Which protocol for prostate biopsies in patients with a positive MRI? Interest of systematic biopsies by sectors.

BACKGROUND: Current prostate biopsy (PBx) protocol for prostate cancer (PCa) diagnosis is to perform systematic biopsies (SBx) combined with targeted biopsies (TBx) in case of positive MRI (i.e. PI-RADS ≥ 3). To assess the utility of performing SBx in combination with TBx, we determined the added value of SBx brought to the diagnosis of PCa according to their sextant location and MRI target characteristics. METHODS: In our local prospectively collected database, we conducted a single-center retrospective study including all patients with a suspicion of PCa, who underwent transrectal ultrasound-guided (TRUS) prostate biopsies (PBx) with a prior MRI and a single lesion classified as PI-RADS ≥ 3. We have characterized the SBx according to their location on MRI: same sextant (S-SBx), adjacent sextant (A-SBx), ipsilateral side (I-SBx) and contralateral side (C-SBx). The added value of SBx and TBx was defined as any upgrading to significant PCa (csPCa) (ISUP ≥2). RESULTS: 371 patients were included in the study. The added value of SBx was 10% overall. Regarding the lesion location and the SBx sextant, the added value of SBx was: 5.1% for S-SBx, 5.4% for A-SBx, 4.9% for I-SBx and 1.9% for C-SBx. The overall added value of SBx was 6.8% for PI-RADS 3 lesions, 14% for PI-RADS 4 lesions and 6.7% for PI-RADS 5 lesions (p = 0.063). The added value of SBx for contralateral side was 1.9% (2/103), 3.1% (5/163) and 0% (0/105) for PI-RADS 3, PI-RADS 4 and PI-RADS 5 lesions, respectively (p = 0,4). The added value of SBx was lower when the number of TBx was higher (OR 0.57; CI 95% 0.37-0.85; p = 0.007). CONCLUSIONS: Our results suggest that the utility of performing SBx in the contralateral lobe toward the MRI lesion was very low, supporting that they might be avoided.

Prognostic significance of PI-RADS 5 lesions in patients treated by radical prostatectomy.

PURPOSE: To analyse the pathological features and survival of patients with a PI-RADS 5 lesion on pre-biopsy MRI. METHODS: We extracted from a European multicentre prospectively gathered database the data of patients with a PI-RADS 5 lesion on pre-biopsy MRI, diagnosed using both systematic and targeted biopsies and subsequently treated by radical prostatectomy. The Kaplan-Meier model was used to assess the biochemical-free survival of the whole cohort and univariable and multivariable Cox models were set up to study factors associated with survival. RESULTS: Between 2013 and 2019, 539 consecutive patients with a PI-RADS 5 lesion on pre-biopsy MRI were treated by radical prostatectomy and included in the analysis. Follow-up data were available for 448 patients. Radical prostatectomy and lymph node dissection specimens showed non-organ confined disease in 297/539 (55%), (including 2 patients with a locally staged pT2 lesion and lymph node involvement (LNI)). With a median follow-up of 25 months (12-39), the median biochemical recurrence-free survival was 54% at 2 years (95% CI 45-61) and 28% at 5 years (95% CI 18-39). Among the factors studied, MRI T stage [T3a vs T2 HR 3.57 (95%CI 1.78-7.16); T3b vs T2 HR 6.17 (95% CI 2.99-12.72)] and PSA density (HR 4.47 95% CI 1.55-12.89) were significantly associated with a higher risk of biochemical recurrence in multivariable analysis. CONCLUSION: Patients with a PI-RADS 5 lesion on pre-biopsy MRI have a high risk of early biochemical recurrence after radical prostatectomy. MRI T stage and PSA density can be used to improve patient selection and counselling.

Direct comparison between Grade Group assessed on systematic and MRI/ultrasound fusion targeted biopsies correlated to the radical prostatectomy specimens in patients with prostate cancer.

