CEST MRI provides amide/amine surrogate biomarkers for treatment-naïve glioma sub-typing

Purpose Accurate glioma classification affects patient management and is challenging on non- or low-enhancing gliomas. This study investigated the clinical value of different chemical exchange saturation transfer (CEST) metrics for glioma classification and assessed the diagnostic effect of the presence of abundant fluid in glioma subpopulations. Methods Forty-five treatment-naïve glioma patients with known isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status received CEST MRI (B1rms = 2μT, Tsat = 3.5 s) at 3 T. Magnetization transfer ratio asymmetry and CEST metrics (amides: offset range 3–4 ppm, amines: 1.5–2.5 ppm, amide/amine ratio) were calculated with two models: ‘asymmetry-based’ (AB) and ‘fluid-suppressed’ (FS). The presence of T2/FLAIR mismatch was noted. Results IDH-wild type had higher amide/amine ratio than IDH-mutant_1p/19qcodel (p < 0.022). Amide/amine ratio and amine levels differentiated IDH-wild type from IDH-mutant (p < 0.0045) and from IDH-mutant_1p/19qret (p < 0.021). IDH-mutant_1p/19qret had higher amides and amines than IDH-mutant_1p/19qcodel (p < 0.035). IDH-mutant_1p/19qret with AB/FS mismatch had higher amines than IDH-mutant_1p/19qret without AB/FS mismatch ( < 0.016). In IDH-mutant_1p/19qret, the presence of AB/FS mismatch was closely related to the presence of T2/FLAIR mismatch (p = 0.014). Conclusions CEST-derived biomarkers for amides, amines, and their ratio can help with histomolecular staging in gliomas without intense contrast enhancement. T2/FLAIR mismatch is reflected in the presence of AB/FS CEST mismatch. The AB/FS CEST mismatch identifies glioma subgroups that may have prognostic and clinical relevance.

Advanced HIV Infection in Treatment Naïve Individuals: Effectiveness and Persistence of Recommended Three-Drug Regimens

Background Approximately 20% of newly diagnosed people with HIV (PWH) in the U.S. have advanced HIV infection, yet literature on current antiretroviral therapy (ART) options is limited. Discontinuation/modification and effectiveness of common regimens were compared among ART-naïve people with advanced HIV infection (CD4 cell count &lt;200 cells/μL). Methods ART-naïve adults with advanced HIV infection initiating bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or a boosted darunavir (bDRV)-, dolutegravir (DTG)- or elvitegravir/cobicistat (EVG/c)-based three-drug regimen between 1JAN2018 and 31JUL2019 in the OPERA cohort were included. The association between regimen and discontinuation or viral suppression (&lt;50 or &lt;200 copies/mL) was assessed using Cox proportional hazards models with inverse probability of treatment weights. Results Overall, 961 PWH were included (416 B/F/TAF, 106 bDRV, 271 DTG, 168 EVG/c); 70% achieved a CD4 cell count ≥200 cells/μL over a 16 months median follow-up. All regimens were associated with a statistically higher likelihood of discontinuation than B/F/TAF (bDRV aHR: 2.65 [95% CI: 1.75, 4.02], DTG: 2.42 [1.75, 3.35], EVG/c: 3.52 [95% CI: 2.44, 5.07]). Compared to B/F/TAF, bDRV initiators were statistically less likely to suppress to &lt;50 copies/mL (0.72 [0.52, 0.99]) and &lt;200 copies/mL (0.55 [0.43, 0.70]); no statistically significant difference was detected with DTG or EVG/c. Conclusions Among people with advanced HIV infection, those initiating B/F/TAF were less likely to discontinue/modify their regimen than those on any other regimen, and more likely to achieve viral suppression compared to those on bDRV but not compared to those on other integrase inhibitors.

