Ixazomib in POEMS syndrome: 'Ixa'ctly what we need?

The role of the proteasome inhibitor ixazomib in the treatment of POEMS syndrome continues to evolve. He and colleagues present the results of a study investigating ixazomib in combination with cyclophosphamide and dexamethasone in newly diagnosed POEMS patients. The triplet showed excellent efficacy and tolerability, and constitutes an effective treatment option for patients with POEMS. Commentary on: He et al. An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly-diagnosed POEMS syndrome. Br J Haematol 2024;205:478-482.

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly diagnosed POEMS syndrome.

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option.

What is the best treatment strategy before autologous peripheral blood stem cell transplantation in POEMS syndrome?

Autologous peripheral blood stem cell transplantation (aPBSCT) provides optimal outcomes in POEMS syndrome but the definition of the best treatment before aPBSCT remains to be defined because of the rarity of the disease and the heterogeneity of published case series. We collected clinical and laboratory data of patients with POEMS syndrome undergoing aPBSCT from 1998 to 2020 in ten Italian centers. The primary endpoint of the study was to evaluate the impact of prior therapies and mobilization regimen on outcome. We divided the patients into three groups: patients who did not receive any treatment before transplant (15 patients, group A: front-line), patients pre-treated with other agents (14 patients, group B) and patients treated with cyclophosphamide as their mobilizing regimen (16 patients, group C). The three groups did not show differences in terms of demographic and clinical characteristics. All 45 patients underwent aPBSCT after a high-dose melphalan conditioning regimen, with a median follow-up of 77 months (range, 37-169 months). The responses were not statistically different between the three groups (P=0.38). Progression-free and overall survival rates at 6 years were: 70% (95% confidence interval: 55-85%) and 91% (95% confidence interval: 82-99) 65%, respectively, and did not differ between the three groups. The cumulative incidence of transplant-related mortality and relapse was 4% and 36%, respectively. In conclusion, in a relatively large number of patients with POEMS syndrome, undergoing an autologous transplant, pre-treatment and disease status at transplant did not appear to have an impact on major transplant outcomes.

Giant papillary hemangioma-A rare tumor with an exceptional size.

Papillary hemangioma (PH) is a recently described vascular tumor with a predilection for the skin of the head and neck. Histopathologically, it is characterized by a bland endothelial proliferation arranged in a papillary configuration, bearing resemblance to glomeruloid hemangioma seen in the context of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome. The largest cutaneous PH reported to date measured 1.5 cm in greatest dimension. Here, we report a case of PH with an alarming size of 10 cm. We present this case to add to the limited literature on this rare tumor, highlight the histopathologic differences between PH and its mimics, and emphasize the variable nature of PH tumor size.

Regular assessment of serum vascular endothelial growth factor levels to monitor POEMS syndrome.

BACKGROUND: To investigate the utility of regular serum VEGF (sVEGF) levels assessment in the monitoring of POEMS syndrome. METHODS: We retrospectively reviewed data of 30 patients with POEMS syndrome whose sVEGF was tested regularly every 6 months. sVEGF levels after treatment were measured and correlated with disability (Overall Neuropathy Limitations Scale, ONLS), clinical impairment (measured with the modified Clinical Response Evaluation Scale, mCRES), and relapse-free survival. The ability of sVEGF to predict disease flares during remission and refractory disease was also analysed. RESULTS: Patients with normalised serum VEGF levels (< 1000 pg/ml) at 6 months showed prolonged relapse-free survival (at 3-year 94% for complete VEGF response, 57% partial, 0% none, p < 0.001) and greater later clinical improvement (median ΔmCRES complete VEGF response -5 vs partial -4, p = 0.019, and vs no VEGF response -2, p = 0.006). After remission, the sensitivity of 6-month sVEGF monitoring in predicting clinical relapse was 58% with a specificity of 100%. In patients refractory to treatment, the sensitivity in predicting further clinical worsening was 15%. In addition, in 25% of the patients in remission and 16% of those refractory to therapy, sVEGF levels only increased at the time of relapse. CONCLUSIONS: Regular sVEGF assessment is a valid biomarker in the prediction of disease reactivation in POEMS syndrome and was particularly useful during the phase of remission.

