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Alterations in lipid profile upon uterine fibroids and its recurrence.
Tonoyan, NM, Chagovets, VV, Starodubtseva, NL, Tokareva, AO, Chingin, K, Kozachenko, IF, Adamyan, LV, Frankevich, VE
Scientific reports. 2021;(1):11447
Abstract
Uterine fibroids (UF) is the most common (about 70% cases) type of gynecological disease, with the recurrence rate varying from 11 to 40%. Because UF has no distinct symptomatology and is often asymptomatic, the specific and sensitive diagnosis of UF as well as the assessment for the probability of UF recurrence pose considerable challenge. The aim of this study was to characterize alterations in the lipid profile of tissues associated with the first-time diagnosed UF and recurrent uterine fibroids (RUF) and to explore the potential of mass spectrometry (MS) lipidomics analysis of blood plasma samples for the sensitive and specific determination of UF and RUF with low invasiveness of analysis. MS analysis of lipid levels in the myometrium tissues, fibroids tissues and blood plasma samples was carried out on 66 patients, including 35 patients with first-time diagnosed UF and 31 patients with RUF. The control group consisted of 15 patients who underwent surgical treatment for the intrauterine septum. Fibroids and myometrium tissue samples were analyzed using direct MS approach. Blood plasma samples were analyzed using high performance liquid chromatography hyphened with mass spectrometry (HPLC/MS). MS data were processed by discriminant analysis with projection into latent structures (OPLS-DA). Significant differences were found between the first-time UF, RUF and control group in the levels of lipids involved in the metabolism of glycerophospholipids, sphingolipids, lipids with an ether bond, triglycerides and fatty acids. Significant differences between the control group and the groups with UF and RUF were found in the blood plasma levels of cholesterol esters, triacylglycerols, (lyso) phosphatidylcholines and sphingomyelins. Significant differences between the UF and RUF groups were found in the blood plasma levels of cholesterol esters, phosphotidylcholines, sphingomyelins and triacylglycerols. Diagnostic models based on the selected differential lipids using logistic regression showed sensitivity and specificity of 88% and 86% for the diagnosis of first-time UF and 95% and 79% for RUF, accordingly. This study confirms the involvement of lipids in the pathogenesis of uterine fibroids. A diagnostically significant panel of differential lipid species has been identified for the diagnosis of UF and RUF by low-invasive blood plasma analysis. The developed diagnostic models demonstrated high potential for clinical use and further research in this direction.
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Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts.
Mehta-Shah, N, Lunning, MA, Moskowitz, AJ, Boruchov, AM, Ruan, J, Lynch, P, Hamlin, PA, Leonard, J, Matasar, MJ, Myskowski, PL, et al
American journal of hematology. 2021;(10):1211-1222
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Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
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Allogeneic hematopoietic stem cell transplantation improves long-term outcome for relapsed AML patients across all ages: results from two East German Study Group Hematology and Oncology (OSHO) trials.
Heinicke, T, Krahl, R, Kahl, C, Cross, M, Scholl, S, Wolf, HH, Hähling, D, Hegenbart, U, Peter, N, Schulze, A, et al
Annals of hematology. 2021;(9):2387-2398
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Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem.
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Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.
Rossini, D, Lonardi, S, Antoniotti, C, Santini, D, Tomasello, G, Ermacora, P, Germani, MM, Bergamo, F, Ricci, V, Caponnetto, S, et al
British journal of cancer. 2021;(1):183-190
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BACKGROUND FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression. METHODS We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction. RESULTS Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045). CONCLUSIONS First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS.
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S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial.
Sunami, E, Kusumoto, T, Ota, M, Sakamoto, Y, Yoshida, K, Tomita, N, Maeda, A, Teshima, J, Okabe, M, Tanaka, C, et al
Clinical colorectal cancer. 2020;(1):22-31.e6
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BACKGROUND The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). PATIENTS AND METHODS Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS). RESULTS A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05). CONCLUSION As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.
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Comparison of 18F-sodium fluoride PET/CT, 18F-fluorocholine PET/CT and diffusion-weighted MRI for the detection of bone metastases in recurrent prostate cancer: a cost-effectiveness analysis in France.
Gauthé, M, Zarca, K, Aveline, C, Lecouvet, F, Balogova, S, Cussenot, O, Talbot, JN, Durand-Zaleski, I
BMC medical imaging. 2020;(1):25
Abstract
BACKGROUND The diagnostic performance of 18F-sodium fluoride positron emission tomography/computed tomography (PET/CT) (NaF), 18F-fluorocholine PET/CT (FCH) and diffusion-weighted whole-body magnetic resonance imaging (DW-MRI) in detecting bone metastases in prostate cancer (PCa) patients with first biochemical recurrence (BCR) has already been published, but their cost-effectiveness in this indication have never been compared. METHODS We performed trial-based and model-based economic evaluations. In the trial, PCa patients with first BCR after previous definitive treatment were prospectively included. Imaging readings were performed both on-site by local specialists and centrally by experts. The economic evaluation extrapolated the diagnostic performances of the imaging techniques using a combination of a decision tree and Markov model based on the natural history of PCa. The health states were non-metastatic and metastatic BCR, non-metastatic and metastatic castration-resistant prostate cancer and death. The state-transition probabilities and utilities associated with each health state were derived from the literature. Real costs were extracted from the National Cost Study of hospital costs and the social health insurance cost schedule. RESULTS There was no significant difference in diagnostic performance among the 3 imaging modalities in detecting bone metastases. FCH was the most cost-effective imaging modality above a threshold incremental cost-effectiveness ratio of 3000€/QALY when imaging was interpreted by local specialists and 9000€/QALY when imaging was interpreted by experts. CONCLUSIONS FCH had a better incremental effect on QALY, independent of imaging reading and should be preferred for detecting bone metastases in patients with biochemical recurrence of prostate cancer. TRIAL REGISTRATION NCT01501630. Registered 29 December 2011.