OBJECTIVES: To compare the correlation of Gleason score (GS) and ISUP grade determined by prostate biopsies (PBx) and radical prostatectomy (RP) specimens according to the biopsy technique: ultrasound randomised (RBx) vs. MRI/ultrasound fusion targeted (TBx). MATERIALS AND METHODS: Between March 2013 and June 2018, we retrospectively included patients who underwent RP for prostate cancer (PCa) histopathologically proven by RBx and/or TBx. All patients had a prebiopsy MRI by a single radiologist (using PI-RADS score), then transrectal RBx (12cores, blinded to MRI lesions) and TBx (2-4 cores/target) with elastic MRI/ultrasound fusion (UroStation™, Koelis, Grenoble, France). Histological findings were compared: PBx vs. RP. RESULTS: One hundred and four patients underwent RP after RBx and/or TBx. ISUP concordance rate was better with the association RBx+TBx 49% (51/104) vs. 43.3% with TBx (P=0.07) and 43.3% with RBx (P=0.13). With RBx, 50% of the patients were downgraded (52/104) against 42.3% (44/104) with TBx (P=0.088). The association RBx+TBx significantly decreased the rate of downgrading of the ISUP score compared to the ISUP score of RP 35.6% (37/104) vs. RBx (50%, P=0.0001) and vs. TBx (42.3%, P=0.016). CONCLUSION: In half of cases, the ISUP score was underestimated in RBx compared to RP specimens. Adding TBx to RBx significantly reduced downgrading. The combination of both biopsy techniques appeared to be the best protocol to get closer to ISUP score and GS of the RP specimens. LEVEL OF EVIDENCE: C.

The use of patient-reported outcome and experience measures for health policy purposes: A scoping review in oncology.

The systematic use of patient-reported measures (PRMs) [i.e., patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs)] is advocated as an effective way to improve care practices. However, whether PRMs can lead to the performance assessment of healthcare organisations (HCOs) through valid quality indicators (QIs) for national purposes (i.e., public reporting and paying for performance) is open to debate. This study undertakes a scoping review to examine the use of PRMs as QIs for health policy purposes and to identify the challenges faced in the emblematic case of oncology. According to PRISMA guidelines, published papers, websites and reports published by national and international initiatives were analysed using five online databases (Web of Science, Scopus, PubMed, JSTOR and Google Advanced Search), and then studied using the same keywords. We selected 61 articles and 19 websites/reports and identified 29 PREMs and 48 PROMs from 14 countries and two international initiatives that routinely used them as QIs for HCOs' comparisons. Four types of barriers to this specific use were identified relating to the definition of a standard set, scientific soundness, data collection, and the actionability of such measures. Despite current developments, different barriers still must be overcome before PRMs can be used for health policy purposes in oncology. Future research is needed to ensure that valid QIs related to PRMs are applied at a national level.

Deep learning in medical image analysis: A third eye for doctors.

AIM AND SCOPE: Artificial intelligence (AI) in medicine is a fast-growing field. The rise of deep learning algorithms, such as convolutional neural networks (CNNs), offers fascinating perspectives for the automation of medical image analysis. In this systematic review article, we screened the current literature and investigated the following question: "Can deep learning algorithms for image recognition improve visual diagnosis in medicine?" MATERIALS AND METHODS: We provide a systematic review of the articles using CNNs for medical image analysis, published in the medical literature before May 2019. Articles were screened based on the following items: type of image analysis approach (detection or classification), algorithm architecture, dataset used, training phase, test, comparison method (with specialists or other), results (accuracy, sensibility and specificity) and conclusion. RESULTS: We identified 352 articles in the PubMed database and excluded 327 items for which performance was not assessed (review articles) or for which tasks other than detection or classification, such as segmentation, were assessed. The 25 included papers were published from 2013 to 2019 and were related to a vast array of medical specialties. Authors were mostly from North America and Asia. Large amounts of qualitative medical images were necessary to train the CNNs, often resulting from international collaboration. The most common CNNs such as AlexNet and GoogleNet, designed for the analysis of natural images, proved their applicability to medical images. CONCLUSION: CNNs are not replacement solutions for medical doctors, but will contribute to optimize routine tasks and thus have a potential positive impact on our practice. Specialties with a strong visual component such as radiology and pathology will be deeply transformed. Medical practitioners, including surgeons, have a key role to play in the development and implementation of such devices.

Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial.

