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Thyroid : Official Journal of the... Jul 2021Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS)...
Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Survival Rate; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome
PubMed: 33509020
DOI: 10.1089/thy.2020.0322 -
International Urology and Nephrology Jul 2021A precise description of renal histological lesions and an appropriate classification of lupus nephritis are both essential for nephrologists to guide treatment and...
BACKGROUND
A precise description of renal histological lesions and an appropriate classification of lupus nephritis are both essential for nephrologists to guide treatment and predict prognosis among patients. The prognostic value of ISN/RPS 2003 classification is controversial. A new classification for lupus nephritis was recently proposed, namely, the revised ISN/RPS 2018 classification.
OBJECTIVE
The study aimed to evaluate the predictive value of the clinical and pathological factors according to ISN/RPS 2018 classification on renal remission among patients with proliferative lupus nephritis.
METHODS
A total number of 41 patients with proliferative lupus nephritis on adequate renal biopsy specimen between 2017 and 2018 were included. Clinical and histological variables were tested for their association with renal remission. Univariate and multivariate logistic regression analysis were performed to identify independent predictors of renal remission after 24 weeks of induction therapy.
RESULTS
After induction therapy, 56.1% of patients reached complete and partial remission and 43.9% reached no remission. In univariate analyses, baseline glomerular filtration rate (GFR), presence of anti-DNA titer, cellular crescents, interstitial inflammation, glomerulosclerosis, interstitial fibrosis, tubular atrophy and total chronicity index strongly impacted renal response. After multivariate logistic regression analysis, we identified aging, presence of cellular crescents, and high total renal chronicity index as independent predictors of renal remission. Receiver operating characteristic (ROC) analysis revealed that baseline estimated GFR (AUC = 0.708; 95% CI 0.527-0.888), anti-DNA titer (AUC = 0.674; 95% CI 0.491-0.858), cellular crescent (AUC = 0.750; 95% CI 0.585-0.915) and renal chronicity index (AUC = 0.765; 95% CI 0.585-0.915) predicted renal remission. Combining all factors achieved a perfect score predicting renal response (AUC 0.924; 95% CI 0.840-1.000).
CONCLUSION
The study identified baseline GFR, anti-DNA titer, cellular crescent, and high chronicity index according to revised ISN/RPS 2018 classification as important predictors of renal response after induction therapy in proliferative lupus nephritis.
Topics: Adolescent; Adult; Female; Humans; Immunosuppression Therapy; Lupus Nephritis; Male; Predictive Value of Tests; Prognosis; Remission Induction; Societies, Medical; Young Adult
PubMed: 33682052
DOI: 10.1007/s11255-020-02732-3 -
The Journal of Clinical Investigation Feb 2020BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of...
BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.
Topics: Adoptive Transfer; Adult; Allografts; Disease-Free Survival; Epstein-Barr Virus Infections; Female; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Lymphoma; Male; Rituximab; Survival Rate; T-Lymphocytes
PubMed: 31689242
DOI: 10.1172/JCI121127 -
Blood Advances Jul 2023Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients...
Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Pyridines; Quinolines; Leukemia, Myeloid, Acute; Prognosis; Isocitrate Dehydrogenase
PubMed: 36724515
DOI: 10.1182/bloodadvances.2022009411 -
Blood Feb 2020Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase...
Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
Topics: Aged; Aged, 80 and over; Blood Transfusion; Female; Glycine; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Pyridines; Remission Induction; Survival Analysis; Translational Research, Biomedical; Treatment Outcome
PubMed: 31841594
DOI: 10.1182/blood.2019002140 -
Blood May 2023Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion....
Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.
Topics: Humans; Middle Aged; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Immunotherapy, Adoptive; T-Lymphocytes; Antigens, CD19; Sialic Acid Binding Ig-like Lectin 2
PubMed: 36821767
DOI: 10.1182/blood.2022018598 -
Renal Failure Dec 2023The treatment of refractory nephrotic syndrome (RNS) is full of challenges and the role of rituximab (RTX) is not well-established, thus this study aims to demonstrate...
BACKGROUND
The treatment of refractory nephrotic syndrome (RNS) is full of challenges and the role of rituximab (RTX) is not well-established, thus this study aims to demonstrate the role of RTX in RNS.
METHODS
This was a multicenter retrospective study of all adult patients receiving RTX for RNS. Patients enrolled were divided into two groups according to pathological pattern: 20 patients as a group of podocytopathy (including minimal change disease [MCD] and focal and segmental glomerulosclerosis [FSGS]), and 26 patients as membranous nephropathy (MN) group. The remission rate, relapse rate, adverse effects, and predictors of remission were analyzed.
RESULTS
A total of 75 patients received RTX for RNS and 48 were available for analysis after exclusion criteria. No significant difference in the remission rate at 6 or 12 months was observed between the MCD/FSGS and MN cases ( > 0.05). The median duration of the first complete remission (CR) was 1 month in the podocytopathy group and 12.5 months in the MN group. Three relapses were associated with infection as the ultimate outcome, and 6 out of 48 remained refractory representing a response rate of 87.5% in RNS. Clinical predictors of cumulative CR were estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m and mean arterial pressure (MAP) ≤103 mmHg at the beginning of therapy in patients with MN. No serious adverse effects were reported.
CONCLUSIONS
RTX appears to be effective in RNS across various clinical and pathological subtypes, exhibiting a low relapse rate and minimal significant side effects in the majority of patients.
