Δευτέρα 18 Ιανουαρίου 2021

CAR19/22 T cell therapy in adult refractory Burkitt’s lymphoma

Cancer shared this article with you from Inoreader

262.jpg

Abstract

The treatment of refractory Burkitt's lymphoma (BL) is still a challenge. Although CAR-T cell therapy has achieved good responses in diffuse large B cell lymphoma, there is no case series report about the efficacy of CAR-T cell therapy in adult Burkitt's lymphoma. In this study, we evaluate the efficacy and safety of CAR19/22 T cell therapy in six refractory Burkitt's lymphoma cases with poor genetic prognostic factors. After CAR-T cell therapy, five cases had grade 1 and one had grade 3 cytokine release syndrome. Three patients achieved an objective response (3/6 50%), including two partial remission and one complete remission. One CR patient received allogeneic hematopoietic stem cell transplantation (HSCT) and one PR patient received CAR22/19-T cells following auto-HSCT, and they were still in remission at 37 and 22 months of follow-up, respectively. Interestingly, patients with bulky disease (case 2, 4 and 5) had higher levels of serum IL-2R, which was secreted by regulatory T cells, lower CAR lentiviral amplification and poorer prognosis with shorter survival time than cases with non-bulky disease. It is suggested that high tumor burden, more immune suppressive cells and limited CAR-T cell expansion might affect the efficacy of CAR-T cell therapy. CAR-T cell therapy in adult BL patients whose best response cannot achieve CR may need to bridge to other treatments (such as HSCT) early.

View on the web

Integrated analysis of mRNA and miRNA profiles revealed the role of miR-193 and miR-210 as potential regulatory biomarkers in different molecular subtypes of breast cancer

Cancer shared this article with you from Inoreader

12885.jpg

Abstract

Background

Breast cancer is the most frequently diagnosed malignancy among women. However, the role of microRNA (miRNA) expression in breast cancer progression is not fully understood. In this study we examined predictive interactions between differentially expressed miRNAs and mRNAs in breast cancer cell lines representative of the common molecular subtypes. Integrative bioinformatics analysis identified miR-193 and miR-210 as potential regulatory biomarkers of mRNA in breast cancer. Several recent studies have investigated these miRNAs in a broad range of tumors, but the mechanism of their involvement in cancer progression has not previously been investigated.

Methods

The miRNA-mRNA interactions in breast cancer cell lines were identified by parallel expression analysis and miRNA target prediction programs. The expression profiles of mRNA and miRNAs from luminal (MCF-7, MCF-7/AZ and T47D), HER2 (BT20 and SK-BR3) and triple negative subtypes (Hs578T e MDA-MB-231) could be clearly separated by unsupervised analysis using HB4A cell line as a control. Breast cancer miRNA data from TCGA patients were grouped according to molecular subtypes and then used to validate these findings. Expression of miR-193 and miR-210 was investigated by miRNA transient silencing assays using the MCF7, BT20 and MDA-MB-231 cell lines. Functional studies included, xCELLigence system, ApoTox-Glo triplex assay, flow cytometry and transwell inserts were performed to determine cell proliferation, cytotoxicity, apoptosis, migration and invasion, respectively.

Results

The most evident effects were associated with cell proliferation after miR-210 silencing in triple negative subtype cell line MDA-MB-231. Using in silico prediction algorithms, TNFRSF10 was identified as one of the potential regulated downstream targets for both miRNAs. The TNFRSF10C and TNFRSF10D mRNA expression inversely correlated with the expression levels of miR-193 and miR210 in breast cell lines and breast cancer patients, respectively. Other potential regulated genes whose expression also inversely correlated with both miRNAs were CCND1, a known mediator on invasion and metastasis, and the tumor suppressor gene RUNX3.

Conclusions

In summary, our findings identify miR-193 and miR-210 as potential regulatory miRNA in different molecular subtypes of breast cancer and suggest that miR-210 may have a specific role in MDA-MB-231 proliferation. Our results highlight important new downstream regulated targets that may serve as promising therapeutic pathways for aggressive breast cancers

View on the web

New maintenance option for AML

Cancer shared this article with you from Inoreader

Message:

Approximately 50% of patients with acute myeloid leukaemia (AML) aged ≥55 years have complete remission after standard induction chemotherapy, but eventually the majority have disease relapse. Haematopoietic stem-cell transplantation (HSCT) is not always feasible for patients in this age group and, therefore, maintenance therapies might be warranted to prolong remission. Now, data from the phase III QUAZAR AML-001 trial demonstrate promising overall survival (OS) outcomes with oral azacitidine in this setting.

In QUAZAR AML-001, patients with AML in complete remission after induction with cytarabine-based chemotherapy and aged ≥55 years were randomly assigned to receive oral azacitidine (n = 238) or placebo (n = 234). The median age was 68 years; 91% of patients had de novo AML, 86% had intermediate-risk cytogenetic characteristics and 80% had received consolidation chemotherapy.

