Acute toxicity of second generation HIV protease-inhibitors in combination with radiotherapy: a retrospective case series

<p>Abstract</p> <p>Background</p> <p>There is little data on the safety of combining radiation therapy and human immunodeficiency virus (HIV) protease inhibitors to treat cancers in HIV-positive patients. We describe acute toxicities observed in a series of HIV-positive patients receiving modern radiation treatments, and compare patients receiving HIV protease inhibitors (PI) with patients not receiving HIV PIs.</p> <p>Methods</p> <p>By reviewing the clinical records beginning January 1, 2009 from the radiation oncology department, we identified 29 HIV-positive patients who received radiation therapy to 34 body sites. Baseline information, treatment regimen, and toxicities were documented by review of medical records: patient age, histology and source of the primary tumor, HIV medication regimen, pre-radiation CD4 count, systemic chemotherapy, radiation therapy dose and fractionation, irradiated body region, toxicities, and duration of follow-up. Patients were grouped according to whether they received concurrent HIV PIs and compared using Pearson's chi-square test.</p> <p>Results</p> <p>At baseline, the patients in the two groups were similar with the exception of HIV medication regimens, CD4 count and presence of AIDS-defining malignancy. Patients taking concurrent PIs were more likely to be taking other HIV medications (p = 0.001) and have CD4 count >500 (p = 0.006). Patients taking PIs were borderline less likely to have an AIDS-defining malignancy (p = 0.06). After radiation treatment, 100 acute toxicities were observed and were equally common in both groups (64 [median 3 per patient, IQR 1-7] with PIs; 36 [median 3 per patient, IQR 2-3] without PIs). The observed toxicities were also equally severe in the two groups (Grades I, II, III respectively: 30, 30, 4 with PIs; 23, 13, 0 without PIs: p = 0.38). There were two cases that were stopped early, one in each group; these were not attributable to toxicity.</p> <p>Conclusions</p> <p>In this study of recent radiotherapy in HIV-positive patients taking second generation PIs, no difference in toxicities was observed in patients taking PIs compared to patients not taking PIs during radiation therapy. This suggests that it is safe to use unmodified doses of PIs and radiation therapy in HIV cancer patients, and that it is feasible to use PIs as a radiosensitizer in cancer therapy, as has been suggested by pre-clinical results.</p

Interim-treatment quantitative PET parameters predict progression and death among patients with hodgkin's disease

PURPOSE: We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients. METHODS: Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS ≥ 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUVmean), maximum SUV (SUVmax) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS). RESULTS: Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUVmax from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTV(int/pre )(p < 0.01), SUVmean(int/pre )(p < 0.05), SUVmax(int/pre )(p = 0.01), and iSUV(int/pre )(p < 0.01). Absolute value SUVmax from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTV(int/pre )(p = 0.01), SUVmax(int/pre )(p = 0.02) and iSUV(int/pre )(p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01). CONCLUSIONS: Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification

Structure-function studies of the bHLH phosphorylation domain of TWIST1 in prostate cancer cells

The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helix-loop-helix (bHLH) transcription factor existing as TWIST1-TWIST1 or TWIST1-E12/47. TWIST1 partner choice and DNA binding can be influenced during development by phosphorylation of Thr125 and Ser127 of the Thr-Gln-Ser (TQS) motif within the bHLH of TWIST1. The significance of these TWIST1 phosphorylation sites for metastasis is unknown. We created stable isogenic prostate cancer cell lines overexpressing TWIST1 wild-type, phospho-mutants, and tethered versions. We assessed these isogenic lines using assays that mimic stages of cancer metastasis. In vitro assays suggested the phospho-mimetic Twist1-DQD mutation could confer cellular properties associated with pro-metastatic behavior. The hypo-phosphorylation mimic Twist1-AQA mutation displayed reduced pro-metastatic activity compared to wild-type TWIST1 in vitro, suggesting that phosphorylation of the TWIST1 TQS motif was necessary for pro-metastatic functions. In vivo analysis demonstrates that the Twist1-AQA mutation exhibits reduced capacity to contribute to metastasis, whereas the expression of the Twist1-DQD mutation exhibits proficient metastatic potential. Tethered TWIST1-E12 heterodimers phenocopied the Twist1-DQD mutation for many in vitro assays, suggesting that TWIST1 phosphorylation may result in heterodimerization in prostate cancer cells. Lastly, the dual phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor BEZ235 strongly attenuated TWIST1-induced migration that was dependent on the TQS motif. TWIST1 TQS phosphorylation state determines the intensity of TWIST1-induced pro-metastatic ability in prostate cancer cells, which may be partly explained mechanistically by TWIST1 dimeric partner choice

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions

A highly N-doped carbon phase "dressing" of macroscopic supports for catalytic applications

© The Royal Society of Chemistry 2015. The straightforward "dressing" of macroscopically shaped supports (i.e. β-SiC and α-Al2O3) with a mesoporous and highly nitrogen-doped carbon-phase starting from food-processing raw materials is described. The as-prepared composites serve as highly efficient and selective metal-free catalysts for promoting industrial key-processes at the heart of renewable energy technology and environmental protection

Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas

Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as "oncogene-addiction." However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.To examine how the MYC and K-ras(G12D) oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras(G12D) to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras(G12D)- or MYC/K-ras(G12D)-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras(G12D)-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras(G12D) resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras(G12D) in maintenance of lung tumors, we found that the down-stream mediators of K-ras(G12D) signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras(G12D) but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras(G12D). Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas

Associations of Underlying Health Conditions With Anxiety and Depression Among Outpatients: Modification Effects of Suspected COVID-19 Symptoms, Health-Related and Preventive Behaviors

Objectives: We explored the association of underlying health conditions (UHC) with depression and anxiety, and examined the modification effects of suspected COVID-19 symptoms (S-COVID-19-S), health-related behaviors (HB), and preventive behaviors (PB).Methods: A cross-sectional study was conducted on 8,291 outpatients aged 18–85 years, in 18 hospitals and health centers across Vietnam from 14th February to May 31, 2020. We collected the data regarding participant's characteristics, UHC, HB, PB, depression, and anxiety.Results: People with UHC had higher odds of depression (OR = 2.11; p &lt; 0.001) and anxiety (OR = 2.86; p &lt; 0.001) than those without UHC. The odds of depression and anxiety were significantly higher for those with UHC and S-COVID-19-S (p &lt; 0.001); and were significantly lower for those had UHC and interacted with “unchanged/more” physical activity (p &lt; 0.001), or “unchanged/more” drinking (p &lt; 0.001 for only anxiety), or “unchanged/healthier” eating (p &lt; 0.001), and high PB score (p &lt; 0.001), as compared to those without UHC and without S-COVID-19-S, “never/stopped/less” physical activity, drinking, “less healthy” eating, and low PB score, respectively.Conclusion: S-COVID-19-S worsen psychological health in patients with UHC. Physical activity, drinking, healthier eating, and high PB score were protective factors