Topics: Humans; Adult; Rituximab; Retrospective Studies; Glomerulosclerosis, Focal Segmental; Nephrotic Syndrome; Treatment Outcome; Nephrosis, Lipoid; Glomerulonephritis, Membranous; Recurrence; Chronic Disease; Immunosuppressive Agents
PubMed: 37482915
DOI: 10.1080/0886022X.2023.2237124 -
Cerebellum (London, England) Oct 2019Thyroid disorders, including hypothyroidism, hyperthyroidism and Hashimoto encephalopathy, are considered the most common cause of cerebellar dysfunction due to hormonal... (Review)
Review
Thyroid disorders, including hypothyroidism, hyperthyroidism and Hashimoto encephalopathy, are considered the most common cause of cerebellar dysfunction due to hormonal imbalance. Typically, cerebellar impairment occurs in the course of hypothyroidism and Hashimoto encephalopathy. Information about demographic, clinical and laboratory features of cerebellar disease associated with thyroid disorders is poor. Our review of the literature (1965 to 2018) identified 28 cases associated with hypothyroidism and 37 cases associated with Hashimoto encephalitis. Both patients with hypothyroidism and Hashimoto encephalopathy presented with signs of ataxia that were similarly distributed in the two groups and were mostly predictive of vermis involvement and frequent impairment of cerebellar hemispheres. Additional neurological signs, like dystonia, psychiatric symptoms, ocular disturbances and myoclonus, could be found in the Hashimoto encephalopathy group alone. When present, atrophy of vermis and often of both cerebellar hemispheres was the main imaging abnormality in both hypothyroidism and Hashimoto encephalopathy. Anti-thyroid antibodies could be detected in three quarters of patients with hypothyroidism and in all patients with Hashimoto encephalopathy. In the patients with hypothyroidism, thyroid replacement therapy yielded complete or partial remission of ataxia. In the Hashimoto encephalopathy group, immunosuppressive treatment provided complete remission of ataxia in about 60% of patients, partial remission in the remaining cases. Owing to the treatable nature of the condition and the high prevalence of thyroid disease among general population, cerebellar syndrome associated with thyroid disorders should be considered an important clinical entity. Information from this review will hopefully stimulate and strengthen awareness of thyroid-associated ataxia among clinicians.
Topics: Cerebellar Diseases; Electroencephalography; Encephalitis; Hashimoto Disease; Humans; Hypothyroidism; Thyroid Diseases
PubMed: 31388971
DOI: 10.1007/s12311-019-01059-9 -
Endocrinologia, Diabetes Y Nutricion Apr 2021Obesity and diabetes are two closely related disorders. Lifestyle changes and drug treatment do not achieve successful diabetes remission. A treatment option for these...
Obesity and diabetes are two closely related disorders. Lifestyle changes and drug treatment do not achieve successful diabetes remission. A treatment option for these patients is bariatric surgery (BS). The partial and complete remission rates vary, depending on the type of technique used (restrictive or malabsorptive), with malabsorptive surgery being more effective in terms of both weight reduction and diabetes remission (DR). Different scales (DiaRem, Ad-DiaRem or 5y-Ad-DiaRem) predict the probability of DR after BS, particularly after gastric bypass surgery. Some studies report higher DR rates in surgery with a greater malabsorptive component. Our aim was to study the benefits of BS at one year and 5 years in terms of the weight and blood glucose profile in patients with obesity and type 2 diabetes mellitus; assess percentage DR according to ADA criteria; determine the DR predictive capacity of different scores; and examine which variables predict DR at one and five years after biliopancreatic diversion (BPD). Percentage overweight reduction and the decrease in both blood glucose and HbA1c were greater with BPD. Complete diabetes remission was approximately 80% at one and 5 years after BS. In general, the scores that determine the probability of DR show poor discriminative capacity in malabsorptive surgery. Presurgery HbA1c predicts DR at one and 5 years after BPD. The type of surgery performed should be individualized, based on the severity of diabetes and the specific characteristics of each patient.
Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Obesity; Remission Induction; Treatment Outcome
PubMed: 34266633
DOI: 10.1016/j.endien.2020.08.014 -
Endocrinologia, Diabetes Y Nutricion Apr 2021Obesity and diabetes are two closely related disorders. Lifestyle changes and drug treatment do not achieve successful diabetes remission. A treatment option for these...
Obesity and diabetes are two closely related disorders. Lifestyle changes and drug treatment do not achieve successful diabetes remission. A treatment option for these patients is bariatric surgery (BS). The partial and complete remission rates vary, depending on the type of technique used (restrictive or malabsorptive), with malabsorptive surgery being more effective in terms of both weight reduction and diabetes remission (DR). Different scales (DiaRem, Ad-DiaRem or 5y-Ad-DiaRem) predict the probability of DR after BS, particularly after gastric bypass surgery. Some studies report higher DR rates in surgery with a greater malabsorptive component. Our aim was to study the benefits of BS at one year and 5 years in terms of the weight and blood glucose profile in patients with obesity and type 2 diabetes mellitus; assess percentage DR according to ADA criteria; determine the DR predictive capacity of different scores; and examine which variables predict DR at one and five years after biliopancreatic diversion (BPD). Percentage overweight reduction and the decrease in both blood glucose and HbA1c were greater with BPD. Complete diabetes remission was approximately 80% at one and 5 years after BS. In general, the scores that determine the probability of DR show poor discriminative capacity in malabsorptive surgery. Presurgery HbA1c predicts DR at one and 5 years after BPD. The type of surgery performed should be individualized, based on the severity of diabetes and the specific characteristics of each patient.
PubMed: 33495112
DOI: 10.1016/j.endinu.2020.08.006