Median OS was significantly longer for patients receiving oral azacitidine than for those receiving placebo (24.7 months versus 14.8 months; P < 0.001). Median relapse-free survival was also significantly longer with oral azacitidine (10.2 months versus 4.8 months; P < 0.001). "The OS benefit with oral azacitidine was observed across different subgroups, including patients with persistent measurable residual disease after intensive chemotherapy," comments lead investigator Andrew Wei.

The incidence of grade 3–4 adverse events (72% versus 63%) and the number of treatment-related deaths (9 versus 4) were higher in the oral azacitidine group than in the placebo group. However, no meaningful differences in patient-reported quality of life were observed between treatment groups using questionnaires to evaluate changes from baseline scores.

"this oral agent represents an attractive option for patients for whom outpatient treatment is preferred"

On the basis of these findings, on 1 September 2020 the FDA approved oral azacitidine for the maintenance treatment of adults with AML in first remission after intensive chemotherapy. "Looking forward, this oral agent represents an attractive option for patients for whom outpatient treatment is preferred," explains Wei. "Future clinical trials will address the feasibility and efficacy of oral azacitidine in combination with other orally administered targeted agents, for example, venetoclax," he adds. In addition, a randomized trial is evaluating oral azacitidine as maintenance therapy for AML after consolidative HSCT. The results of this study are eagerly awaited.

References
Original article
Wei, A. H. et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N. Engl. J. Med. 383, 2526–2537 (2020)

CAS

Article

Google Scholar

Nature Reviews Clinical Oncology, Published online: 18 January 2021; doi:10.1038/s41571-021-00475-3

New maintenance option for AML
View on the web

Clinical significance of skeletal muscle density and sarcopenia in patients with pancreatic cancer undergoing first-line chemotherapy: a retrospective observational study

Cancer shared this article with you from Inoreader

12885.jpg

Abstract

Background

To investigate the clinical impact of sarcopenia and skeletal muscle density (SMD) among patients with metastatic pancreatic adenocarcinoma who underwent palliative first line gemcitabine-based chemotherapy.

Methods

A total of 330 patients treated with first line gemcitabine-based chemotherapy between January 2010 and March 2017 were included. CT scans before chemotherapy and after 8±2 weeks were evaluated. The L3 skeletal muscle index (SMI) was used to detect sarcopenia and calculated as the total area of the L3 skeletal muscle divided by the height-squared (cm2/m2). SMD was quantified as the mean muscle radiation attenuation of the muscle cross-sectional area across the L3 vertebral body level and was assessed between − 29 and + 150 Hounsfield units.

Results

A SMI to SMD comparison revealed a positive correlation (R2 = 0.058, P < 0.001). Compared with high SMD, the risks of low SMI were 1.516 (95% confidence interval [CI]: 1.164–1.973) among patients with low SMD. Kaplan–Meier analysis showed that the low SMD was related to poor overall survival (OS, median, 6.1 versus [vs.] 7.9 months, P = 0.010). Multivariate analysis using Cox regression showed that low SMI (hazard ratio [HR]: 1.35, 95% CI: 1.03–1.78, P = 0.032) and low SMD (HR: 1.45, 95% CI: 1.09–1.93, P = 0.011) were poor prognostic factors for OS, respectively. Co-presence of low SMI and low SMD had more powerful prognostic implication for OS (HR: 1.58, 95% CI: 1.12–2.23, P = 0.010). Grade 3 or higher toxicity of chemotherapy was more frequently observed in patients who have a low SMI (43% vs. 59%, P = 0.019) and low SMD (44% vs. 60%, P = 0.023). OS was not related to S MD status among patients who were chemotherapy responders (complete or partial responses). However, among non-responders (stable or progressive disease), low SMD groups had significantly poorer OS in comparison with high SMD groups (median, 5.6 vs 7.4 months, P = 0.006).

Conclusions

Sarcopenia and SMD status can be considered a prognostic factor in patients with metastatic pancreatic adenocarcinoma who received palliative first line gemcitabine-based chemotherapy. Severe chemotherapy toxicity occurred in the sarcopenia and low SMD groups. Our data suggest that a comprehensive assessment of skeletal muscle parameters may be more useful prognostic factors.

View on the web

Racial/ethnic differences in average CA125 and CA15.3 values and its correlates among postmenopausal women

Cancer shared this article with you from Inoreader

10552.jpg

Abstract

Purpose

Among healthy postmenopausal women, levels of CA125 and CA15.3 are influenced by demographic and reproductive factors, including race/ethnicity. In this study, we sought to examine the interaction between race/ethnicity and other correlates of these biomarkers and whether the racial differences observed are simply determined by other correlates with racial differences.