A Multicenter Analysis of Clinical Features and Long-Term Outcomes of POEMS Syndrome in Korea.

BACKGROUND: POEMS syndrome is a rare form of plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Owing to its low incidence, there are few reports regarding this syndrome. This multicenter study included 84 patients diagnosed with POEMS syndrome in South Korea. METHODS: We retrospectively evaluated 84 patients diagnosed with POEMS syndrome at 8 hospitals in South Korea between January 2000 and October 2022. The clinical characteristics and treatment outcomes were analyzed. RESULTS: The median patient age was 53 years (range, 26-77 years), and 63.1% of the patients were male. All patients had peripheral neuropathy, and 81 (96.4%) had monoclonal plasma cell proliferation. Plasma vascular endothelial growth factor levels were available for 32 patients with a median of 821 pg/mL (range, 26-12,900 pg/mL). Other common features included skin changes (54.2%), volume overload (71.4%), and organomegaly (72.6%). Of the 84 patients, 75 received initial treatment (local radiotherapy, 6 [8.0%]; chemotherapy, 17 [22.7%]; both chemotherapy and local radiotherapy, 9 [12.0%]), upfront autologous stem cell transplantation (ASCT), 43 (57.3%; with induction chemotherapy, n = 12, 16.0%; without induction chemotherapy, n = 31, 41.3%). The median follow-up duration was 40.7 months. The 5-year overall survival (OS) was 78%, and the 5-year progression-free survival (PFS) was 55%. Patients who underwent upfront ASCT and were diagnosed after 2014 had a longer OS and PFS. CONCLUSION: The demographics of Korean patients with POEMS syndrome were similar to those reported previously. Because of the introduction of new treatment agents and the reduced rate of transplant-related mortality related to ASCT, the treatment outcomes of Korean patients with POEMS syndrome have improved in recent years.

[POEMS Syndrome: Report of Two Cases]. / Síndrome de POEMS: Reporte de dos casos.

POEMS syndrome is a multisystem disorder caused by a neoplasm of plasma cells. The acronym "POEMS" refers to some of its characteristics: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. It's a rare condition, and available information has been presented as case series. Its exact incidence is unknown. The pathophysiology is not yet fully clear, but the role of proinflammatory cytokines and overproduction of vascular endothelial growth factor is recognized. Diagnosis is based on criteria defined by the International Myeloma Working Group. However, atypical cases that do not meet all the criteria have been described, in which observation is chosen until symptoms appear or empirical treatment is initiated based on symptomatic involvement. We describe a series of 2 cases of patients with POEMS syndrome studied and treated at Carlos Van Buren Hospital in Valparaíso, Chile. Both meet the criteria for diagnosis but with variable presentations due to different elements of the minor criteria. Large retrospective series report polyneuropathy as the most common finding. Additionally, they have monoclonal gammopathy of undetermined significance (GMSI). Both patients underwent the same therapy regimen with melphalan/dexamethasone. Nowadays, both patients are stable and undergoing outpatient monitoring.

[Diagnosis and management of POEMS syndrome].

POEMS syndrome is a plasma cell neoplasm that presents with peripheral neuropathy, organomegaly, fluid retention, skin manifestations, osteosclerotic lesions, and λ-type M-proteinemia. The pathogenesis of POEMS syndrome is poorly understood, as the genetic profile of plasma cells in POEMS syndrome differs from that of myeloma. In most cases, POEMS syndrome is difficult to distinguish from chronic inflammatory demyelinating polyneuropathy (CIDP). Consequently, it is essential not to miss characteristic signs of POEMS syndrome such as M-protein, VEGF, pleural effusion, and osteosclerotic lesions. Novel agents for myeloma, such as thalidomide, lenalidomide, and bortezomib, are effective. For younger patients, these agents followed by autologous transplantation with high-dose melphalan is the standard of care. More relapses are now being reported in results of long-term observation, and treatment strategies for relapsed disease must be established.