“Double-Hit” Chronic Lymphocytic Leukemia, Involving the TP53 and MYC Genes

Although the 17p deletion [del(17p)] is rare in cases of treatment-naive chronic lymphocytic leukemia (CLL), its frequency is higher in refractory/relapsed CLL – particularly in patients undergoing chemo(immuno)therapy. TP53 disruption (deletion and/or mutation) is the strongest prognostic factor for refractoriness to chemotherapy; the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is then indicated. Rare cases of CLL can also harbor translocation or gain of the MYC oncogene. “Double-hit CLL” (with del(17p) and MYC gain) is associated with a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies must now be evaluated.

Pangenotypic and Genotype-Specific Antivirals in the Treatment of HCV Genotype 4 Infected Patients with HCV Monoinfection and HIV/HCV Coinfection

The introduction of the direct-acting antivirals (DAA) has substantially improved the effectiveness of the therapy in patients with chronic hepatitis C. We aimed to compare the efficacy of pangenotypic and genotype-specific DAA in the cohort of genotype (GT) four patients with HCV monoinfection and HIV coinfection. A total of 662 GT4-infected patients treated in 2015–2020—of whom 168 (25.3%) were coinfected with HIV, selected from the retrospective EpiTer-2 database—were enrolled in the analysis. Among HIV-coinfected patients, 54% (90) were treated with genotype-specific regimens and 46% (78) with pangenotypic options, while among HCV-monoinfected patients, the rates were 72% and 28%, respectively. Significantly higher rate of males (67.9% vs. 57.7%, p = 0.01), a lower rate of liver cirrhosis (10.2% vs. 18.1%, p = 0.02), and higher of treatment-naïve patients (87.5% vs. 76.7%, p = 0.003) were documented in the HIV coinfected population. The overall sustained virologic response after exclusion of non-virologic failures was achieved in 98% with no significant difference between HIV-positive and HIV-negative patients, 96.2% vs. 98.5%, respectively. While the genotype-specific regimens resulted in a similar cure rate regardless of the HIV status, the pangenotypic options were more efficacious in patients with HCV monoinfection (99.3% vs. 94.4%, p = 0.05). Hereby, we demonstrated the high effectiveness and good safety profile of the DAA therapy in the population of HCV GT4 infected patients with HIV coinfection supporting the current recommendations to treat HCV/HIV coinfected patients with the same options as those with HCV monoinfection.

Surgical Resection is Preferred in Selected Solitary Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

Backgrounds: Sorafenib is the standard care for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT), though it offers limited survival. This study was designed to compare clinical outcomes between liver resection (surgery) and trans-arterial chemoembolization plus radiotherapy (TACE-RT) as the initial treatment modality for resectable treatment-naïve solitary HCC combined with subsegmental (Vp1), segmental (Vp2), and lobar (Vp3) PVTT. Methods: From the institutional HCC registry, we identified 116 patients diagnosed with resectable treatment-naïve HCC with Vp1-Vp3 PVTT based on radiologic images who received surgery (n=44) or TACE-RT (n=72) as a primary treatment between 2010 and 2015. A propensity score matching (PSM) model was created. Results: The TACE-RT group had a higher tumor burden (tumor size, extent, and markers) than the surgery group. Cumulative patient survival curve in the surgery group was significantly higher than in the TACE-RT group before and after PSM. Liver function was relatively well-preserved in the surgery group compared with the TACE-RT group. TACE-RT group, male, increased alkaline phosphatase, and increased platelet count were predisposing factors for patient death in resectable treatment-naïve solitary HCC with PVTT. Conclusions: The present study suggests that surgery should be considered as an initial treatment in resectable treatment-naïve solitary HCC with Vp1-Vp3 PVTT.

