice Patterns of US Hematologists/Oncologists

Management of Follicular Lymphoma: Assessment of Practice Patterns of US Hematologists/Oncologists

First-Line Management of Follicular Lymphoma

First-Line Management of Follicular Lymphoma

Diagnosis and treatment of follicular lymphoma: an update.

Over the last few years, there have been many changes in the management of patients with follicular lymphoma, resulting in improvements in progression-free survival and quality of life. In addition to established regimens such as radiotherapy and immunochemotherapy, new treatment options are on the horizon. Furthermore, even the use of established chemotherapy agents has evolved, with new combinations moving to the forefront of the current treatment strategy. Nevertheless, there remains an unmet need for patients who have early relapses, those who are not responsive to anti-CD20 treatment regimens and for those in whom minimal residual disease persists even after immunochemotherapy. This review provides a summary of current developments in the diagnosis, treatment and management of follicular lymphoma, focusing on the clinical issues from a Swiss perspective.