PURPOSE: To compare the overall survival rates of good-prognosis carcinomas of an unknown primary site (CUPS) patients treated with cisplatin alone (C) or in combination with gemcitabine (CG). PATIENTS AND METHODS: Good prognosis was defined according to the GEFCAPI (Groupe d'Etude Français des Carcinomes de site Primitif Inconnu) classification by PS (Performance Status) ≤ 1 and LDH (Lactate Deshydrogenase) within the normal range. Patients were randomly assigned to receive C or CG. Patients in the C arm received cisplatin 100 mg/m(2) repeated every 3 weeks. In the CG arm, chemotherapy consisted of gemcitabine 1250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) IV on day 1, repeated every 3 weeks. The original plan was to accrue 192 patients in order to detect a 20% difference in overall survival. RESULTS: Fifty-two patients were enrolled (arm A: 25; arm B: 27). The trial was stopped early due to insufficient accrual. The median overall survival (OS) rate was 11 months [95% confidence interval: 9-20] and 8 months [95%CI: 6-12], in the CG arm and in the C arm, respectively. The 1-year survival rate was 46% [95%CI: 28-64] in the combination arm and 35% [95%CI: 19-56] in the C arm (log rank test: p=0.73). The median progression-free survival (PFS) rate was 5 [95%CI: 3-11] and 3 [95%CI: 1-8] months in the CG and in the C arm, respectively. The 1-year PFS rate was 29% [95%CI: 15-48] in the combination arm and 15% [95%CI: 5-35] in the C arm (log rank test: p=0.27). No toxic deaths occurred. Grade 3-4 neutropenia (63% versus 12%) and grade 3-4 thrombocytopenia (37% versus 4%) were more frequent in the CG arm than in the C arm. CONCLUSION: A non-significantly better outcome was observed with CG as compared to C in patients with CUP and a non-unfavourable prognosis. The toxicity profile of the combined arm was represented by haematologic toxicity with thrombocytopenia and leuconeutropenia. International collaboration is required to conduct phase III trials in patients with CUP.

[Assessment of the French surgical checklist: the experience of 17 French cancer centres]. / Évaluation et applicabilité de la check-list HAS au quotidien: expérience des centres de lutte contre le cancer.

INTRODUCTION: The use of WHO checklist has been associated to a decrease of complication incidence and mortality. This control is mandatory since January the 1st 2010. Evaluation of the quality of documentation is important and includes filling rate, which is a reflexion of participant adhesion and analysis of the circumstances where the team answers "no" during the control. METHODS: This study concerned 17 among 20 French cancer centres. Percentage of documented checklist, exhaustivity of the answers in each checklist and "no" answers have been compared during two periods: January 2010 and October 2010. RESULTS: Rate of filled document is satisfactory and stable during the two periods (95.5% versus 95.8%). Exhaustivity was slightly better during the second period (64 and 68%, P=0,039). Nevertheless, variability between centres was large; one centre improved and four centres worsened their scores. Rate of "no" answers was low and increased during the second period (1.5% in January 1.9% in October P<0.001). They mainly concerned antibiotic administration and at a lesser degree bleeding risk, the name of the procedure, equipment problem to be addressed and postoperative management. DISCUSSION: There is a large discrepancy between centres and for a given centre in reporting quality. Significant progress should be expected using target improvement. This approach implies multiple critical analysis of checklist content in each hospital and in multicentre enquiries.

Prolonged display or rapid internalization of the IgG-binding protein ZZ anchored to the surface of cells using the diphtheria toxin T domain.

We have shown previously that the diphtheria toxin transmembrane domain (T) may function as a membrane anchor for soluble proteins fused at its C-terminus. Binding to membranes is triggered by acidic pH. Here, we further characterized this anchoring device. Soluble proteins may be fused at the N-terminus of the T domain or at both extremities, without modifying its membrane binding properties. This allows one to choose the orientation of the protein to be attached to the membrane. Maximum binding to the cell surface is reached within 1 h. Anchoring occurs on cells previously treated with proteinase K, suggesting that T interacts with the lipid phase of the membrane without the help of cell surface proteins. Binding does not permeabilize cells or affect cell viability, despite the fact that it permeabilizes liposomes and alters their structure. When attached to L929 fibroblasts, the proteins are not internalized and remain displayed at their surface for more than 24 h. When bound to K562 myeloid cells, the molecules are internalized and degraded. Thus, depending on the cell type, soluble proteins may be anchored to the surface of cells by the T domain for an extended time or directed towards an internalization pathway.

Short unligated sticky ends enable the observation of circularised DNA by atomic force and electron microscopies.