First Results From a Propensity Matching Trial of Mycophenolate Mofetil vs. Azathioprine in Treatment-Naive AIH Patients

Background/AimsAs previous real-world studies and meta-analyses have shown that mycophenolate mofetil (MMF) might have better efficacy than azathioprine (AZA) in autoimmune hepatitis (AIH), we conducted a propensity matching study to assess the efficacy and safety of MMF vs. AZA.MethodsAll 126 consecutive treatment-naive adult AIH patients, diagnosed and followed in our department since 2016, were included. Patients received prednisolone 0.5–1 mg/kg/day plus either AZA 1–2 mg/kg/day or 1.5–2 g/day MMF. The tapering of prednisolone was identical between groups.ResultsAfter propensity matching score and adjustment for known factors affecting response to treatment and outcome, 64 patients were included in the study (MMF = 32 and AZA = 32). Rates of non-response, complete biochemical response (CBR) at 6 and 12 months, and prednisolone withdrawal (6 months, 12 months, and end of follow-up) were identical between groups. However, MMF treatment was significantly associated with CBR at the end of follow-up [odds ratio (OR) 11.259; 95% CI: 1.3–97.4, p = 0.028]. AZA patients were more prone to stop treatment due to AZA intolerance/insufficient response (p = 0.0001). At the end of follow-up, the overall efficacy of each schedule was also significantly higher in the MMF group compared to the AZA group (p = 0.0001).ConclusionWe showed for the first time in a propensity matching study that MMF can be used as first-line therapy in AIH as attested by the significantly higher CBR at end of follow-up compared to AZA. Whether this better efficacy is also associated with higher histological remission rates and sustained CBR off immunosuppression needs further evaluation.

Synergistic Analysis of Circulating Tumor Cells Reveals Prognostic Signatures in Pilot Study of Treatment-Naïve Metastatic Pancreatic Cancer Patients

Pancreatic ductal adenocarcinoma is typically diagnosed at late stages and has one of the lowest five-year survival rates of all malignancies. In this pilot study, we identify signatures related to survival and treatment response found in circulating tumor cells (CTCs). Patients with poor survival had increased mutant KRAS expression and deregulation of connected pathways such as PI3K-AKT and MAPK signaling. Further, in a subset of these patients, expression patterns of gemcitabine resistance mechanisms were observed, even prior to initiating treatment. This work highlights the need for identifying patients with these resistance profiles and designing treatment regimens to circumvent these mechanisms.

The Presence of Non-organ-specific Autoantibodies in Chronic Hepatitis C Treatment-naive Patients

Background: In the patients with hepatitis C virus (HCV) various immune mediated phenomena are described, and non organ specific autoantibodies (NOSAs) in particular are common. The aim of the present study was to investigate the NOSAs prevalence in chronic hepatitis C treatment naive patients. Patients and Methods: Sera of 76 consecutive HCV treatment naive patients were considered to be eligible for this study for evaluation of Antinuclear, antismooth muscle, antimitochondrial, antineutrophil cytoplasmatic and antiliver kidney microsomal antibodies. Criteria of eligibility were serum antiHCV antibody and HCV RNA positivity, chronic inflammation revealed by histological analysis of the liver, genotyping, treatment naive patients, and no have the diagnosis of probable or definite autoimmune hepatitis. Results: Mean chronological age for the 76 patients (44 females and 32 males) was 51.3 years (range: 20 to 67 years). Nineteen patients (25.0%) infected with HCV had detectable levels of NOSAs at before combined antiviral treatment. SMA was present in 16 (21.0%) of 76 patients, ANA in 2 patients (2.6%), and pANCA (perinuclear ANCA) in 1 patients (1.3%). No patient had specimens reactive to AMA, LMK, or cANCA (cytoplasmic ANCA). Conclusions: In this study, we show the NOSAs positivity in chronic hepatitis c treatment naive patients. Assigned to high prevalence of SMA positivity is associated with high METAVIR score, and HCV genotype 1 and 1b, may reflect a release of intracellular antigens at the time of hepatocellular injury triggering immune responses in the form of autoantibody production or a direct infection of immunocytes by the HCV. Keywords: hepatitis C, treatment naive, non organ specific antibodies, chronic liver disease