[A race against time: POEMS syndrome]. / "Verseny az idovel": a POEMS szindróma.

Background - POEMS syndrome is a potentially well manageable disease with an ascendant therapeutic arsenal nowadays. The early recognition of the syndrome is key to prevent serious multiorgan damage, and that is still a big challenge for physicians. With the following two case reports the authors aimed to highlight the consequences of late recognition of the disease and summarize the potential therapeutic options for POEMS syndrome.

Results - We have presented two patients’ cases with a long history of examination and treatment because of uncleared polyneuropathy. Through these cases we could see how serious could be the consequences of late diagnosis and despite multiorgan impairment there are still therapeutic options which could improve the patient’s condition. Although the diagnosis of POEMS syndrome is not easy, it must raise our mind the thought and be prudent when we start a treatment in polyneuropathy.

Evidence-based medical treatment of POEMS syndrome.

POEMS syndrome is a rare multisystem paraneoplastic disorder due to an underlying low-level plasma cell dyscrasia. Due to its rarity, there are limited data to guide treatment and there are no consensus guidelines. Therapy choices are dictated by patient characteristics, disease factors and local funding arrangements. The goals of therapy are to eradicate the underlying clone in order to improve quality of life and overall survival. Most evidence has been garnered in the front-line setting. Localised disease responds well to radiotherapy, whilst for those with systemic disease, the best outcomes are demonstrated with induction chemotherapy followed up with high-dose melphalan and stem cell rescue if eligible. For transplant-ineligible patients lenalidomide-dexamethasone remains a preferred treatment option. Data in the relapse setting are scarce. Supportive care including management of neuropathy, endocrinopathy, thrombotic risk and anti-infective agents is necessary. Future international collaboration is crucial to define optimal treatment strategies particularly in the relapse setting.

Small vessel platelet thrombosis in the peripheral nerves in POEMS syndrome.

INTRODUCTION/AIMS: Vascular thrombosis is prevalent among patients with polyneuropathy, organomegaly, endocrinopathy M-protein, and skin changes (POEMS) syndrome. The endothelial cells in the endoneurium are often hypertrophied and the lumen is frequently occluded. Consequent local hypoxia may increase vascular endothelial growth factor (VEGF), which induces hypercoagulation and vascular permeability. METHODS: This study presents two patients in the fifth decade of life, who had rare nerve biopsy findings of vascular occlusion mainly by platelets. Before the cases presented here, we encountered nine confirmed POEMS patients whose nerve biopsies did not show similar findings. RESULTS: A small artery and a vein were occluded, but no atherosclerotic changes were observed. The endothelial cells that adhered to the packed platelets lost their junctions. DISCUSSION: Platelet aggregation, degranulation, and ischemia may cause a loose endothelial barrier and leak proinflammatory cytokines, such as interleukin-12. This may increase production of VEGF and may cause nerve demyelination. Small vessel platelet thrombosis may contribute to the pathogenesis of this disorder.

Treatment-responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy.

BACKGROUND: Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, and include sporadic late onset nemaline myopathy, light chain amyloid myopathy, and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy-associated myopathy (MGAM) in a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) patient. METHOD: Case report. RESULTS: A 51-year-old woman presented with a 6-month history of progressive bilateral foot drop, lower limb edema, and a 15-lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length-dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinating and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen-filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next-generation sequencing of glycogen storage and polyglucosan body myopathy-related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant. CONCLUSIONS: This patient expands a spectrum of MGAM. Recognition of this condition and other subtypes of MGAM is of utmost important because they are treatable.

