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Clonal evolution (CE) is a driving force behind the development and progression of acute myeloid leukemia (AML). Advances in molecular and cytogenetic assays have improved the depth and breadth of detection of CE in AML, which is defined here as a detected change in cytogenetic or molecular profile at relapsed or refractory (RR) disease. In this study, we demonstrate the clinical impact of CE in a cohort of patients with RR AML treated between 2013 and 2023. We discovered CE is significantly more frequent in relapsed disease (58.2%, [46.6%, 69.2%]) than in refractory disease (21.1%, [14.4%, 29.2%], p < 0.001). CE negatively impacts prognosis when detected by conventional karyotyping in refractory disease (4.2 vs. 13.9 months, p < 0.011). In contrast with prior literature, CE had no impact on overall survival if detected in relapsed disease. Surprisingly, those who achieved negative measurable residual disease (MRD) were no more likely to eliminate their original clone than those who did not (p = 1). We found several cytogenetic and molecular signatures which may predispose to CE: aberrations of chromosome 17, trisomy 8, TP53, KRAS, and FLT3‐TKD. Finally, physicians were less likely to retreat those with CE with IC after receiving IC as first‐line therapy (35.0% vs. 70.9%, p = 0.004). This study illustrates the role of CE in chemotherapy‐resistant AML; we identify unique cytogenetic and molecular signatures that define a subset of patients associated with a dismal prognosis. As next‐generation sequencing panels expand and new methods to characterize cytogenetic abnormalities emerge, our findings establish a basis for future studies investigating the prognostic and therapeutic impact of CE. [ABSTRACT FROM AUTHOR]

Thrombotic Thrombocytopenic Purpura (TTP) is a thrombotic microangiopathy in which decreased activity of the von Willebrand Factor (vWF) multimer-cleaving protease ADAMTS13 leads to microvascular thrombosis. This condition can manifest as a pentad of symptoms that includes fever, thrombocytopenia, Microangiopathic Haemolytic Anemia (MAHA), renal disease and neurological disease. Authors hereby, detail the case of a 29-year-old female with a rare combination of TTP and Systemic Lupus Erythematosus (SLE), which presents challenges in diagnosis, clinical progression and therapeutic response. The patient had an unusual presentation of a ruptured ovarian cyst with haemoperitoneum, which was surgically treated with emergency laparotomy. This patient also presented with a malar rash, confusion, thrombocytopenia and haematuria, raising suspicion for SLE, which was confirmed with positive autoantibodies. Continued neurological deterioration led to subdural haemorrhage with generalised tonic-clonic seizures and refractory severe thrombocytopenia, treatment with intravenous methylprednisolone, suggesting an underlying haematological condition. Clinical findings, including schistocytes on peripheral smear, elevated lactate dehydrogenase and indirect bilirubin, prompted investigation for ADAMTS13 activity.

Abstract Background Despite advances in chemotherapy, the prognosis of adult acute myeloid leukemia (AML) patients remains poor, with a 5-year survival rate below 25%. In the tumor microenvironment of AML, tumor-associated macrophages (TAMs) are very important in the microenvironment of AML tumors because they help leukemic cells to survive, grow and migrate. They also play a key role in how the disease progresses. M2 macrophages highly express both CD206 (mannose receptor, C type I, and CD163 (hemoglobin scavenger receptor), a monocyte/macrophage receptor, as markers for M2 macrophages. Soluble CD206 (sCD206) and CD163 (sCD163) emerge as prognostic players for hematopoietic neoplasms. This study aimed to assess the prognostic potential of sCD206 and sCD163 as serological markers in AML. The study included 60 AML patients and 20 healthy volunteers as controls. The levels of serological markers sCD206 and sCD163 were measured by ELISA, and their prognostic values were evaluated. Results Serum levels of sCD206 and sCD163 were statistically significantly (P

Up to one-third of patients with classical Hodgkin lymphoma (cHL) are not responsive to first-line therapy or eventually relapse. Immune checkpoint inhibitors (ICIs) have been successfully employed to treat relapsed/refractory cHL (r/r cHL) but place patients at risk of financial toxicity. Early-phase trials and observational data suggest that low doses of ICIs may achieve similar results to those obtained with high doses. In this study, we report a single-center experience using low-dose nivolumab (LD-Nivo) in different combinations for r/r cHL, including monotherapy, LD-Nivo plus brentuximab vedotin (BV), and LD-Nivo plus chemotherapy. The primary outcome was to assess the efficacy of LD-nivo in patients with r/r cHL. We included 23 consecutive patients (median age 27 years; 57% female). LD-Nivo was prescribed in 40, 100, and 140 mg fixed doses Q2W. Survival analysis was performed employing the Kaplan–Meier method. 73% of patients achieved an overall response, 43% complete response, and 30% partial response. One-year overall survival was 94.4% (95% CI, 0.84–1), and the 1-year progression-free survival was 89.4% (95% CI, 0.77–1). OS and PFS were similar accross combinations. The median dose of nivolumab was 0.78 mg/kg (range, 0.62–1.11), and the median number of cycles until a response was documented was 6 (range, 2–9). During follow-up, 18 patients received transplantation (11 autologous, 6 allogeneic). No statistically significant differences in survival or response were detected between nivolumab combinations or doses. Adverse events were observed in 61% of the patients, with none grade 3–4. LD-Nivo demonstrated promising results in relapsed/refractory HL, highlighting its potential as a cost-effective treatment option. Further research is needed to validate these findings and guide clinical practice. [ABSTRACT FROM AUTHOR]

