Synergistic activities of Panobinostat and doxorubicin in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS. METHODS: Panobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays. RESULTS: Synergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

Prognostic and predictive biomarkers with therapeutic targets in breast cancer: A 2022 update on current developments, evidence, and recommendations.

OBJECTIVE: To evaluate and validate the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in breast cancer. DATA SOURCES: A literature search from January 2015 to March 2022 was performed using the key terms breast cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, predictive and/or prognostic biomarkers, and targeted therapies. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials, meta-analyses, seminal articles, and published evidence- and consensus-based clinical practice guidelines in the English language were identified, reviewed and evaluated. DATA SYNTHESIS: Breast cancer is a biologically heterogeneous disease, leading to wide variability in treatment responses and survival outcomes. Biomarkers for breast cancer are evolving from traditional biomarkers in immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor type 2 (HER2) to genetic biomarkers with therapeutic implications (e.g. breast cancer susceptibility gene 1/2 [BRCA1/2], estrogen receptor α [ESR1] gene mutation, HER2 gene mutation, microsatellite instability [MSI], phosphatidylinositol 3-kinase catalytic subunit 3Cα [PIK3CA] gene mutation, neurotrophic tyrosine receptor kinase [NTRK] gene mutation). In addition, current data are most robust for biomarkers in immunotherapy (e.g. programmed cell death receptor ligand-1 [PD-L1], microsatellite instability-high [MSI-H] or deficient mismatch repair [dMMR]). Oncotype DX assay remains the best validated gene expression assay that is both predictive and prognostic whereas MammaPrint is prognostic for genomic risk. CONCLUSIONS: Biomarker-driven therapies have the potential to confer greater therapeutic advantages than standard-of-care therapies. The purported survival benefits associated with biomarker-driven therapies should be weighed against their potential harms.

The radiobiological effect of using Acuros XB vs anisotropic analytical algorithm on hepatocellular carcinoma stereotactic body radiation therapy.

The purpose of this work was to study the radiobiological effect of using Acuros XB (AXB) vs Analytic Anisotropic Algorithm (AAA) on hepatocellular carcinoma (HCC) stereotactic body radiation therapy (SBRT). Seventy SBRT volumetric modulated arc therapy (VMAT) plans for HCC were calculated using AAA and AXB respectively with the same treatment parameters. Published tumor control probability (TCP) and normal tissue complication probability (NTCP) models were used to quantify the effect of dosimetric difference between AAA and AXB on TCP, NTCP and uncomplicated tumor control probability (UTCP). There was an average decrease of 2.5% in 6-month TCP. Normal liver has the largest average decrease in NTCP which was 59.7%. Bowels followed with 26.6% average decrease in NTCP. Duodenum, stomach and esophagus had 10.2%, 5.1%, and 4.3% average decrease in NTCP. There was an average decrease of 1.8% and up to 7.2% in 6-month UTCP. There was an overall decrease in TCP, NTCP, and UTCP for HCC SBRT plans calculated using AXB compared to AAA which could be clinically significant.

The effect on tumour control probability of using AXB algorithm in replacement of AAA for SBRT of hepatocellular carcinoma located at lung-liver boundary region.

OBJECTIVE: To retrospectively analyze the clinical impact on stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) located at lung-liver boundary due to the use of Acuros XB algorithm (AXB) in replacement of anisotropic analytical algorithm (AAA). METHODS: 23 SBRT volumetric modulated arc therapy (VMAT) plans for HCC located at lung-liver boundary were calculated using AAA and AXB respectively with the same treatment parameters. The dose-volume data of the planned target volumes (PTVs) were compared. A published tumour control probability (TCP) model was used to calculate the effect of dosimetric difference between AAA and AXB on tumour control probability. RESULTS: For dose calculated by AXB (Dose to medium), the D95% and D98% of the PTV were on average 2.4 and 3.1% less than that calculated by AAA. For dose calculated by AXB (dose to water), the D95% and D98% of the PTV were on average 1.8%, and 2.7% less than that calculated by AAA. Up to 5% difference in D95% and 8% difference in D98% were observed in the worst cases. The significant decrease in D95% calculated by AXB compared to AAA could result in a % decrease in 2 year TCP up to 8% in the worst case (from 46.8 to 42.9%). CONCLUSION: The difference in dose calculated by AAA and AXB could lead to significant difference in TCP for HCC SBRT located at lung-liver boundary region. ADVANCES IN KNOWLEDGE: The difference in calculated dose and tumour control probability for HCC SBRT between AAA and AXB algorithm at lung-liver boundary region was compared.