A comparative study of the stabilisation of DNA sticky ends by divalent cations was carried out by atomic force microscopy (AFM), electron microscopy and agarose gel electrophoresis. At room temperature, molecules bearing such extremities are immediately oligomerised or circularised by addition of Mg2+or Ca2+. This phenomenon, more clearly detected by AFM, requires the presence of uranyl salt, which stabilises the structures induced by Mg2+or Ca2+. DNA fragments were obtained by restriction enzymes producing sticky ends of 2 or 4 nucleotides (nt) in length with different guanine plus cytosine (GC) contents. The stability of the pairing is high when ends of 4 nt display a 100% GC-content. In that case, 95% of DNA fragments are maintained circular by the divalent cations, although 2 nt GC-sticky ends are sufficient for a stable pairing. DNA fragments with one blunt end and the other sticky appear as dimers in the presence of Mg2+. Dimerisation was analysed by varying the lengths and concentrations of DNA fragments, the base composition of the sticky ends, and also the temperature. Our observation provides a new powerful tool for construction of inverted dimers, and circularisation, ligation analysis or short bases sequence interaction studies.

Analysis of various sequence-specific triplexes by electron and atomic force microscopies.

Sequence-specific interactions of 20-mer G,A-containing triple helix-forming oligonucleotides (TFOs) and bis-PNAs (peptide nucleic acids) with double-stranded DNA was visualized by electron (EM) and atomic force (AFM) microscopies. Triplexes formed by biotinylated TFOs are easily detected by both EM and AFM in which streptavidin is a marker. AFM images of the unlabeled triplex within a long plasmid DNA show a approximately 0.4-nm height increment of the double helix within the target site position. TFOs conjugated to a 74-nt-long oligonucleotide forming a 33-bp-long hairpin form extremely stable triplexes with the target site that are readily imaged by both EM and AFM as protruding DNA. The short duplex protrudes in a perpendicular direction relative to the double helix axis, either in the plane of the support or out of it. In the latter case, the apparent height of the protrusion is approximately 1.5 nm, when that of the triplex site is increased by 0.3-0.4 nm. Triplex formation by bis-PNA, in which two decamers of PNA are connected via a flexible linker, causes deformations of the double helix at the target site, which is readily detected as kinks by both EM and AFM. Moreover, AFM shows that these kinks are often accompanied by an increase in the DNA apparent height of approximately 35%. This work shows the first direct visualization of sequence-specific interaction of TFOs and PNAs, with their target sequences within long plasmid DNAs, through the measurements of the apparent height of the DNA double helix by AFM.

[Complementarity of microscopies in the structural analysis of DNA minicircles associated to protein MC1]. / Complémentarité des microscopies dans l'analyse structurale de minicercles d'ADN associés à la protéine MC1.

Electron microscopy of DNA, either free or complexed with ligands, allows the analysis of local conformational variations along individual molecules. Electron microscopy is unique, in that it has the capacity to determine the average behaviour of a population of molecules observed individually, and can thus provide a better appreciation of variability within the series of molecules than biophysical or biochemical methods. Very encouraging results have been obtained by cryoelectron and near-field microscopies, especially atomic force microscopy, in parallel with traditional techniques for visualizing DNA molecules adsorbed onto a support film. Differences in sample processing procedures and image formation modes render these 3 types of microscopies complementary. The torsional stress of a DNA molecule together with a local curvature induced by the protein MC1 from archaebacteria, can be detected within minicircles comprising 207 base pairs.

Observation of binding and polymerization of Fur repressor onto operator-containing DNA with electron and atomic force microscopes.

The Fur (ferric uptake regulation) protein is a global regulator that, in the presence of Fe2+, represses the expression of a number of iron-acquisition genes and virulence determinants such as toxins. Dark-field electron microscopy of positively stained Fur-DNA complexes in addition to atomic force microscopy allowed direct visualization of Fur interactions with the regulatory regions of aerobactin and hemolysin operons and provided complementary information about the structure of the complexes. According to the DNA used and the protein/DNA ratio, Fur binding to DNA results in partial or total covering of the fragments, indicating that the protein initiates polymerization along the DNA molecules at specific sites. Negative staining of Fur-DNA complexes revealed a well-ordered structure of the polymer suggesting a helical arrangement. Local rigidification of the DNA molecules resulting from Fur binding could be involved in the repression process.

[Evaluation of hospital care. An experiment at the Public Assistance Hospitals in Paris]. / L'évaluation des soins à l'hôpital. Une expérience à l'Assistance Publique-Hôpitaux de Paris.