Background: Despite advances in chemotherapy, the prognosis of adult acute myeloid leukemia (AML) patients remains poor, with a 5-year survival rate below 25%. In the tumor microenvironment of AML, tumor-associated macrophages (TAMs) are very important in the microenvironment of AML tumors because they help leukemic cells to survive, grow and migrate. They also play a key role in how the disease progresses. M2 macrophages highly express both CD206 (mannose receptor, C type I, and CD163 (hemoglobin scavenger receptor), a monocyte/macrophage receptor, as markers for M2 macrophages. Soluble CD206 (sCD206) and CD163 (sCD163) emerge as prognostic players for hematopoietic neoplasms. This study aimed to assess the prognostic potential of sCD206 and sCD163 as serological markers in AML. The study included 60 AML patients and 20 healthy volunteers as controls. The levels of serological markers sCD206 and sCD163 were measured by ELISA, and their prognostic values were evaluated. Results: Serum levels of sCD206 and sCD163 were statistically significantly (P < 0.001) higher in AML cases than in controls. AML patients were categorized into two subgroups based on the response outcome to induction therapy: 36 patients (60%) had complete response (CR), and the other 24 patients (40%) had refractory disease. Interestingly, based on response outcome, serum levels of sCD206 and sCD163 as well as total leukocytic count (TLC), absolute neutrophils count (ANC) and absolute lymphocyte count (ALC) were significantly higher (all P < 0.001) in refractory group than in CR group. Further, a significant positive correlation of both sCD206 and sCD163 with TLC, ANC and ALC was observed (all P < 0.001). Conclusion: Levels of sCD206 and sCD163 emerge as promising prognostic biomarkers for AML outcome and progression. [ABSTRACT FROM AUTHOR]

Therapy for relapsed or refractory (R/R) aggressive B‐cell non‐Hodgkin lymphoma (aB‐NHL) post autologous stem cell transplantation (ASCT) or in elderly patients can be challenging. In this single‐center, single‐arm, phase II clinical study, we investigated the efficacy of ibrutinib (560 mg once daily) in combination with bendamustine and rituximab (IBR) given for six 28‐day cycles in their standard dose, to patients with R/R aB‐NHL who were either transplant ineligible in first or second relapse or post‐ASCT for second relapse. The primary endpoint was overall response rate (ORR). Fifty‐six patients (54% male, median age 69.7 years) were included. ORR was 49.1% among 55 patients treated with ≥ 1 cycle of IBR and 69.4% among 36 patients treated with ≥ 3 cycles. Patients with relapsed disease had significantly higher ORR compared to those with refractory disease (72.3% vs. 37.8%, p = 0.024). Median overall survival (OS) was 11.6 months (95% CI, 7.1–22.3) and median progression‐free survival was 5.3 months (95% CI, 2.5–7.4). Patients with complete and partial responses had significantly longer median OS compared to those with stable and progressive disease (28.1 vs. 5.2 months, p < 0.0001). Adverse events included thrombocytopenia (19.6%), anemia (16.1%), neutropenia (7.1%), fatigue (35.7%), diarrhea (28.6%) and nausea (28.6%). At the first efficacy evaluation 8 patients were referred to transplantation, and 3 more were referred during follow‐up. These data indicate that the IBR regimen is a safe and effective treatment option that can also be used for bridging to transplantation in patients with R/R aB‐NHL.Trial Registration:ClinicalTrials.gov: NCT02747732 [ABSTRACT FROM AUTHOR]

Background: With conventional standard treatment modalities, children and adolescents with Hodgkin lymphoma (HL) have long-term overall survival rates of over 90%. However, primary refractory disease may occur in 5%-10% of HL patients, while relapse occurs in 5%--10% of patients with early stage disease and up to 30% in an advanced stage. This retrospective study evaluated patient characteristics in cases of HL relapse and refractory and their response to second-line treatment of standalone chemotherapy or in combination with radiotherapy. Methodology: A retrospective study was conducted by Indus Hospital and Health Network to determine the outcomes of paediatric patients with first and second relapses of HL between 2013 and 2022. Results: A total of 742 patients were diagnosed with HL at Indus Hospital & Health Network. Of these, 48 (6.5%) patients presented with relapse and 35 (4.7%) with refractory disease after initial chemotherapy. In HL relapse patients, 57% were stage IV at initial diagnosis with the most common pathology being nodular sclerosis constituting 42.9% of patients. The most common age group was 6--10 years, 45.8%. B symptoms were experienced by 25 (52%) patients. A time to relapse of >12 months following diagnosis was seen in 69% and 3-12 months was seen in 31%. After receiving second-line treatment, complete remission was achieved by 34 (70.8%) patients, partial remission (PR) was seen in 5 (10.4%), disease progression in 5 (10.4%), 3 (6.3%) patients left during treatment and 1 (2.1%) had a treatment-related mortality. Reradiation in second-line treatment was only required for 2 patients. The second relapse was seen in 11 (28.2%) of 39 complete and PR patients. Conclusion: Major limitations in the treatment of HL relapse in a low-resource setting are the non-availability of immunotherapy and autologous stem cell transplantation due to extreme financial burden and lack of capacity in facilities. Dedicated efforts are required to provide these facilities free of cost in low--middle income countries (LMICs). [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatitis is a common cause of gastrointestinal upset in dogs. Despite its common occurrence, treatment options are limited, and veterinarians are often restricted to providing supportive and symptomatic care. In this study, we document the use of a mesenchymal stem cell (MSC) infusion in a small number of dogs with acute pancreatitis and compare it to a population of dogs receiving a routine standard-of-care treatment. In this pilot study, we found no significant differences in the measured biochemical or clinical score systems, but clinical improvements were noted in two dogs with previously refractory disease. While MSCs appear safe, larger trials are needed to investigate the use of this treatment in dogs with acute pancreatitis. MSCs may be considered by veterinarians for refractory disease, while additional data are pending. Mesenchymal stem cells (MSCs) have significant anti-inflammatory properties and are beneficial in rodent models of pancreatitis. The safety and efficacy of MSCs is unknown in dogs with acute pancreatitis (AP). Dogs with AP who were treated with MSCs (n = 4) were identified prospectively for this pilot study from an academic hospital. Serum Spec cPL and C-reactive protein (CRP) concentrations were measured on the day of MSC administration and 2 days later. The clinical severity, via the Modified Clinical Activity Index (MCAI), was also calculated. Two dogs received MSCs shortly after AP diagnosis, while the remaining dogs received MSCs due to clinically refractory disease. Changes in Spec cPL, CRP, and MCAI in the MSC-treated dogs were compared to a control population (n = 7) receiving the standard-of-care treatment for AP. No significant differences were noted between the populations for changes in Spec cPL (p = 0.79), CRP (p = 0.67), or MCAI (p = 0.91). However, subjective clinical improvements were noted within 24 h of MSC infusion in the two dogs with previously refractory disease. MSC infusions appear safe in the management of AP in dogs and may be considered in refractory disease. However, given the nature of this pilot study and its limitations, larger randomized controlled clinical trials are needed to truly evaluate the efficacy of MSC infusions in dogs with AP. [ABSTRACT FROM AUTHOR]