Analysis of Hepatocellular Carcinoma Stereotactic Body Radiation Therapy Dose Prescription Method Using Uncomplicated Tumor Control Probability Model.

PURPOSE: This work was to establish an uncomplicated tumor control probability (UTCP) model using hepatocellular carcinoma (HCC) stereotactic body radiation therapy (SBRT) clinical data in our institution. The model was then used to analyze the current dose prescription method and to seek the opportunity for improvement. METHODS AND MATERIALS: A tumor control probability (TCP) model was generated based on local clinical data using the maximum likelihood method. A UTCP model was then formed by combining the established TCP model with the normal tissue complication probability model based on the study by Dawson et al. The authors investigated the dependence of maximum achievable UTCP on planning target volume equivalent uniform dose (EUD) at various ratio between planning target volume EUD and normal liver EUD (T/N EUD ratios). A new term uncomplicated tumor control efficiency (UTCE) was also introduced to analyze the outcome. A UTCE value of 1 implied that the theoretical maximum UTCP for the corresponding T/N EUD ratio was achieved. RESULTS: The UTCE of the HCC SBRT patients based on the current dose prescription method was found to be 0.93 ± 0.05. It was found that the UTCE could be increased to 0.99 ± 0.03 by using a new dose prescription scheme, for which the UTCP could be maximized while keeping the normal tissue complication probability value smaller than 5%. CONCLUSIONS: The dose prescription method of the current HCC SBRT in our institution was analyzed using a UTCP model established based on local clinical data. It was shown that there could be a potential to increase the prescription dose of HCC SBRT. A new dose prescription scheme was proposed to achieve better UTCP. Additional clinical trials would be required to validate the proposed dose prescription scheme in the future.

A randomized study of olanzapine-containing versus standard antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting in Chinese breast cancer patients.

OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) are distressing symptoms. This randomized study evaluated the antiemetic efficacies of standard antiemetic regimen with/without olanzapine. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive Chinese breast cancer patients who were planned for (neo)adjuvant doxorubicin/cyclophosphamide. Antiemetic regimen for all studied population included aprepitant, ondansetron and dexamethasone; patients were randomized to Olanzapine (with olanzapine) or Standard arms (without olanzapine). Patients filled in self-reported diaries and completed visual analogue scales for nausea, as well as Functional Living Index-Emesis questionnaires. Blood profiles including fasting glucose and lipids were monitored. RESULTS: 120 patients were randomized. In Cycle 1 doxorubicin/cyclophosphamide, the Olanzapine arm had significantly higher rates of "Complete Response" than the Standard arm: 65.0% vs 38.3% in the overall period (p = 0.0035), 70.0% vs 51.7% in the acute period (p = 0.0397) and 92.9% vs 74.2% in the delayed period (p = 0.0254). Olanzapine arm also had significantly higher rates of "No significant nausea" and "No nausea" during all 3 time-frames and better QOL. Similar findings were also revealed throughout multiple cycles. Pre-study abnormalities in glucose and lipids occurred in 39.7% and 34.2% of the studied population respectively; there were no differences in these parameters between the two arms at end-of-study assessment. CONCLUSION: The addition of olanzapine to standard aprepitant-based antiemetic regimen provides clinically meaningful improvement in controlling CINV. This was associated with a positive impact on QOL and tolerable toxicity profiles among Chinese breast cancer patients receiving doxorubicin/cyclophosphamide chemotherapy. Further studies on metabolic profiles of breast cancer patients are warranted.