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A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab-resistant head and neck cancer: The MAESTRO study.
Seiwert, TY, Kochanny, S, Wood, K, Worden, FP, Adkins, D, Wade, JL, Sleckman, BG, Anderson, D, Brisson, RJ, Karrison, T, et al
Cancer. 2020;(14):3237-3243
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BACKGROUND Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance. METHODS In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes. RESULTS Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms. CONCLUSIONS The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation.
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Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract.
Frumovitz, M, Westin, SN, Salvo, G, Zarifa, A, Xu, M, Yap, TA, Rodon, AJ, Karp, DD, Abonofal, A, Jazaeri, AA, et al
Gynecologic oncology. 2020;(3):570-575
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OBJECTIVE To investigate the efficacy and safety of pembrolizumab in women with recurrent small cell neuroendocrine tumors of the lower genital tract. METHODS We conducted an open-label, investigator-initiated phase II basket trial of pembrolizumab 200 mg intravenously every 3 weeks in patients with rare tumors (ClinicalTrials.gov: NCT02721732). The trial had prespecified cohorts, including small cell malignancies of extrapulmonary origin. Eligibility criteria included disease progression during standard treatment in the 6 months before study enrollment. Patients were enrolled from February 2017 to February 2019. The primary endpoint was the proportion of patients alive without progression at 27 weeks. Response to pembrolizumab was evaluated every 9 weeks (3 cycles) with radiographic imaging. RESULTS Seven women with gynecologic extrapulmonary small cell carcinoma were enrolled, 6 with cervical and 1 with vulvar carcinoma. No patient was progression free at 27 weeks. At first radiologic assessment, 1 patient had stable disease, while 6 had progression. The single patient with stable disease at 6 weeks had disease progression at 14 weeks. The median progression-free interval was 2.1 months (range 0.8-3.3 months). Severe treatment-related adverse events (≥grade 3) were seen in 2 of 7 patients (29%); 1 patient had grade 3 asymptomatic elevation of serum alkaline phosphatase, and 1 had grade 3 asymptomatic elevation of serum alanine aminotransferase. CONCLUSIONS Pembrolizumab alone showed minimal activity in women with recurrent small cell neuroendocrine tumors of the lower genital tract. Treatment was well tolerated in the majority of study participants, and the rate of severe adverse events was low.
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PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer.
Tuyaerts, S, Van Nuffel, AMT, Naert, E, Van Dam, PA, Vuylsteke, P, De Caluwé, A, Aspeslagh, S, Dirix, P, Lippens, L, De Jaeghere, E, et al
BMC cancer. 2019;(1):506
Abstract
BACKGROUND Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. METHODS PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. DISCUSSION In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. TRIAL REGISTRATION EU Clinical Trials Register: EudraCT 2016-001569-97 , registered on 19-6-2017. Clinicaltrials.gov: NCT03192059 , registered on 19-6-2017.
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Diffusion-weighted MRI is not superior to FDG-PET/CT for the detection of neck recurrence in well-differentiated thyroid carcinoma.
Vera, P, Edet-Sanson, A, Quieffin, F, Le Cloirec, J, Bertrand, AS, Cailleaux, M, Menard, JF, Lussey-Lepoutre, C, Callonnec, F
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.... 2019;(3):311-320
Abstract
BACKGROUND Management of patients with well-differentiated thyroid carcinoma (WDTC) and positive thyroglobulin (Tg)/negative iodine-131 whole body scintigraphy (WBS) remains challenging. Here, we investigate the specific role of diffusion-weighted magnetic resonance imaging of the neck (DW-MRI) as compared to rhTSH stimulated FDG-PET/CT in such patients. METHODS Patients with WDTC, positive Tg/negative WBS were prospectively enrolled in the study. FDG-PET/CT and neck DW-MRI were performed on the same day after rhTSH stimulation. Neck-US was performed 24 hours after FDG-PET/CT and MRI to guide fine-needle aspiration (FNA). Patients with positive FNA underwent surgery. Patient with negative workup underwent new explorations at 6 and 18 months. RESULTS A total of 86 FDG-PET/CT and 83 DW-MRI tests were performed in 40 patients (23 females; 17 males; 52±16 years). For detection of neck recurrences, sensitivity was equivalent for FDG-PET/CT and to DW-MRI at baseline (46% vs. 43%), at 6 months (30% vs. 20%) and at 18 months (11 vs. 10%). The comparison with a non-weighted Kappa test shows significant concordance between FDG-PET/CT and DW-MRI (K=0.741±0.062; P<0.0001). A relationship was observed between Tg and results of FDG-PET/CT, but not for DW-MRI. FDG-PET/CT permitted to detect iodine-refractory distant metastasis in 4 patients. CONCLUSIONS In Tg-positive/WBS-negative DTC patients, low tumour burden, neck DW-MRI does not provide additional information compared to rhTSH-stimulated FDG-PET/CT. FDG-PET/CT has the best sensitivity, is acceptable for patients, allows whole body exploration and distant metastasis detections, and is correlated with Tg levels.