Primary and secondary non-response affects approximately 50% of patients with Crohns disease treated with anti-tumour necrosis factor (TNF) monoclonal antibodies. To date, very little single cell research exists regarding drug repurposing in Crohns disease. We aimed to elucidate the cellular phenomena underlying resistance to anti-TNF therapy in patients with Crohns disease and to identify potential drug candidates for these patients. Single-cell transcriptome analyses were performed using data (GSE134809) from the Gene Expression Omnibus and Library of Integrated Network-Based Cellular Signatures L1000 Project. Data aligned to the Genome Reference Consortium Human Build 38 reference genome using the Cell Ranger software were processed using the Seurat package. To capture significant functional terms, gene ontology functional enrichment analysis was performed on the marker genes. For biological analysis, 93,893 cells were retained (median 20,163 genes). Through marker genes, seven major cell lineages were identified: B-cells, T-cells, natural killer cells, monocytes, endothelial cells, epithelial cells, and tissue stem cells. In the anti-TNF-resistant samples, the top 10 differentially expressed genes were HLA-DQB-1, IGHG1, RPS23, RPL7A, ARID5B, LTB, STAT1, NAMPT, COTL1, ISG20, IGHA1, IGKC, and JCHAIN, which were robustly distributed in all cell lineages, mainly in B-cells. Through molecular function analyses, we found that the biological functions of both monocyte and T-cell groups mainly involved immune-mediated functions. According to multi-cluster drug repurposing prediction, vorinostat is the top drug candidate for patients with anti-TNF-refractory Crohns disease. Differences in cell populations and immune-related activity within tissues may influence the responsiveness of Crohns disease to anti-TNF agents. Vorinostat may serve as a promising novel therapy for anti-TNF-resistant Crohns disease.

Abstract Background The current EULAR definition of difficult-to-treat rheumatoid arthritis (D2T-RA) identifies patients with active disease refractory to multiple treatments at a single time point, without considering the persistence of this condition over time. The study aimed to assess difficult-to-treat rheumatoid arthritis (D2T-RA) over 12 months, considering persistence over time rather than a single time point, in a real-life cohort. Methods In a single-center real-life cohort, demographic and clinic data were cross-sectionally collected for each patient at baseline and retrospectively over the previous 12 months bimonthly. For each timepoint, the prevalence of D2T-RA patients was calculated, and patients meeting the EULAR definition for at least 6 months were defined as persistent D2T-RA (pD2T-RA). Finally, the clinical characteristics associated with the time-based definition of pD2T-RA were analyzed. Results Among 610 adult RA patients, 104 were refractory to ≥ 2 treatments. Initially, 41.3% met D2T-RA criteria, but only 27.9% fulfilled persistent D2T-RA (pD2T-RA) criteria over 6 months. The pD2T-RA group was associated with male gender, higher HAQ and Charlson Comorbidity Index scores, more failed treatments, and use of non-NSAID analgesics. Logistic regression linked pD2T-RA to higher SDAI and CRP values, and the use of glucocorticoids or analgesics. Chronic use of glucocorticoids was strongly associated with pD2T-RA. Conclusions The application of a temporal criterion allowed for the selection of a subgroup of pD2T-RA patients who differ from those who meet the definition of D2T-RA only episodically. Chronic use of glucocorticoids was the factor most strongly associated with pD2T-RA status.

We present a challenging case of a patient admitted to an intensive care unit with influenza-associated pulmonary aspergillosis (IAPA). The clinical course was characterised by refractory fungal pneumonia and tracheobronchitis, suspected drug-induced liver injury due to triazole antifungals, and secondary bacterial infections with multidrug-resistant microorganisms, resulting in a fatal outcome despite the optimisation of antifungal treatment through therapeutic drug monitoring. This case underscores the complexity that clinicians face in managing critically ill patients with invasive fungal infections. [ABSTRACT FROM AUTHOR]

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Background: Relapse and refractory (R/R) rates after first‐line R‐CHOP in diffuse large B cell lymphomas (DLBCL) are ~40% and ~15% respectively. Aims: We conducted a retrospective real‐world analysis aimed at evaluating clinical outcomes of R/R DLBCL patients. Material and Methods: Overall, 403 consecutive DLBCL patients treated in two large hematological centers in Torino, Italy were reviewed. Results: At a median follow up of 50 months, 5‐year overall survival from diagnosis (OS‐1) was 66.5%, and 2‐year progression free survival (PFS‐1) was 68%. 134 (34.4%) patients relapsed (n = 46, 11.8%) or were refractory (n = 88, 22.6%) to R‐CHOP. Most employed salvage treatments included platinum salt‐based regimens in 38/134 (28.4%), lenalidomide in 14 (10.4%). Median OS and PFS after disease relapse or progression (OS‐2 and PFS‐2) were 6.7 and 5.1 months respectively. No significant difference in overall response rate, OS‐2 or PFS‐2 in patients treated with platinum‐based regimens versus other regimens was observed. By multivariate analysis, age between 60 and 80 years, germinal center B cell type cell of origin and extranodal involvement of <2 sites were associated with better OS‐2. Discussion: Our findings confirm very poor outcomes of R/R DLBCL in the rituximab era. Widespread approval by national Medicine Agencies of novel treatments such as CAR‐T cells and bispecific antibodies as second‐line is eagerly awaited to improve these outcomes. [ABSTRACT FROM AUTHOR]