Methods

In archived sera from 946 postmenopausal women who participated in the 2001–2002 cycle of the National Health and Nutrition Examination Survey, we measured CA125 and CA15.3 and examined their associations with health survey and examination data available in this cohort. We used multivariable linear regression to examine the association between CA125 and CA15.3 and race/ethnicity. We then calculated geometric means of these markers by demographic and reproductive factors stratified by race/ethnicity and used likelihood ratio tests to evaluate heterogeneity.

Results

Non-white race was associated with lower CA125, with Non-Hispanic Black women being associated with − 29.0% (95% CI − 42.5%, − 12.2%) difference and Mexican American women being associated with − 6.4% (95% CI − 18.1%, 6.9%) difference on average compared to Non-Hispanic White women. Associations between CA125 and age and parity varied by race/ethnicity. Non-Hispanic Black women were associated with higher CA15.3 compared to Non-Hispanic White women, with 17.3% (95% CI − 0.5%, 38.3%) differences on average. Associations between CA15.3 and age, number of births, and age at natural menopause varied by race/ethnicity.

Conclusions

Among postmenopausal women, Non-Hispanic Black women were associated with lower CA125 and higher CA15.3 levels compared to Non-Hispanic White women. Our results support that race/ethnicity should be considered when assigning thresholds for these biomarkers being tested for diagnostic or screening purposes.

View on the web

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial

Cancer shared this article with you from Inoreader
Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases.
View on the web

HIPEC for colorectal peritoneal metastases

Cancer shared this article with you from Inoreader
The treatment of patients with metastatic colorectal cancer has changed profoundly over the past 25 years. In 1995, fluorouracil was the only active chemotherapy available for the disease, and long-term survival (ie, for at least 5 years) was rarely achieved with chemotherapy alone.1 Only patients with surgically resectable liver and lung metastases had a reasonable chance of long-term survival.1 Since then, more chemotherapeutic drugs have been approved, and median survival has increased to 2–3 years (from around 6–12 months), with 20–25% of patients surviving for at least 5 years.
View on the web

Broadening treatment options for patients with non-small-cell lung cancer

Cancer shared this article with you from Inoreader
The use of immune-checkpoint inhibitors targeting the CTLA-4, PD-1, or PD-L1 signalling axis in the modulation of anti-tumour T-cell activity has revolutionised the treatment of lung cancer in different settings.1 In patients with PD-L1 expression of at least 50%, pembrolizumab (anti PD-1) and atezolizumab (anti PD-L1) have been approved by the US Food and Drug Administration as first-line single-agent treatments because they significantly prolong overall survival compared with platinum-based chemotherapy, in patients with both squamous and non-squamous tumours without sensitising EGFR mutations or ALK rearrangements.
View on the web

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial

Cancer shared this article with you from Inoreader
Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk–benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.
View on the web

Longitudinal study of intravenous versus subcutaneous immunoglobulin replacement therapy in hematological malignancy

Cancer shared this article with you from Inoreader
Longitudinal study of intravenous versus subcutaneous immunoglobulin replacement therapy in hematological malignancy

First longitudinal study on the clinical impact and patient perception of intravenous versus subcutaneous immunoglobulin replacement therapy in patients with acquired hypogammaglobulinemia secondary to hematological malignancy.


Abstract

Aim

To present findings from a longitudinal study on infection risk, mortality, and patient perspective of intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) treatment for patients with hypogammaglobulinemia secondary to hematological malignancy or its treatment (abbreviated as SID).

Methods

Observational study period included final year of IVIg (13 patients) and of the first 3 years of SCIg (17 patients) with SID. Data were collected on clinical outcomes from medical records and patient perception via study specific questionnaire.

Results

The median age was 63 years (53‐76 years), and for 82.4% of patients their hematological malignancy was in complete remission. The annual mean serum IgG trough levels remained stable over the 4 years and were 7.0 g/L (±2.77 g/L) with IVIg, and 8.0 g/L (±1.75 g/L), 8.7 g/L (±2.75 g/L), and 7.6 g/L (±2.89 g/L) (year 1, 2, and 3, respectively) with SCIg. While the annual infection rate was similar, the rate of hospitalization due to infection fluctuated, with 37%, 9%, 15%, and 32% in year 1, 2, 3, and 4 respectively. There were no systemic adverse events with IVIg or SCIg. Patients reported a strong preference for SCIg. One patient died due to progression of underlying disease and infection within the study period.

Conclusion

SCIg was the preferred treatment mode over IVIg in our cohort, but both were well tolerated without any systemic adverse events in 4‐year follow up. The dosage and serum IgG levels were stable throughout. However, the number of infections requiring hospitalization fluctuated. It is anticipated that these findings encourage more hospitals to offer SCIg for SID patients.

View on the web

To betray or to fight? The dual identity of the mitochondria in cancer

Cancer shared this article with you from Inoreader
Future Oncology, Ahead of Print.
View on the web