POEMS syndrome: Update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: POEMS syndrome is a life-threatening condition due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder, sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. DIAGNOSIS: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. RISK STRATIFICATION: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced estimated glomerular filtration rate. RISK-ADAPTED THERAPY: For those patients with a dominant plasmacytoma, first-line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement should receive systemic therapy. Corticosteroids are temporizing, but alkylators and lenalidomide are the mainstays of treatment, the former either in the form of low-dose conventional therapy or as high-dose conditioning for stem cell transplantation. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Daratumumab combinations also appear promising based on case series. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Pulmonary manifestations of POEM syndrome: a retrospective analysis of 282 cases.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystemic clonal plasma cell disorder. Pulmonary involvement is frequently found in patients with POEMS syndrome, manifesting various clinical features. Therefore, to improve diagnostic accuracy and provide treatment strategies, a comprehensive analysis of pulmonary manifestations of POEMS syndrome is needed. METHODS: This retrospective study included patients with POEMS syndrome at Peking Union Medical College Hospital, a major referral medical center in China, between June 1, 2013, and June 1, 2023. Demographic data, laboratory findings, pulmonary function test results, echocardiograms, and chest imaging data were extracted. Continuous variables were compared using the t-test or Mann-Whitney method. Pearson's chi-square test or Fisher's exact test was conducted to compare categorical data. RESULTS: Overall, 282 individuals diagnosed with POEMS syndrome were included in this study, of which 56% were male with an average age of 48.7 years. Respiratory symptoms were found in 40.1% of the patients, with dyspnea as the most common symptom (34.4%). Chest computed tomography and echocardiography findings showed that 56.4% of patients exhibited pleural effusion, 62.8% displayed mediastinal or hilar lymphadenopathy, 46.5% presented pleural thickening, 27.3% demonstrated bone lesions of the ribs or thoracic vertebra, 7.8% showed lung interstitial abnormalities, and 35.5% had pulmonary hypertension. Decreased diffuse capacity and restrictive ventilatory patterns were identified in 85.2% (115 cases) and 47.4% (64 cases) of patients, respectively. Patients with respiratory symptoms exhibited higher declined lung function measures than those having no respiratory symptoms. High-risk patients with poor prognosis showed more pulmonary function abnormalities. CONCLUSION: Abnormalities in pulmonary manifestations constitute the significant features of POEMS syndrome. Several patients with POEMS syndrome presented with respiratory symptoms at the initial evaluation. These findings underscore the importance of early identification and accurate diagnosis of POEMS syndrome by clinicians, particularly in cases involving lung and multisystem.

Ultrasound-based radiomic analysis of the peripheral nerves for differentiation between CIDP and POEMS syndrome.

BACKGROUND: Demyelinating peripheral neuropathy is characteristic of both polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). We hypothesized that the different pathogeneses underlying these entities would affect the sonographic imaging features. PURPOSE: To investigate whether ultrasound (US)-based radiomic analysis could extract features to describe the differences between CIDP and POEMS syndrome. MATERIAL AND METHODS: In this retrospective study, we evaluated nerve US images from 26 with typical CIDP and 34 patients with POEMS syndrome. Cross-sectional area (CSA) and echogenicity of the median and ulnar nerves were evaluated in each US image of the wrist, forearm, elbow, and mid-arm. Radiomic analysis was performed on these US images. All radiomic features were examined using receiver operating characteristic analysis. Optimal features were selected using a three-step feature selection method and were inputted into XGBoost to build predictive machine-learning models. RESULTS: The CSAs were more enlarged in patients with CIDP than in those with POEMS syndrome without significant differences, except for that of the ulnar nerve at the wrist. Nerve echogenicity was significantly more heterogeneous in patients with CIDP than in those with POEMS syndrome. The radiomic analysis yielded four features with the highest area under the curve (AUC) value of 0.83. The machine-learning model showed an AUC of 0.90. CONCLUSION: US-based radiomic analysis has high AUC values in differentiating POEM syndrome from CIDP. Machine-learning algorithms further improved the discriminative ability.

[POEMS Syndrome with Peripheral Edema and Ascites as the Main Manifestations:Report of One Case].

POEMS syndrome is a rare disease caused by monoclonal plasma cell proliferative disorder.The typical signs include peripheral neuropathy,organ enlargement,endocrine disease,M proteinemia,and skin changes.In clinical practice,the atypical,complex,and changeable clinical manifestations of this syndrome can easily lead to misdiagnosis and missed diagnosis.A case of POEMS syndrome with peripheral edema and ascites as the main manifestations is reported in this paper.