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of non-Hodgkin's lymphoma that predominantly affects young females. Despite advances in the understanding of its biology, there is still no consensus on the optimal treatment strategy. First-line regimens such as R-CHOP and DA-EPOCH-R result in 2-year progression--free survival (PFS) rates of c.80% and overall survival (OS) rates of c.90%. However, the role of radiotherapy as a consolidation treatment remains unclear, with some studies suggesting limited benefits for patients with negative PET scans at the end of treatment. In cases of relapse or refractoriness, second-line therapies are comparable to those employed in the treatment of diffuse large B-cell lymphoma. Autologous stem cell transplantation remains a crucial salvage option, with 3-year OS and PFS rates of c.65% and 60%, respectively. New treatment approaches, including immune checkpoint inhibitors (e.g. pembrolizumab and nivolumab), chimeric antigen receptor-T (CAR-T) cell therapy, and bispecific antibodies, have demonstrated promising results. Further research into novel molecular targets and treatment combinations is necessary to improve clinical outcomes and minimize treatment-related toxicities in PMBCL. [ABSTRACT FROM AUTHOR]

The outcome of patients with metastatic colorectal cancer (mCRC) has improved significantly in the last few decades. Metastatic colorectal cancer is a highly heterogenous cancer. Beyond second line chemotherapy, treatment decisions are often based on molecular testing. In this narrative review, we provide a comprehensive summary of data from key clinical trials and discuss how to integrate these agents into the current treatment landscape of metastatic colorectal cancer. In the era of precision medicine, molecular testing plays an increasingly important role in the management of mCRC. Efforts need to be made to target treatment based on molecular test results. [ABSTRACT FROM AUTHOR]

Data on the efficacy of high-dose chemotherapy and autologous stem cell transplantation (ASCT) for classical Hodgkin lymphoma (cHL) patients who failed a PET-driven first-line therapy are limited. We retrospectively evaluated 220 adult cHL patients who underwent ASCT from 2009 to 2021 at 11 centers in Italy. Overall, 49.5% had refractory disease, 23.2% relapsed < 12 and 27.3% ≥12 months from the end of first-line chemotherapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 73.8% and 89.4%. In univariable analysis for PFS events PET-2+ (HR 2.69, p =.001), anemia (HR 2.22, p =.019), refractory disease (HR 1.76, p =.045), less than CR before ASCT (HR 3.24, p <.001) and >2 lines of salvage therapy (HR 2.52; p =.004) were associated with a higher risk of failure after ASCT. In multivariable analysis, >2 lines of salvage therapy (HR 3.28, p =.004) and RT before ASCT (HR 3.00, p = 0.041) retained significance. ASCT is an effective salvage approach for cHL patients treated in the era of PET-adapted therapies. [ABSTRACT FROM AUTHOR]

To recognize patients at high risk of refractory disease, the identification of novel prognostic parameters improving stratification of newly diagnosed Hodgkin Lymphoma (HL) is still needed. This study investigates the potential value of metabolic and texture features, extracted from baseline 18F‐FDG Positron Emission Tomography/Computed Tomography (PET) and Contrast‐Enhanced Computed Tomography scan (CECT), together with clinical data, in predicting first‐line therapy refractoriness (R) of classical HL (cHL) with mediastinal bulk involvement. We reviewed 69 cHL patients who underwent staging PET and CECT. Lesion segmentation and texture parameter extraction were performed using the freeware software LIFEx 6.3. The prognostic significance of clinical and imaging features was evaluated in relation to the development of refractory disease. Receiver operating characteristic curve, Cox proportional hazard regression and Kaplan‐Meier analyses were performed to examine the potential independent predictors and to evaluate their prognostic value. Among clinical characteristics, only stage according to the German Hodgkin Group (GHSG) classification system significantly differed between R and not‐R. Among CECT variables, only parameters derived from second order matrices (gray‐level co‐occurrence matrix (GLCM) and gray‐level run length matrix (GLRLM) demonstrated significant prognostic power. Among PET variables, SUVmean, several variables derived from first (histograms, shape), and second order analyses (GLCM, GLRLM, NGLDM) exhibited significant predictive power. Such variables obtained accuracies greater than 70% at receiver operating characteristic analysis and their PFS curves resulted statistically significant in predicting refractoriness. At multivariate analysis, only HISTO_EntropyPET extracted from PET (HISTO_EntropyPET) and GHSG stage resulted as significant independent predictors. Their combination identified 4 patient groups with significantly different PFS curves, with worst prognosis in patients with higher HISTO_EntropyPET values, regardless of the stage. Imaging radiomics may provide a reference for prognostic evaluation of patients with mediastinal bulky cHL. The best prognostic value in the prediction of R versus not‐R disease was reached by combining HISTO_EntropyPET with GHSG stage. [ABSTRACT FROM AUTHOR]

We report the case of 2 patients with relapsed/refractory peripheral T-cell lymphoma treated with valemetostat tosylate, a selective dual inhibitor of histone-lysine N-methyltransferases enhancer of zest homolog 1 and 2, and subsequently bridged to allogeneic stem cell transplantation. Valemetostat led to a quick response and was well tolerated, offering a promising bridge therapy to transplantation for patients with relapsed/refractory peripheral T-cell lymphoma, which is still an unmet medical need. [ABSTRACT FROM AUTHOR]

