Response Criteria Research Articles

Quantifying morphologic variations as an alternate to standard response criteria for unresectable primary liver tumors after checkpoint inhibition therapy.

The aim of this study was to assess the feasibility of quantifying morphologic changes in tumors during immunotherapy, as a reflection of response or survival. A retrospective single-center analysis was performed in patients with unresectable liver cancer previously enrolled in clinical trials combining immunotherapy (tremelimumab ± durvalumab) and locoregional treatment (either ablation or transarterial chemoembolization). Conventional response (RECIST 1.1) was assessed at 6-month follow-up. For morphologic assessment, the largest target lesion was manually segmented on axial slices in two dimensions using contrast-enhanced CT. Solidity and circularity of tumors were calculated at baseline, 3-month follow-up, and at 6-months follow-up. Survival analysis was performed. From the 68 patients enrolled in clinical trials, 28 did not have target lesions separate from lesions treated by locoregional therapies, and 3 had no follow-up imaging. Thirty-seven patients (9 with biliary cancer and 28 with hepatocellular carcinoma) were included. Shape features and shape variation were not correlated with RECIST 1.1 status at 6-month follow-up. However, patients with low solidity tumors at 6-month follow-up showed poorer prognosis compared with patients with high solidity tumors at 6-month follow-up (p = 0.01). Solidity variation analysis confirmed that a decrease of tumor solidity at 6-month follow-up was associated with poorer prognosis (p = 0.01). No association was found between shape features at baseline or shape features at 3-month follow-up with overall survival. Evolution and variation of tumor morphology during treatment may reflect or correlate with outcomes and contribute toward adapted response criteria.

Challenges in developing response evaluation criteria for peptide receptor radionuclide therapy: A consensus report from the European Neuroendocrine Tumor Society Advisory Board Meeting 2022 and the ENETS Theranostics Task Force.

Assessing the response to systemic therapy in neuroendocrine tumors (NET) is challenging since morphological imaging response is often delayed and not necessarily reflective of clinical benefit. Peptide receptor radionuclide therapy (PRRT) has a complex mechanism of action, further complicating response assessment. In response to these challenges, the European Neuroendocrine Tumor Society (ENETS) Theranostics Task Force conducted a statement-based survey among experts to identify the current landscape and unmet needs in PRRT response assessment. The survey, presented at the 2022 ENETS Advisory Board (AB) meeting in Vienna, was completed by 70% of AB members, most of whom (81%) were from ENETS Centers of Excellence (CoE). It comprised a set of 13 questions with two substatements in three questions. Six (46%) of the statements achieved more than 75% agreement, while five (39%) additional statements reached over 60% consensus. Key points from the survey include: AB members agreed that lesions deemed equivocal on computed tomography (CT) or magnetic resonance imaging (MRI) should be characterized by somatostatin receptor (SST) positron emission tomography (PET)/CT before being designated as target lesions. It was agreed that interim response assessments should occur after the second or third PRRT cycle. Over half (54%) preferred using both conventional cross-sectional imaging (CT and/or MRI) and hybrid imaging (SST PET/CT) for this purpose. Almost all AB members supported further response assessment 3 months after the final PRRT cycle. A majority (62%) preferred using a combination of conventional cross-sectional imaging and SST PET/CT. For cases showing equivocal progression (ambiguous lesions or nontarget lesions) on CT and/or MRI, further confirmation using SST PET/CT was recommended. A significant majority (74%) preferred assessing pseudo-progression and delayed response by combining SST PET with diagnostic CT and/ or MRI. Though just below the 75% consensus threshold, there was substantial agreement on selecting target lesions based on SST PET/CT uptake intensity and homogeneity. Sixty-nine percent noted the importance of documenting and closely following heterogeneity in lesions in liver, lymph nodes, primary tumors, or other organs. As to the statement on parameters for new response criteria, AB members recommended exploring maximum standard unit value, tumor-to-background ratio, Hounsfield Unit (Choi Criteria), total tumor burden, and novel serum or molecular markers for future response evaluation criteria. Sixty-five percent supported the use of a single SST PET/CT for response assessment of NET lesions treated with PRRT. These findings highlight the importance of integrating advanced imaging techniques and recognizing the need for more nuanced criteria in assessing the efficacy of PRRT in NET patients. This approach aims to enhance the accuracy of treatment monitoring and improve patient outcomes.

Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer

BackgroundDenileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. Patients and methodsA phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. ResultsThe maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1–2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood. ConclusionsDenileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels.Clinical Trial Registration:ClinicalTrials.gov # NCT00357448

Prospective evaluation of quantitative response parameter in patients with Gastrointestinal Stroma Tumorundergoing tyrosine kinase inhibitor therapy-Impact on clinical outcome.

The purpose of this study was to determine if dual-energy CT (DECT) vital iodine tumor burden (ViTB), a direct assessment of tumor vascularity, allows reliable response assessment in patients with GIST compared to established CT criteria such as RECIST1.1 and modified Choi (mChoi). From 03/2014 to 12/2019, 138 patients (64 years [32-94 years]) with biopsy proven GIST were entered in this prospective, multi-center trial. All patients were treated with tyrosine kinase inhibitors (TKI) and underwent pre-treatment and follow-up DECT examinations for a minimum of 24 months. Response assessment was performed according to RECIST1.1, mChoi, vascular tumor burden (VTB) and DECT ViTB. A change in therapy management could be because of imaging (RECIST1.1 or mChoi) and/or clinical progression. The DECT ViTB criteria had the highest discrimination ability for progression-free survival (PFS) of all criteria in both first line and second line and thereafter treatment, and was significantly superior to RECIST1.1 and mChoi (p < .034). Both, the mChoi and DECT ViTB criteria demonstrated a significantly early median time-to-progression (both delta 2.5 months; both p < .036). Multivariable analysis revealed 6 variables associated with shorter overall survival: secondary mutation (HR = 4.62), polymetastatic disease (HR = 3.02), metastatic second line and thereafter treatment(HR = 2.33), shorter PFS determined by the DECT ViTB criteria (HR = 1.72), multiple organ metastases (HR = 1.51) and lower age (HR = 1.04). DECT ViTB is a reliable response criteria and provides additional value for assessing TKI treatment in GIST patients. A significant superior response discrimination ability for median PFS was observed, including non-responders at first follow-up and patients developing resistance while on therapy.

Ivarmacitinib, a selective Janus kinase 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis and inadequate response to conventional synthetic DMARDs: results from a phase III randomised clinical trial

ObjectiveTo assess the efficacy/safety of ivarmacitinib, a selective Janus kinase (JAK) 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic disease-modifying...

Efficacy and safety of bendamustine, rituximab and bortezomib treatment in relapsed/refractory Waldenstrom Macroglobulinaemia: results of phase 2 single-arm FIL-BRB trial.

This multicentre phase II study Fondazione Italiana Linfomi (FIL)-bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90 mg/m2 on days 1-2), rituximab (375 mg/m2 intravenously on day 1) and bortezomib (1.3 mg/m2 sc on days 1, 8, 15, 22) every 28 days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinaemia (RR-WM). Moreover, MYD88L265P and CXCR4S338X mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30 months, progression-free survival was 84.2% (95% CI 68.2%-92.6%), 81.5% (95%CI 65.1-90.7) and 78.8% (95%CI 62.0-88.8) respectively. At 18 months, the Overall survival was 92.1% (95%CI 77.5%-97.4%). Overall, 19 patients (50%) experienced grade 3-4 haematological toxicity, mainly thrombocytopenia, and grade 1-3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia patients. MRD monitoring showed promising efficacy in clearing the residual disease.

Prognosis of patients with Hodgkin lymphoma and indeterminate response to PD-1 inhibitor therapy: considerations for application of LYRIC criteria in real clinical practice.

PD-1 inhibitors have shown unconventional response patterns in classic Hodgkin lymphoma (cHL). These include the phenomenon of pseudoprogression, highlighting the need for specialized response criteria such as the LyRIC, which stringened definitions for disease progression with introduction of indeterminate response category. Despite their potential utility, these provisional criteria are currently underutilized and require further refinement through clinical practice data collection. In this retrospective study LyRIC criteria were systematically used for response assessments in 180 patients with refractory cHL treated with nivolumab. Median follow-up was 60months. Indeterminate response (IR) was a frequent phenomenon in study population: at 3months of therapy 63 (35%) patients had an indeterminate response (IR1 7%, IR2 23%, IR3 6%). Among them 18 (29%) achieved an objective response with continued monotherapy. There were no differences in OS or TTNT depending on the type of IR. IR was the best achieved response in 45 (25%) patients. Patients with IR had favorable prognosis with no difference in OS, PFS and TTNT comparing to patients with PR when subsequent therapy was initiated due to disease progression. Patients with IR may achieve prolonged disease control or a deeper response upon continuing treatment. These findings support the broader implementation and adjustment of LyRIC criteria in clinical practice to enhance decision-making in cHL patients treated with immunotherapy.