Since 1990 the Assistance Publique--Hôpitaux de Paris (AP-HP) developed a policy of health care assessment in agreement with the implications of the law of July 31, 1991. The department of Evaluation of health care, in close collaboration with the local Committees which operate in most of the hospitals of AP-HP, performed during the last three years about fifty studies dealing with two main topics: professional procedures and quality of care. Through three specific selected studies, the authors emphasize the requirements of an assessment policy to efficiently contribute to the improvement of quality of care.

3'-Deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin conquers multidrug resistance by rapid influx following higher frequency of formation of DNA single- and double-strand breaks.

The mechanism of action of 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) was examined in a human leukemia cell line (K562) and its Adriamycin (ADM)-resistant subline (K562/ADM). ADM and MX2 showed an equivalent antitumor effect against K562. K562/ADM was highly resistant to ADM. In cellular pharmacokinetic studies, MX2 showed faster and greater influx than did ADM in both K562 and K562/ADM. The efflux of ADM was rapid in K562/ADM but not in K562. On the other hand, the efflux of MX2 was rapid in both cell lines. The formation of DNA single-strand breaks and double-strand breaks by ADM was significantly lower in K562/ADM than K562. On the other hand, formation of those breaks by MX2 was not decreased. Although some of the DNA breaks induced by MX2 were resealed, there was no difference in the degree of resealing in K562 and K562/ADM cells. On the other hand, most of the small number of DNA breaks in K562/ADM induced by ADM were resealed. The topoisomerase II activity in K562 and K562/ADM was not significantly different. It is concluded that MX2 conquers multidrug resistance by rapid influx following a higher frequency of formation of DNA single- and double-strand breaks in K562/ADM cells.

Effect of doxorubicin on mouse hybridoma B cells: stimulation of immunoglobulin synthesis and secretion.

The purpose of these studies was to investigate whether the cell-differentiating effect of anthracyclines can trigger an over-production and secretion of molecules that may interfere with the tumor-host relationship. We exposed mouse hybridoma B-cells, which are devoted to immunoglobulin production, to doxorubicin (10-40 ng/ml). We found that most doxorubicin-treated cells secreted 3- to 5-fold higher amounts of immunoglobulin than untreated cells, along with an accumulation of 50% of them in the G2+M phase of the cell cycle. The antigenic specificity of the immunoglobulin and its size pattern as determined by polyacrylamide gel electrophoresis were similar whether or not cells were treated with doxorubicin. The enhancement of immunoglobulin secretion by doxorubicin was associated with an increase of the intracellular pool of heavy and light chains of the immunoglobulin. Furthermore, an elevated synthesis of immunoglobulin was observed. The synthesis of other proteins also appeared to be modified in these circumstances. These data suggest that doxorubicin can potentiate the biological functions of target cells when used at low concentrations, elevating the production and secretion of effector molecules that interfere with the tumor-host relationship.

Potentiation of adriamycin accumulation and effectiveness in adriamycin-resistant cells by aclacinomycin A.

Variants of Friend leukemia cells (FLC) selected for resistance to either adriamycin (ADM), daunorubicin (DNR) or aclacinomycin A (ACM) by step-wise exposure to each drug, were found to be cross-resistant to ADM and DNR but not to ACM. In addition, an epithelial cell line isolated from normal monkey kidney (CV-1) was found to be intrinsically resistant to ADM and DNR but not to ACM. In contrast, a human breast carcinoma cell line (MCF-7) was found to be sensitive to all three compounds. In these latter cell lines as well as in the FLC variants, lowered intracellular amounts of ADM and DNR correlated with resistance, but ACM levels were the same in sensitive and resistant cells. When cells with either acquired or intrinsic resistance were treated with ACM in combination with ADM or DNR, significant increases in the intracellular amounts of these latter compounds were found. Increased drug accumulation in resistant cells treated this way was accompanied by increased cytotoxicity. When resistant cells were exposed to ACM in combination with other anthracyclines, similar results were obtained. In comparison, these phenomena were not observed when either one of the sensitive cell types (parental FLC and MCF-7) were treated similarly. Since ADM and DNR resistant cells are sensitive to ACM and their resistance circumvented by ACM, this drug may have important clinical applications when used in combination with other anthracyclines.