Platelet parameters have been recognized as important markers for disease severity in various types of diseases. The aim of our study was to investigate whether platelet count could be used as a potential predictor of refractory Takayasu arteritis (TAK). In this retrospective study, fifty-seven patients were selected as development data group to identify the associated risk factors and potential predictors of refractory TAK. Ninety-two TAK patients were included in the validation data group to verify the predictive value of platelet count for refractory TAK. Refractory TAK patients had higher levels of platelet (PLT) than non-refractory TAK patients (305.5 vs. 272.0 × 109/L, P = 0.043). For PLT, the best cut-off value was 296.5 × 109/L to predict refractory TAK. Elevated PLT (> 296.5 × 109/L) was found to be statistically related to refractory TAK (OR [95%CI] 4.000 [1.233–12.974], p = 0.021). In the validation data group, the proportion of refractory TAK in patients with elevated PLT was significantly higher than that in patients with non-elevated PLT (55.6% vs. 32.2%, P = 0.037). The 1-, 3- and 5-year cumulative incidence of refractory TAK were 37.0%, 44.4% and 55.6% in patients with elevated PLT, respectively. Elevated PLT (p = 0.035, hazard ratio (HR) 2.106) was identified as a potential predictor of refractory TAK. Clinicians should pay close attention to platelet levels in patients with TAK. For TAK patients with PLT greater than 296.5 × 109/L, closer monitoring of the disease and comprehensive assessment of disease activity are recommended to be alert to the occurrence of refractory TAK. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to determine whether there is a relationship between the age at diagnosis and the clinical, laboratory, and prognostic features in pediatric immunoglobulin A vasculitis (IgAV) patients. Patients and methods: In this study, 539 pediatric IgAV patients (298 males, 241 females; mean age: 7.74±3.36 years; range, 1 to 17.8 years) were retrospectively evaluated between January 2005 and July 2020. The relationship between clinical findings and age at diagnosis was analyzed by univariate logistic regression analysis. Factors associated with renal involvement, steroid-dependent or refractory disease, and recurrence were examined. Results: The median age of diagnosis was 7.1 (1-17.8) years in all patients. At the time of admission, purpura, abdominal pain, and arthritis were the most common clinical findings. At the time of diagnosis, there was a positive association between age and purpura and an inverse association with the presence of arthritis. There were associations between renal involvement and age at diagnosis (odds ratio=1.22, 95% confidence interval 1.13-1.31, p<0.001), follow-up time (p<0.001), no history of previous infection (p<0.001), and presence of gastrointestinal (GI) involvement (p=0.003). Significant relationships were found between the age at diagnosis, follow-up time, GI involvement, renal involvement, scrotal involvement, the C-reactive protein value at the time of diagnosis, and the presence of steroid-dependent disease. An association was found between recurrence and GI involvement. All refractory patients had renal involvement. Age at diagnosis (p<0.001) and follow-up time (p<0.001) was found to be associated with refractory disease. Conclusion: Age at diagnosis and follow-up time may be associated with renal involvement and refractory and steroid-dependent disease in IgAV. In addition, there may be a relationship between steroid-dependent disease and renal, GI, and scrotal involvement and between GI involvement and recurrence. [ABSTRACT FROM AUTHOR]

Purpose of Review: We review the recent practice-changing trials of anti-CD19 chimeric antigen receptor (CAR) T cell therapies in large B cell lymphoma (LBCL) including phase 3 comparisons with second-line standard-of-care (SOC) and phase 2 investigations in transplant-ineligible patients or as part of first-line treatment. Recent Findings: ZUMA-7 found significantly improved overall survival and event-free survival (EFS) with axicabtagene ciloleucel (axi-cel) versus SOC of salvage chemotherapy followed by autologous stem-cell transplantation. This represents the first such survival improvement in nearly 30 years for early-relapsed or refractory (r/r) LBCL. TRANSFORM demonstrated prolonged EFS for lisocabtagene maraleucel (liso-cel) versus SOC but BELINDA did not for tisagenlecleucel. Second-line CAR T cell was a viable curative-intent therapy in elderly (ZUMA-7; axi-cel) and/or transplant-ineligible (PILOT; liso-cel) patients. ZUMA-12 demonstrated effectiveness for axi-cel as part of first-line treatment for high-risk LBCL. Summary: These results support a role for CAR T cell therapy as new second-line SOC for r/r LBCL and highlight its potential evolution into future first-line treatment for high-risk disease. [ABSTRACT FROM AUTHOR]

Summary: Defining immune thrombocytopenia (ITP) in two age groups—children and adults—overlooks the specific clinical features and needs of adolescents and young adults (AYAS). We previously reported a high risk of chronic disease at 12 months (50%); however, data on the course of chronic ITP, the risk of refractoriness and treatment strategies in AYAS are limited. Data from patients aged 12–25 years with chronic primary ITP at 12 months were extracted from three large registries between 2004 and 2021. Clinical and laboratory data were evaluated until 48 months of follow‐up (FU). Refractory ITP was defined as the administration of ≥3 different lines of therapy. A total of 427 AYAS (64% female) with chronic ITP were included. Overall, 7% and 14% were classified as 'refractory' at 12 and 48 months of FU respectively. The proportion of males was greater in the refractory group than in the non‐refractory group (43% vs. 35%). AYAS with refractory disease displayed lower median platelet counts, more bleeding and a higher need for treatment at initial diagnosis and FU than non‐refractory patients. This study reveals that refractory ITP is uncommon in AYAS; however, AYAS with refractory ITP display a high disease burden at all time points, including at initial diagnosis. [ABSTRACT FROM AUTHOR]

Primary and secondary non-response affects approximately 50% of patients with Crohn's disease treated with anti-tumour necrosis factor (TNF) monoclonal antibodies. To date, very little single cell research exists regarding drug repurposing in Crohn's disease. We aimed to elucidate the cellular phenomena underlying resistance to anti-TNF therapy in patients with Crohn's disease and to identify potential drug candidates for these patients. Single-cell transcriptome analyses were performed using data (GSE134809) from the Gene Expression Omnibus and Library of Integrated Network-Based Cellular Signatures L1000 Project. Data aligned to the Genome Reference Consortium Human Build 38 reference genome using the Cell Ranger software were processed using the Seurat package. To capture significant functional terms, gene ontology functional enrichment analysis was performed on the marker genes. For biological analysis, 93,893 cells were retained (median 20,163 genes). Through marker genes, seven major cell lineages were identified: B-cells, T-cells, natural killer cells, monocytes, endothelial cells, epithelial cells, and tissue stem cells. In the anti-TNF-resistant samples, the top 10 differentially expressed genes were HLA-DQB-1, IGHG1, RPS23, RPL7A, ARID5B, LTB, STAT1, NAMPT, COTL1, ISG20, IGHA1, IGKC, and JCHAIN, which were robustly distributed in all cell lineages, mainly in B-cells. Through molecular function analyses, we found that the biological functions of both monocyte and T-cell groups mainly involved immune-mediated functions. According to multi-cluster drug repurposing prediction, vorinostat is the top drug candidate for patients with anti-TNF-refractory Crohn's disease. Differences in cell populations and immune-related activity within tissues may influence the responsiveness of Crohn's disease to anti-TNF agents. Vorinostat may serve as a promising novel therapy for anti-TNF-resistant Crohn's disease. [ABSTRACT FROM AUTHOR]

Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease.Key Points:Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy.There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months.SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs.Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies.