Use of MM-SES-CD Endoscopic Improvement Thresholds Enhances Effect Size Differentiation between Adalimumab vs. Placebo: A Post-hoc Analysis of the EXTEND Trial.

The Modified Multiplier of the SES-CD (MM-SES-CD) refines the assessment of endoscopic Crohn's Disease (CD) severity by differentially weighting parameters in the original SES-CD. A threshold of <22.5 for MM-SES-CD suggests endoscopic remission and correlates with a low risk of long-term disease progression. This study examines whether MM-SES-CD-defined endoscopic remission (ER) and response criteria are more sensitive to treatment effects compared to conventional SES-CD definitions. This post-hoc analysis of the EXTEND trial compared various SES-CD and MM-SES-CD definitions of ER and endoscopic response in CD patients treated with adalimumab or placebo. The study included participants with moderate-severe CD and a baseline MM-SES-CD score ≥22.5. The primary outcome of ER, defined as MM-SES-CD <22.5, was evaluated at weeks 12 and 52. AUC analyses compared thresholds for predicting week 52 ER. Of the 100 participants (77.5% of the EXTEND population), 51 received adalimumab and 49 placebo. At week 12, 62% achieved MM-SES-CD ≥20% reduction from baseline, compared to 39% with SES-CD ≥50% reduction. At week 52, 56.9% of adalimumab-treated participants achieved MM-SES-CD <22.5, compared to 10.2% in the placebo group. MM-SES-CD ≥20% reduction at week 12 better predicted week 52 ER than SES-CD ≥50% reduction (AUC: 0.73 vs. 0.62, p=0.002). MM-SES-CD definitions improved discrimination between treatment and placebo and offered superior predictive accuracy for week 52 ER. Its use may enhance trial efficiency and better predict long-term disease outcomes.

SURG-39. LONG-TERM RESULTS OF INTERVENTION FOR GROWING INCIDENTAL MENINGIOMAS OR CONTINUED ACTIVE SURVEILLANCE, A PROSPECTIVE COHORT STUDY

Abstract Incidental meningiomas are common findings. They represent a clinically challenging cohort, without a detailed consensus on their management. The risk of tumor progression and that of intervention must be considered. Long-term prospective data on incidental meningiomas are sparse. We aimed to evaluate the long-term effect of Gamma Knife Radiosurgery (GKRS), surgical resection and continued observation for growing incidental meningiomas. A prospective database of 62 patients (70 tumors) commenced under active surveillance was established in 2009. Radiological and clinical data was obtained until sept 2023. The results of long-term observation (group 1) and intervention with GKRS (group 2) or surgery (group 3) at progression was analyzed. Due to growth, 41 (58.6%) tumors were treated. The mean growth rate was higher prior to GKRS (2.1 cm 3 /y) and surgery (0.4 cm 3 /y) than during long-term active surveillance (0.009 cm 3 /y) (p &amp;lt; 0.001). The meningiomas became in mean 31.3% and 99.1% smaller after GKRS and resection, respectively. In comparison, tumors under long-term surveillance increased in mean 27.2% (p &amp;lt; 0.001). According to the RANO response criteria, the complete, partial, and minimal response versus stable disease rates were higher following intervention, the overall progressive disease rates were similar (Group 1; 20.7%, group 2: 11.4% and group 3: 16.7%) (p = 0.232). Treatment versus no-treatment did not affect overall survival (Group 1; 10.3 y, group 2: 11.8 y and group 3: 13.5 y (p = 0.264). No symptom development was registered in group 1. In group 2, 2.9% experienced transient (grade 2) adverse events, and in group 3, 50% suffered permanent (grade 4) adverse events according to the Common Terminology Criteria for Adverse Events (CTCEAv5). Intervention reduces tumor volume; however, the clinical significance remains uncertain and side effects are not negligible. Active surveillance is safe, saves &amp;gt; 40% of patients from unnecessary interventions and does not compromise future treatments. The optimal timing of intervention should be further explored.

