Magnetic Resonance Imaging Follow-up of Targeted Biopsy-negative Prostate Lesions

BACKGROUND: The optimal radiological follow-up of prostate lesions negative on magnetic resonance imaging (MRI)-targeted biopsy (MRI-TB) is yet to be optimised. OBJECTIVE: To present medium-term radiological and clinical follow-up of biopsy-negative lesions. DESIGN, SETTING, AND PARTICIPANTS: The records for men who underwent multiparametric MRI at the UCLH one-stop clinic for suspected prostate cancer between September 2017 and March 2020 were reviewed (n = 1199). Patients with Likert 4 or 5 lesions were considered (n = 495), and those with a subsequent negative MRI-TB comprised the final study population (n = 91). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline and follow-up MRI and biopsy data (including prostate-specific antigen [PSA], prostate volume, radiological scores, and presence of any noncancerous pathology) were extracted from reports. The last follow-up date was the date of the last test or review in clinic. RESULTS AND LIMITATIONS: Median follow-up was 1.8 yr (656 d, interquartile range [IQR] 359-1008). At baseline, the median age was 65.4 yr (IQR 60.7-70.0), median PSA was 7.1 ng/ml (IQR 4.7-10.0), median prostate volume was 54 ml (IQR 39.5-75.0), and median PSA density (PSAD) was 0.13 ng/ml2 (IQR 0.09-0.18). Eighty-six men (95%) had Likert 4 lesions, while the remaining five (5%) had Likert 5 lesions. Only 21 men (23%) had a single lesion; most had at least two. Atrophy was the most prevalent pathology on MRI-TB, present in 64 men (74%), and followed by acute inflammation in 42 (46%), prostatic intraepithelial neoplasia in 33 (36%), chronic inflammation in 18 (20%), atypia in 13 (14%), and granulomatous inflammation in three (3%). Fifty-eight men had a second MRI study (median 376 d, IQR 361-412). At the second MRI, median PSAD decreased to 0.11 ng/ml2 (IQR 0.08-0.18). A Likert 4 or 5 score persisted only in five men (9%); 40 men (69%) were scored Likert 3, while the remaining 13 (22%) were scored Likert 2 (no lesion). Of 45 men with a Likert ≥3 score, most only had one lesion at the second MRI (28 men; 62%). Of six men with repeat MRI-TB during the study period, two were subsequently diagnosed with prostate cancer and both had persistent Likert 4 scores (at baseline and at least one follow-up MRI). CONCLUSIONS: Most biopsy-negative MRI lesions in the prostate resolve over time, but any persistent lesions should be closely monitored. PATIENT SUMMARY: Lesions in the prostate detected via magnetic resonance imaging (MRI) scans that are negative for cancer on biopsy usually resolve. Repeat MRI can indicate persistent lesions that might need a second biopsy

The Phenolic Glycolipid of Mycobacterium tuberculosis Differentially Modulates the Early Host Cytokine Response but Does Not in Itself Confer Hypervirulence▿

Mycobacterium tuberculosis possesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinical M. tuberculosis isolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group of M. tuberculosis strains with an intact pks1-15 gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intact pks1-15 do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinical M. tuberculosis isolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence of M. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain

Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

International audienceMinimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse

The Impact of DNMT3A Status on NPM1 MRD Predictive Value and Survival in Elderly AML Patients Treated Intensively

International audienceSimple Summary DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of acute myeloid leukemia (AML) patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. A 4log reduction of NPM1 MRD was associated with a better outcome. DNMT3A negative patients who achieved a 4log reduction had a superior outcome to those who did not. However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identify a subgroup of patients at high risk of relapse. Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a >= 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached >= 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse

Effects of Lipid-Lowering Drugs on Vancomycin Susceptibility of Mycobacteria

Tuberculosis is still a cause of major concern, partly due to the emergence of multidrug-resistant strains. New drugs are therefore needed. Vancomycin can target mycobacteria with cell envelope deficiency. In this study, we used a vancomycin susceptibility assay to detect drugs hampering lipid synthesis in Mycobacterium bovis BCG and in Mycobacterium tuberculosis We tested three drugs already used to treat human obesity: tetrahydrolipstatin (THL), simvastatin, and fenofibrate. Only vancomycin and THL were able to synergize on M. bovis BCG and on M. tuberculosis, although mycobacteria could also be inhibited by simvastatin alone. Lipid analysis allowed us to identify several lipid modifications in M. tuberculosis H37Rv treated with those drugs. THL treatment mainly reduced the phthiocerol dimycocerosate (PDIM) content in the mycobacterial cell wall, providing an explanation for the synergy, since PDIM deficiency has been related to vancomycin susceptibility. Proteomic analysis suggested that bacteria treated with THL, in contrast to bacteria treated with simvastatin, tried to recover, inducing, among other reactions, lipid synthesis. The combination of THL and vancomycin should be considered a promising solution in developing new strategies to treat multidrug-resistant tuberculosis.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Magnetic Resonance Imaging Follow-up of Targeted Biopsy–negative Prostate Lesions

International audienc