Background: Allogeneic transplant is an effective salvage therapy in patients with Hodgkin lymphoma (HL) relapsed or refractory (R/R) to previous treatments. In recent years, immunotherapies (conjugated antibody and checkpoint inhibitors [CPI]) showed interesting results and were used as bridge therapies to allotransplant. Aim: The aim of this retrospective study in Lazio region was to evaluate the impact of these new therapies on outcome after allogeneic hematopoietic stem cell transplantation (allo-SCT) in comparison with standard chemotherapies used in the past. Methods: We selected all consecutive patients with diagnosis of HL transplanted in four hematology transplant units, and we collected data obtained from patients' records concerning all the treatments before allo-SCT. Results: A total of 56 patients were enrolled in this study. All patients underwent allo-SCT for R/R HL. Seventeen patients (30%) received chemotherapy prior to allo-SCT (group B); they were treated between 2008 and 2015; and 39 patients (70%) received brentuximab vedotin (BV), CPI, or both before allo-SCT as a bridge to transplant (group A); they were treated between 2012 and 2020. Twenty-five patients were treated with BV alone, 2 with CPI alone, and 12 first with BV and then with CPI. No patient received concomitant BV and CPI. At 5 years from allo-SCT, overall survival (OS) was 59% and progression-free survival (PFS) was 65%. No statistical differences in OS or PFS were observed between patients in groups A and B. Relapse was significantly associated with a lower survival. The only factor associated with a reduced risk of relapse was development of any grade acute graft versus host disease (GVHD) (p > 0.02). Conclusions: This regional real-world experience shows the changes that have taken place in the last 10 years in R/R HL using new drugs to render a patient eligible for allo-SCT. This strategy appears to guarantee an impressive disease control with an increased risk of complications, for example, aGVHD, that appear to nullify this advantage at least in part. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to explore patients' and clinicians' understanding and experiences of refractory disease (RD) and persistent physical and emotional symptoms (PPES) in patients with inflammatory arthritis (IA), namely rheumatoid arthritis or polyarticular juvenile idiopathic arthritis from their perspectives through interviews and/or focus groups., Design: A qualitative study was conducted, following a pragmatic epistemology approach with framework analysis employed., Methods: Semi-structured interviews or focus groups with IA patients (n = 25) and multi-disciplinary rheumatology HCPs (n = 32) were conducted at one time point to obtain participants respective understanding and experiences of managing RD/PPES, and its impact on the patient-professional relationship., Results: Three key themes were identified from both patients and professionals' experiences of RD/PPES: (1) relevant treatment experiences, (2) symptoms (with or without inflammation) and (3) impact: physical, psychological and social. These themes included 28 specific categories that would be considered as components characterizing RD/PPES, most common to both patients and HCPs with six being patient-specific and only one HCP-specific. The specific biopsychosocial symptoms and impacts of RD/PPES pertain to pain, fatigue, stiffness, joint involvement and physical, psychological and social functioning and quality of life, covering disease-related distress, mobility and independence. Wider influential factors such as comorbidities, non-adherence, health/medication beliefs and behaviours and social support were also identified., Conclusion: Common persistent symptoms that have both mental and physical impact characterize RD/PPES in IA and therefore a more integrated holistic approach to treatment is needed from multi-disciplinary HCPs, including health psychologists., (© 2025 The Author(s). British Journal of Health Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease. Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy. There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months. SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs. Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies. [ABSTRACT FROM AUTHOR]

L'amylose systémique à chaînes légères (AL) d'immunoglobulines est caractérisée par le dépôt de fibrilles amyloïdes de chaînes légères produites par des plasmocytes clonaux CD38 +, entraînant un dysfonctionnement des organes. L'atteinte cardiaque a une valeur pronostique majeure. La chimiothérapie antiplasmocytaire réduit la synthèse des chaînes légères des immunoglobulines (précurseurs des dépôts amyloïdes). Nous décrivons un cas d'amylose AL chez une patiente de 95 ans. Notre patiente a mal répondu au traitement par rituximab, cyclophosphamide-bortézomib-dexaméthasone et rituximab-bendamustine. Finalement le daratumumab, anticorps anti-CD38, a été associé à la meilleure réponse hématologique sans effet indésirable significatif. En conclusion, notre cas suggère que le daratumumab est une alternative à la chimiothérapie efficace et bien tolérée dans le traitement de l'amylose AL des patients très âgés. Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38 + plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Extra-Nodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoma representing approximately 5-10% of T-cell non-Hodgkin lymphomas diagnosed in the United States each year. Patients with advanced stage III/IV ENKL and relapsed refractory ENKL have a poor prognosis even despite aggressive therapy and stem cell transplantation (SCT). We conducted a review of the management of 37 patients with advanced-stage and relapsed/refractory ENKL in a predominantly non-Asian cohort evaluating both chemotherapy and SCT outcomes. PATIENTS AND METHODS: We evaluated clinical outcomes in all patients treated for advanced stage III/IV or relapsed/refractory ENKL at MD Anderson cancer center between 2000-2014. Next, we collected stem cell transplant data from four transplant institutions to further evaluate outcomes of both allogeneic (allo-SCT) and autologous (auto-SCT) stem cell transplantation in ENKL. RESULTS: OS and PFS were 73% and 45% at one year, and 30% and 19% at 3-years, respectively. SMILE chemotherapy was more effective in maintaining a CR compared to CHOP (83% vs 17%). Only achievement of CR was prognostic for OS (HR 0.245, p=0.002) and PFS (HR 0.072, p) CONCLUSION: Our results suggest that achievement of a CR is imperative in patients with advanced ENKL, and is desirable for any patient for whom auto-SCT is utilized. SMILE-based chemotherapy appeared effective in attaining a CR, and was also an effective salvage regimen. For patients attaining a first CR, auto-SCT should be strongly considered, but should definitely be utilized in patients attaining CR2. For patients with refractory disease, allo-SCT can be considered in a selected group of patients.