NIMG-54. AUTOMATED IMAGING RESPONSE EVALUATION SYSTEM (AIRES) FOR NEURO-ONCOLOGY: PROTOTYPE SOFTWARE TOOL FOR DETERMINING STANDARDIZED RADIOGRAPHIC RESPONSE ASSESSMENT FOR GLIOBLASTOMA CLINICAL TRIALS

Abstract Standardized radiographic response assessment criteria like Modified Response Assessment in Neuro-Oncology (mRANO) and now the RANO 2.0 are utilized for evaluating progression-free survival and objective response rate during glioblastoma clinical trials. After measuring tumor size with either bidimensional diameters or volumetric segmentations, the crucial and final time-consuming step of categorizing progression, stable disease, and response based on multiple criteria and numerical thresholds (e.g. ≥40% volumetric growth = progressive disease) is currently done manually. We developed an application prototype, Automated Imaging Response Evaluation System (AIRES) for Neuro-Oncology, that uses the mRANO criteria to label each timepoint as treatment response, stable disease, or disease progression based on either bidimensional or volumetric measurements as well as optional inputs of clinical status and corticosteroid dosage. These inputs may be uploaded via CSV files, which can integrate with automated tumor segmentation volumetry workflows, or entered in the AIRES graphical user interface (GUI). The AIRES GUI displays a patient report consisting of a table and graph that contain the lesion size, percent change from baseline, percent change from nadir, and the mRANO response category for each timepoint. To test AIRES in a real-world application, tumor size measurements from 367 scans across 41 patients from NUTMEG, a phase II multicenter clinical trial, were used to perform mRANO reads and calculate progression-free survival and time to response. AIRES-assisted reads performed by reader 1 were significantly quicker than fully manual reads performed by reader 2 (37.1±8.6 vs 107.7±58.6 seconds, P&amp;lt;0.0001). These results show that the AIRES app can make the reads quicker and potentially feasible for non-trained personnel, while reducing the amount of error-prone manual steps. Additionally, the underlying logic of AIRES is easily adaptable to integrate other response criteria including but not limited to RANO 2.0 and other future response assessment updates.

A Phase 1b, Dose Escalation/Dose Expansion, Multicenter, Open-Label Study to Assess the Safety and Tolerability of OPN-6602 Monotherapy and in Combination with Dexamethasone in Subjects with Relapsed and/or Refractory Multiple Myeloma