[Identification of transcriptional features and surface markers of plasma cell clones in POEMS syndrome by single-cell RNA sequencing].

POEMS syndrome is a rare monoclonal plasma cell disorder with unique symptoms distinct from other plasma cell neoplasms. To identify and find the transcriptional features of clonal plasma cells in POEMS syndrome (POEMS clones), single-cell RNA sequencing was performed on patient-derived bone marrow plasma cells. POEMS clones were identified in 5 out of 10 patients, and the proportions of POEMS clones in the plasma cells were markedly smaller than that of other plasma cell malignancies such as multiple myeloma and MGUS. The transcriptional features of POEMS clones differed from those of other plasma cell diseases, and representative MM-related oncogenes were not upregulated in POEMS clones. Notably, POEMS clones are negative for CD19 and express significantly lower MHC-II levels than normal plasma cells; thus, CD19- HLA-DRlo is confirmed as a useful marker to identify POEMS clones in patients. These findings unveil the unique features of POEMS clones and contribute to the understanding of the pathogenesis of POEMS syndrome.

Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected because of the highly restrictive usage of 2 λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations after PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in the case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (rapid amplification of cDNA ends-based repertoire sequencing [RACE-RepSeq]), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 83% of patients with POEMS syndrome, including some in whom BM tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+ monoclonal PCs. Twenty-four (83%) of the 29 LC clonal sequences found were derived from the IGLV1-40 and IGLV1-44 germline genes, as well as 2 from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid, and specific tool to detect low-abundance PC clones in BM and assign them to POEMS syndrome, with all the consequences for therapeutic options.

Characteristics and risk factors for thrombosis in POEMS syndrome: A retrospective evaluation of 230 patients.

Thromboses are prevalent in POEMS syndrome, but few risk factors for POEMS-associated thrombosis have been identified. The objective of this study is to identify novel risk factors for POEMS-associated thrombosis. In this retrospective cohort of 230 POEMS patients, 27% developed thrombosis. Arterial events were slightly more common than venous. Stroke accounted for 26% of all thromboses and 53% of arterial events. There were differences in baseline features between the thrombosis group and the no thrombosis group, and these were driven by patients with arterial thrombosis. Risk factors for arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly. Hyperprolactinemia appeared to be a risk factor for venous thrombosis. The risk of thrombosis was most striking among men with elevated hemoglobin (32% vs. 5%, p < .001) and hematocrit (42% vs. 5%, p < .001) compared to men without. Most thromboses occurred prior to POEMS directed therapy, and most that occurred during therapy happened within 3 months of diagnosis. Twenty-one percent of patients with thrombosis had recurrence. In recognition of high overall rates of thrombosis in this population, all patients with POEMS syndrome should receive prophylactic antiplatelet therapy, and clinicians should consider anticoagulation in patients with risk factors for POEMS-associated thrombosis.

Rasch-built overall disability scale for POEMS syndrome (POEMS-RODS).

Patient-reported outcome measures engage patients in disease severity measurement and the metrics reported can be meaningful to their lives. The Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome (POEMS) is a complex multisystem disorder with disabling neuropathy which is distinct from other acquired inflammatory neuropathies. No current POEMS-specific validated disability scales exist. To address this, we have produced a Rasch-built overall disability scale (RODS) specific to POEMS. A 146-item preliminary questionnaire containing relevant activity and participation items for neuropathic disability was applied to 49 clinically stable patients with POEMS from the UK national POEMS cohort. A total of 123 items not fulfilling Rasch model expectations were sequentially removed. The final 23-item POEMS-RODS fulfilled Rasch model expectations and showed acceptable test-retest reliability. The 23-item POEMS-RODS is a disease-specific patient-reported outcome measure able to detect activity limitations within the range of ability demonstrated by the UK POEMS cohort. Larger international studies are needed to confirm the broader applicability and responsiveness of this scale in other countries.