Mycosis fungoides (MF) is the most common subtype of primary cutaneous T cell lymphoma (CTCL). The erythrodermic form (T4) especially impairs health-related quality of life (HR-QoL), making patients often incapable of self-care. Mycosis fungoides and Sézary syndrome (SS) are immunogenic neoplasms and can be recognized by the patient’s immune system. The disease is chronic and immunotherapy allows for long-term control of CTCL. The paper presents a description of 2 cases of nivolumab use in the salvage treatment of erythroderma in the course of refractory mycosis fungoides. Nivolumab was used as emergency treatment, and previously patients exhausted the available treatment options. The discussed cases confirm the effectiveness of immunotherapy in the treatment of primary cutaneous T cell lymphomas. The applied treatment achieved the effect of more than one year of response (15 months), as well as a significant benefit in terms of subjective and objective quality of life. The effect was mainly related to the condition of the skin. The use of the PD-1 checkpoint inhibitor allowed for over 12 months of control in advanced, refractory and heavily pretreated cutaneous lymphoma, and was very well tolerated. More research is needed on the use of such inhibitors in the treatment of cutaneous lymphomas.

Kai-Cai Liu,1 Wei-Fu lv,2 Dong Lu,2 Chang-Long Hou,2 Jun Xie,3 Yu-He Lu,4 Qi-Sheng Cao,5 Yu-Lin Tan,6 Ying-Zhan Zhang,7 Jie Liu8 1Infection Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of China; 2Department of Interventional Radiology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of China; 3Department of Interventional Radiology, Fuyang People’s Hospital, Fuyang, People’s Republic of China; 4Department of Interventional Radiology, Chuzhou First People’s Hospital, Chuzhou, People’s Republic of China; 5Department of Interventional Radiology, Ma’anshan People’s Hospital, Ma’anshan, People’s Republic of China; 6Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China; 7Department of Interventional Radiology, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China; 8Department of Interventional Radiology, Yingshang People’s Hospital, Fuyang, People’s Republic of ChinaCorrespondence: Wei-Fu lv; Dong LuDepartment of Interventional Radiology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of ChinaEmail weifulv@ustc.edu.cn; ahslludong@163.comPurpose: To investigate the potential safety and efficacy of drug-eluting bead-transcatheter arterial chemoembolization (DEB-TACE) in treating TACE-refractory hepatocellular carcinoma (HCC).Methods: We retrospectively evaluated the treatment outcomes of DEB-TACE for 41 HCC nodules in 30 patients who were refractory to conventional TACE (c-TACE) according to tumor response. The antitumor response was evaluated according to mRECIST criteria, and changes in alpha-fetoprotein (AFP), albumin-bilirubin score, the incidence of adverse events, and the time to disease progression were observed.Results: The objective response rate and disease control rates were 60.98% and 95.12% at 4 weeks after DEB-TACE, 63.41% and 92.68% at 8 weeks, respectively. The median time of disease progression was 4.60 ± 0.23 months. The AFP of patients decreased continuously at 2– 6 weeks after operation, and the AFP at 4 weeks was significantly lower than that at 2 weeks (P = 0.038). Adverse reactions were well tolerated, and no grade 4 adverse reactions were reported. The albumin-bilirubin score did not deteriorate within 6 weeks.Conclusion: DEB-TACE has potential efficacy and safety after failure of c-TACE in patients with advanced liver cancer. Further studies are needed to confirm the efficacy of DEB-TACE treatment after failure of c-TACE.Keywords: transcatheter arterial chemoembolization, refractory disease, drug-eluting bead, hepatocellular carcinoma, efficacy

BackgroundDespite the introduction of effective, novel agents, the outcome of patients with refractory multiple myeloma remains poor, particularly those who are refractory to both proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). Limited data are available on the role of autologous hematopoietic stem cell transplantation in this population.MethodsPatients with refractory myeloma who underwent first autologous hematopoietic stem cell transplantation (auto-HCT) between March 2000 and October 2015 were retrospectively analyzed. Those who had primary refractory disease and those with relapsed and refractory disease were included. Disease that was refractory to at least 1 PI and at least 1 IMiD was classified as double-refractory multiple myeloma (DR-MM).ResultsIn total, 233 patients were identified, including 105 (45%) classified with DR-MM and 128 (55%) classified with nondouble-refractory myeloma (NDR-MM). At a median follow-up of 42 months for surviving patients, at least a partial response was observed in 188 patients (81%; 83 patients in the DR-MM group [79%] and 105 patients in the NDR-MM [82%]; P = .77). A near complete response or better was observed in 52 patients (22%; 25 patients in the DR-MM group [24%] and 27 patients in the NDR-MM group [21%]; P = .77). The median progression-free survival was 17.6 months (14.4 months in the DR-MM group and 18.2 months in the NDR-MM group), and the 2-year progression-free survival rate was 38% (35% in the DR-MM group and 40% in the NDR-MM group; P = .40). The median overall survival was 48 months (38.9 months in the DR-MM group and 56.6 months in the NDR-MM group), and the 2-year overall survival rate was 74% (71% in the DR-MM group and 76% in the NDR-MM group; P = .27).ConclusionsThe current findings indicate that auto-HCT is an effective and safe therapy in patients with refractory multiple myeloma, including those who are refractory to IMiDs and PIs. Cancer 2017;123:3568-75. © 2017 American Cancer Society.

PRECONNECT is a multicenter study demonstrating the efficacy and tolerability of trifluridine/tipiracil in adult patients with histologically confirmed adenocarcinoma of the colon or rectum and pretreated metastatic lesions. The current article describes the characteristics and outcomes of the Brazilian cohort of patients who underwent trifluridine/tipiracil therapy within PRECONNECT. Brazilian patients (n=55) received oral trifluridine/tipiracil 35mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was safety including time to ECOG (Eastern Cooperative Oncology Group) PS (performance status) deterioration, and the secondary endpoints included progression-free survival (PFS) and quality of life (QoL). Baseline characteristics showed only 34.5% of patients underwent ≥3 lines of treatment, 29.1% presented ≥3 metastatic sites and 52.7% showed an ECOG PS of 0. The disease control rate (DCR) was 32.0% and 28.6% in patients with one and two metastatic sites, respectively, the median PFS was 3.0 months (95%CI: 2.5-3.4), and the time to ECOG PS deterioration (≥2) was 5.4 months. Drug-related treatment-emergent adverse events (TEAE) were observed at least once in 87.3% of patients, and the most common (≥40% of patients) hematological TEAEs were neutropenia and anemia; there was no febrile neutropenia case. The shorter time to ECOG PS deterioration showed in the Brazilian subset of patients is likely due to late diagnosis setting compared to the global population, despite that trifluridine/tipiracil showed good DCR results, including patients with two metastatic sites. In conclusion, safety and efficacy results provide confidence in routine practice use and are in line with the PRECONNECT study

Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2- targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Objectives: Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor. Methods: Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second‐line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate. Result: We performed a biomarker analysis of programmed death ligand‐1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high‐dose chemotherapy. The median number of nivolumab doses was 3 (range 2–46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well‐tolerated, with only two Grade 3 adverse events observed. Programmed death ligand‐1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand‐1 is unreliable to measure response. Conclusions: Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response. [ABSTRACT FROM AUTHOR]

Abstract Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a very rare lymphoma with an aggressive clinical course and a dismal outcome. The prognosis is linked to a pronounced resistance to chemotherapy and radiotherapy. No standard treatment approach is defined due to the low frequency of the disease and lack of prospective studies. CD30 is expressed in almost half of the cases of PCGD-TCL, which offers a potential therapeutic option. We report the successful treatment of a 68-year-old man who suffered PCGD-TCL with a combination of Brentuximab Vedotin and Gemcitabine after the failure of two lines of previous chemotherapy. CD30 expression was only partial. The treatment was very well tolerated and allowed the patient to benefit from allogeneic hematopoietic stem cell transplantation.

Summary: As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third‐line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO‐DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5‐year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third‐line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third‐line therapy can be cured. [ABSTRACT FROM AUTHOR]

Objectives The aim was to evaluate the proportion of RA patients who are refractory to multiple targeted therapies (TTs) in a real-world cohort of patients in a tertiary rheumatology referral centre, to describe patterns of drug sequencing associated with the development of refractory RA (RefRA) and to identify whether there is a subgroup of RefRA patients in whom successive drugs have shown primary lack of efficacy. Methods Patients at a single centre were defined as refractory if they had failed two or more classes of TT and were identified from a dedicated TT clinic database. Reasons for drug failure were recorded, and patients were categorized pragmatically as having mild [failure of two biologic DMARD (bDMARD) classes], moderate [failure of at least three bDMARD classes] or severe [failure of at least two bDMARD classes and JAK inhibitor] refractory disease. Results One hundred and seventy-two patients were identified as RefRA (>10% of our TT-exposed cohort); median [interquartile range (IQR)] TT exposures of four (two), 81.5% female, 82% seropositive, mean (s. d.) age of 63 (12.3) years. Detailed analysis of 60 patients showed a median (IQR) disease duration of 22 (10.75) years, median (IQR) time from diagnosis to initiation of first TT of 5 (10) years, and mean (s. d.) baseline DAS28CRP before starting first-line TT of 5.91 (0.84). Among RefRA patients, 15% were severely refractory, and 6% had demonstrated no clinical response to any TT. Conclusion A small proportion of patients have true RefRA. Most patients fail multiple therapies owing to a combination of inefficacy and adverse events. [ABSTRACT FROM AUTHOR]

Abstract Background Biological therapies have improved the clinical course and quality of life of rheumatoid arthritis (RA) patients. Despite the availability and effectiveness of these treatments, some patients experience multiple failures to biologic disease-modifying antirheumatic drugs (bDMARDs), constituting a particular challenge to clinicians. Objectives This study aims to determine the percentage of rheumatoid arthritis (RA) patients who fail to respond to subsequent bDMARDs, describe their characteristics, and identify specific baseline and early features during the first bDMARD as possible predictors of consecutive multiple bDMARD failure. Methods This is a longitudinal study involving RA patients from the prospective biological cohort drawn from the La Paz University Hospital RA Registry (RA-Paz), starting a bDMARD during the years 2000 to 2019. Patients who presented insufficient response (due to primary or secondary inefficacy) to at least three bDMARDs or two bDMARDs with different mechanism of action were considered multi-refractory (MR-patients). Patients who achieved low disease activity or remission (by DAS-28) with the first bDMARD and maintained this over a follow-up period of at least 5 years were considered non-refractory (NR-patients). Results A total of 41 out of 402 (10%) patients were MR-patients and 71 (18%) NR-patients. In the multivariate analysis, the presence of erosions, younger age, higher baseline DAS-28 and mostly achieving delta-DAS

Pemphigus is a serious autoimmune disease with few appropriate therapeutic options. Although rituximab (RTX) has recently shown great promise in this regard, the best protocol of its administration is remains to be elucidated. This study aimed to evaluate the patients who need at least 3 cycles of treatment with RTX to identify hard‐to‐treat patients' characteristics, which might lead to consider more prompt protocols for treatment of them. A retrospective cross‐sectional study was conducted on 45 patients with pemphigus vulgaris who received at least 3 cycles of RTX. Their demographic, clinical, and laboratory data as well as details of treatment protocol and final clinical situation of patients were evaluated. Totally, 45 patients (21 men and 24 women) with mean age of 44.33 years were included in this paper. Women were about 8 years older than men (mean age: 48.1 years versus 40.1 years, p: 0.011) and needed RTX approximately 2 years later in their course of disease (gap: 41.04 months vs. 14.85 months, p: 0.003). Buccal, truncal, and scalp regions were the most frequent sites of involvement respectively. A significant decrease in both anti‐Dsg1, 3 was seen at last visit compared to baseline. However, the amount of this decrement was not significantly different between them (p: 0.083). Partial remission in 31.11%, complete remission in 24.44%, relapse in 15.56%, partial remission on treatment in 15.56% and complete remission on treatment in 13.33% were seen at the last follow‐up session. RTX is an effective medication for PV even in patients with refractory disease and its therapeutic effect is increased with each subsequent cycle. Male gender, severe oral mucosal involvement on disease onset and extensive scalp and truncal lesions as first cutaneous manifestation of disease are more likely to be signs of refractory PV. Hence, it is reasonable to consider more prompt protocols for treatment of these cases. Moreover, late prescription of RTX during the course of disease might play a role in presence of more resistant form of disease. [ABSTRACT FROM AUTHOR]