Background and Significance: OPN-6602 is a potent, selective, and orally active small molecule dual cyclic-AMP response element-binding protein (CBP) and E1A binding protein (EP300) bromodomain (BRD) inhibitor. It has low nanomolar potency against EP300 and CBP, with greater than 100-fold less activity against BRD3, which was the most potent among all the other BRDs evaluated. OPN-6602 suppresses known oncogenes interferon regulatory factor 4 (IRF4) with downstream suppression of MYC resulting in antitumor activity through EP300/CBP inhibition. It is a potent inhibitor of multiple myeloma (MM) cell growth in the MM cell lines, OPM-2 and MM.1S, and a potent inhibitor of histone acetylation via BRD intramolecular modulation of histone acetyltransferase (HAT) activity. EP300 and CBP are transcription coactivators that contain both epigenetic writer HAT and reader BRDs that regulate transcription of genes via chromatin remodeling. EP300 and CBP are highly conserved and ubiquitously expressed enzymes that belong to the KAT3 family of acetyltransferases. EP300 and CBP interact with numerous other proteins to function as global transcriptional coactivators through the modification of lysines on both histone and non-histone nuclear proteins, affecting proteins such as IRF4 and MYC. IRF4/MYC act as lineage-specific transcription factors controlling the survival and growth of MM. EP300/CBP inhibition causes cell cycle arrest and apoptosis in MM through suppression of IRF4 and MYC, rendering EP300/CBP as a novel target for MM (Conery 2016). Recently, unbiased analysis of vulnerability genes identified EP300 as a specific and highly relevant target for MM (de Matos Simoes 2023). OPN-6602 pharmacokinetic (PK) studies in mice, rats, and dogs consistently showed moderate clearance and short terminal half-life. In definitive 28-day GLP toxicology studies, OPN-6602 showed near dose-proportional increases in exposure over the dose range evaluated. These PK properties were specifically engineered to enable daily ‘pulsatile’ dosing. The potent selective inhibition of EP300 and CBP can be exploited to address several unmet medical needs through different mechanisms. In particular, a selective inhibitor of EP300 and CBP such as OPN-6602 has the potential to be a promising treatment for MM. Study Design and Methods: Study OPN6602-C01 is a Phase 1b, open-label study evaluating the safety, tolerability, PK, preliminary antitumor activity, and pharmacodynamics of OPN-6602 monotherapy and in combination with dexamethasone in subjects with relapsed and/or refractory MM. OPN-6602 as monotherapy or in combination with dexamethasone will be administered orally once daily in 21-day cycles. This study consists of 3 parts: Part 1a OPN-6602 monotherapy dose escalation (Part 1a), Part 1b OPN-6602 combination with dexamethasone dose escalation (Part 1b), and Part 2 dose expansion of the preferred regimen (Part 2) to select and optimize the dose with 1:1 randomization of at least 2 potential dose levels of 20 subjects at each dose level (ie, the provisional recommended Phase 2 dose [RP2D] identified in Part 1a or Part 1b and 1 additional dose level). Either OPN-6602 monotherapy or OPN-6602 in combination with dexamethasone will be selected for Part 2. Up to 130 total evaluable subjects will be enrolled across dose escalation and dose expansion. The primary objective and endpoint for Part 1a and Part 1b is to characterize the tolerability of OPN-6602 (with and without dexamethasone). Dose limiting toxicities, treatment-emergent adverse events and changes in safety and lab parameters will be characterized in order to identify the RP2D. The primary objective and endpoint for dose expansion of OPN-6602 monotherapy or in combination with dexamethasone is to evaluate the preliminary antitumor activity using overall response rate based on the 2011 International Myeloma Working Group (IMWG) response criteria. Eligibility criteria include a confirmed diagnosis of MM per IMWG criteria, disease that is relapsed or refractory to 3 or more different prior lines of therapy that include immunomodulatory agents, proteasome inhibitors and an anti-CD38 antibody, measurable disease and adequate hematologic, renal and liver function. This multi-center study (NCT06433947) is currently open in the United States with additional sites planned to open in Switzerland, United Kingdom and the European Union.

Redefining Clinical Response Criteria in Myelodysplastic Syndromes to Better Forecast Post-Transplant Outcomes

Redefining Clinical Response Criteria in Myelodysplastic Syndromes to Better Forecast Post-Transplant Outcomes

Response-spectrum-based design method for gain-scheduling control of active base-isolated structures with nonlinear viscous dampers

The response-spectrum-based design method has been developed for linear active base-isolation to eliminate numerical simulations and trial-and-error testing. On the other hand, gain-scheduling is an effective control method for nonlinear systems and provides a way to apply linear system design methods. In this paper, we extend the response-spectrum-based design method to incorporate the gain-scheduling control strategy for active base-isolated structures with nonlinear viscous dampers (NVDs), aiming to effectively control these structures and simplify the design process. The gain scheduling of the controller is achieved based on the linear time-varying viscous coefficient of NVDs. The active base-isolated structure with NVDs is described as a pseudo linear parameter varying model. The stability of the system is proven and analyzed using a common Lyapunov function. Moreover, this paper proposes a control-force spectrum for estimating the maximum required control force without numerical simulations. Numerical examples are used to validate the effectiveness of the proposed spectra. Finally, we also detail the design process and verify the design method through a design example. The results show that this method directly determines the design parameters from the spectra and satisfies the design criteria of response and control force without numerical simulations, offering a promising design approach for active control of buildings with nonlinear energy dissipating devices.

Early minimal residual disease eradication in light chain amyloidosis generates deeper and faster cardiac response

Minimal residual disease (MRD) is of growing interest in light chain (AL) amyloidosis and is associated with higher rates of cardiac response. A new graded cardiac response criteria has been proposed for better assessment of cardiac improvement. We evaluated MRD status in 63 patients with cardiac AL amyloidosis using next generation flow cytometry (sensitivity ≥ 1*10–5) within four cycles after treatment initiation and cardiac response kinetics. All patients were treated with first-line proteasome inhibitor (100%) and predominantly bortezomib (87.3%). The overall early MRD negative rates were 33.3%. Patients who achieved early MRD negativity were less likely to harbor t(11;14) (21.1% vs 57.5%, P = 0.009). The MRD negative rates amongst patients in hematologic complete response were 66.7% (14/21), and in very good partial response 29.2% (7/24). Early MRD negativity was associated with a higher likelihood of achieving ≥ cardiac partial response (≥ CarPR) (66.7% vs 38.1%, P = 0.032) and ≥ cardiac very good partial response (≥ CarVGPR) (38.1% vs 11.9%, P = 0.023) throughout first-line therapy. The cumulative incidence curve of achieving ≥ CarPR (P = 0.034) and ≥ CarVGPR (P = 0.026) showed significant difference between early MRD negative and positive group. After a median follow-up time of 27.2 months, the median progression free survival was longer in early MRD negative group (not reached vs 31.3 months, P = 0.033). Early MRD eradication in cardiac AL amyloidosis generated deeper and faster cardiac organ response.

Unilateral and bilateral theta burst stimulation for treatment-resistant depression: Follow up on a naturalistic observation study

ObjectivesTheta burst stimulation (TBS) is a novel and faster modality of transcranial magnetic stimulation, which is showing promise as a treatment-resistant depression (TRD) treatment. Though TBS can be applied unilaterally or bilaterally, few studies have compared the effectiveness of both approaches in a naturalistic clinical sample. In this retrospective chart review, we aimed to: (1) replicate previous bilateral sequential TBS effectiveness in a larger cohort of patients at a single centre, (2) present treatment outcome data between unilateral and bilateral TBS approaches, (3) investigate baseline factors associated with our observed outcomes, and (4) examine the sustainability of response, with follow-up data up to 6 months from patients. MethodsWe included 161 patients who received TBS (unilateral: n = 64 (40%), 45.55 ± 14.25 years old, 55% females; bilateral: n = 97 (60%), 47.67 ± 15.11 years old, 58% females). ResultsFirstly, we observed 47% response and 34% remission in the bilateral group, replicating findings from a smaller naturalistic study from our group; patients receiving unilateral TBS displayed 36% response and 26% remission, with no significant differences found between unilateral and bilateral TBS in remission and response rates. Secondly, bilaterally stimulated patients needed fewer treatments than those stimulated unilaterally (27 vs 29 on average respectively, t [159] = 3.31, p = .001), and had significantly lower anxiety symptoms post treatment (GAD-7) relative to patients receiving unilateral stimulation, F (1,148) = 3.95, p = .049. Thirdly, no baseline factors were found to predict treatment outcomes. Lastly, after six months, 69% of patients who met the response criteria did not require additional treatment or a change in medication. ConclusionsOur findings support the efficacy and tolerability of TBS in TRD and indicate that bilateral TBS may have a superior anxiolytic effect and offer a slightly faster time to response.

Clinical Presentation and Long-Term Survival Outcomes of Patients With Monoclonal Gammopathy of Renal Significance (MGRS): A Multicenter Retrospective Study.

MGRS are new rare clinical entities, whose recognition and optimal management is evolving. To implement real-life data, we retrospectively analysed a multicentre cohort of 60 patients with renal biopsy-proven MGRS receiving mainly novel treatments (between 2006 and 2021) in eight Italian centres. Based on renal biopsy, patients were divided into two subgroups: AL amyloidosis (70%, n = 42) and other-MGRS (30%, n = 18). Baseline characteristics follow typical manifestations of MGRS disorders in terms of small clonal burden, laboratory and clinical features. More patients with AL amyloidosis had monotypic lambda light-chain disease, estimated glomerular filtration rate (eGFR) ≥ 60 mL/min and nephrotic proteinuria than other-MGRS group. The most widely used drug was bortezomib, and about one-third of patients underwent ASCT. Overall response rate was 86% with no differences in the two subgroups. However, high-quality hematologic responses ≥very good partial response (VGPR) were greater in AL amyloidosis than in other-MGRS group (67% vs 28%, p = 0.015). The depth of haematological response influenced renal response, obtained in 32 (59%) of evaluable patients, similarly in the subgroups. Indeed, 75% patients with ≥ VGPR (p = 0.049) and none with stable disease (p ≤ 0.001) obtained a renal response. No association between renal response and histotypes (p = 0.9) or type of first-line therapy (p = 0.3) was found. At a median follow-up of 54.4 months (IQR 24.8-102.8), median progression-free survival (PFS) was 100.1 months (95% CI 34.9-NR), and median overall survival not reached (95% CI 129.8-NR). No significant difference emerged between the two groups in terms of survival outcomes. Achieving ≥ VGPR was confirmed as the main independent predictor of prolonged PFS in the general population (HR = 0.29, p = 0.023) and AL amyloidosis group (HR 0.23; p = 0.023). Preserved renal function at diagnosis was predictive of improved PFS in the AL amyloidosis group (eGFR ≥ 60 mL/min: HR = 0.003; p = 0.018; eGFR 30-60 mL/min: HR = 0.04, p = 0.046). Further research is warranted to develop standardised response criteria and treatment strategies to improve MGRS management.

Why Is the Group of Non-responders to Cardiac Resynchronization Therapy so Large? Some Ethical and Medical Aspects of the Topic

The aim of this single centre study (“St. Ekaterina” Hospital) is to assess the effect of a second successful cardiac resynchronization therapy (CRT) in patients who had already had an unsuccessful implantation of a CRT system at other medical centres in Bulgaria and were defined as “non-responders”. This is a prospective observational study. The patients have previously had an unsuccessful implantation of a left ventricular (LV) lead or the latter has not been placed in the target vessel. After the successful implantation of a new LV lead in another target vessel, the post-procedure criteria for echocardiographic (EchoCG) and clinical response were monitored. Over the period 2017–2019, 18 CRT systems have been implanted in 18 patients with an average age 65±1 years with initial heart failure (HF) according to the Classification of the New York Heart Association (NYHA) class III. The average LV ejection fraction (LVEF) was 28±1%. After the successful implantation of a new LV lead, patients presented with HF class II–III and LVEF 36±1%. In the new “upgrading” procedure, 15 patients (83%) had a good clinical and EchoCG response, and two of those 15 patients were “super responders”. The remaining three patients (17%) were “poor responders”. After the good clinical and echocardiographic response to the therapy with a second successful implantation of a LV lead in another target vessel, an important question arises, whether all “non-responders” to the CRT are actually supposed to be defined as such.

Efficacy of Tocilizumab in Refractory Graves Orbitopathy From Real-World Clinical Practice: An Observational Study.

The efficacy of tocilizumab (TCZ) in treating Graves orbitopathy (GO) remains uncertain due to the small sample sizes of earlier studies, and there is a lack of research on the drug for juvenile GO. To evaluate the effectiveness of TCZ in treating GO that is resistant to conventional therapy. This observational study at a tertiary care center included 79 Chinese GO patients, 15 of whom were pediatric patients, with 52 of these patients having moderate to severe active GO (all adult patients having steroid-resistant GO). Intravenous infusion of TCZ 8 mg/kg was given every 28 days for 4 months. Changes from baseline in visual acuity (VA), intraocular pressure (IOP), proptosis, clinical activity score (CAS), and thyrotropin receptor antibody (TRAb) levels throughout TCZ therapy were assessed at baseline (T0), the fifth month (T4), and follow-up (T5). Additionally, improvements in CAS by at least 2 points and CAS < 4 points at T4 and T5 were evaluated. Significant improvements were found in VA, IOP, proptosis, CAS, and TRAb levels in the adult group, and proptosis in the pediatric group at T5 (P < .05). Additionally, significant improvements were identified in TRAb levels and CAS (active GO at T0) in the pediatric group at T4 (P < .05). In the adult and pediatric group with active GO at T5, 71.4% and 60% experienced a decrease in CAS by ≥ 2 points, respectively; 89.3% and 60% achieved the response criterion of low activity disease (CAS < 4 points), respectively. TCZ emerged as a valuable therapeutic option for Chinese patients with active, corticosteroid-resistant, moderate to severe GO.

Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study

Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma. VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment. Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0-74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0-73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8-13·8). 52 (44%; 95% CI 35-53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3-4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported. These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile. Daiichi Sankyo.

Ketamine and chronic treatment-resistant depression: real-world practice and after relapse

BackgroundChronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients.MethodsIn this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months.Results23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts.ConclusionsIntroducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality.