Influence of Different Measurement Methods of Arterial Input Function on Quantitative Dynamic Contrast-Enhanced MRI Parameters in Head and Neck Cancer.

BACKGROUND: Head and neck cancer (HNC) is the sixth most prevalent cancer worldwide. Dynamic contrast-enhanced MRI (DCE-MRI) helps in diagnosis and prognosis. Quantitative DCE-MRI requires an arterial input function (AIF), which affects the values of pharmacokinetic parameters (PKP). PURPOSE: To evaluate influence of four individual AIF measurement methods on quantitative DCE-MRI parameters values (Ktrans , ve , kep , and vp ), for HNC and muscle. STUDY TYPE: Prospective. POPULATION: A total of 34 HNC patients (23 males, 11 females, age range 24-91) FIELD STRENGTH/SEQUENCE: A 3 T; 3D SPGR gradient echo sequence with partial saturation of inflowing spins. ASSESSMENT: Four AIF methods were applied: automatic AIF (AIFa) with up to 50 voxels selected from the whole FOV, manual AIF (AIFm) with four voxels selected from the internal carotid artery, both conditions without (Mc-) or with (Mc+) motion correction. Comparison endpoints were peak AIF values, PKP values in tumor and muscle, and tumor/muscle PKP ratios. STATISTICAL TESTS: Nonparametric Friedman test for multiple comparisons. Nonparametric Wilcoxon test, without and with Benjamini Hochberg correction, for pairwise comparison of AIF peak values and PKP values for tumor, muscle and tumor/muscle ratio, P value ≤ 0.05 was considered statistically significant. RESULTS: Peak AIF values differed significantly for all AIF methods, with mean AIFmMc+ peaks being up to 66.4% higher than those for AIFaMc+. Almost all PKP values were significantly higher for AIFa in both, tumor and muscle, up to 76% for mean Ktrans values. Motion correction effect was smaller. Considering tumor/muscle parameter ratios, most differences were not significant (0.068 ≤ Wilcoxon P value ≤ 0.8). DATA CONCLUSION: We observed important differences in PKP values when using either AIFa or AIFm, consequently choice of a standardized AIF method is mandatory for DCE-MRI on HNC. From the study findings, AIFm and inflow compensation are recommended. The use of the tumor/muscle PKP ratio should be of interest for multicenter studies. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

High-Relaxivity Molecular MRI Contrast Agent to Target Gb3-Expressing Cancer Cells.

Targeted contrast agents (CAs) can improve magnetic resonance imaging (MRI) for accurate cancer diagnosis. In this work, we used the Shiga toxin B-subunit (STxB) as a targeting agent, which binds to Gb3, a glycosphingolipid highly overexpressed on the surface of tumor cells. We developed STxB-targeted MRI probes from cyclic peptide scaffolds functionalized with six to nine monoamide DO3A[Gd(III)] chelates. The influence of structural constraints on the longitudinal relaxivity (r1) of the CAs has been studied. The cyclic peptide carrying nine monoamide DO3A[Gd(III)] exhibited a r1 per compound of 32 and 93 mM-1s-1 at 9.4 and 1.5 T, respectively. Its conjugation to the pentameric STxB protein led to a 70 kDa compound with a higher r1 of 150 and 475 mM-1 s-1 at 9.4 and 1.5 T, respectively. Specific accumulation and cellular distribution of this conjugate in Gb3-expressing cancer cells were demonstrated using immunofluorescence microscopy and quantified by an inductively coupled plasma-mass spectrometry dosage of Gd(III). Such an agent should enable the in vivo detection by MRI of tumors expressing Gb3 receptors.

New method for quantification of intratumoral heterogeneity: a feasibility study on Ktrans maps from preclinical DCE-MRI.

OBJECT: To develop new imaging biomarkers of therapeutic efficacy through the quantification of intratumoral microvascular heterogeneity. MATERIALS AND METHODS: The described method was a combination of non-supervised clustering and extraction of intratumoral complexity features (ICF): number of non-connected objects, volume fraction. It was applied to a set of 3D DCE-MRI Ktrans maps acquired previously on tumor bearing mice prior to and on day 4 of anti-angiogenic treatment. Evolutions of ICF were compared to conventional summary statistics (CSS) and to heterogeneity related whole tumor texture features (TF) on treated (n = 9) and control (n = 6) mice. RESULTS: Computed optimal number of clusters per tumor was 4. Several intratumoral features extracted from the clusters were able to monitor a therapy effect. Whereas no feature significantly changed for the control group, 6 features significantly changed for the treated group (4 ICF, 2 CSS). Among these, 5 also significantly differentiated the two groups (3 ICF, 2 CSS). TF failed in demonstrating differences within and between the two groups. DISCUSSION: ICF are potential imaging biomarkers for anti-angiogenic therapy assessment. The presented method may be expected to have advantages with respect to texture analysis-based methods regarding interpretability of results and setup of standardized image analysis protocols.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Impact of Intraoperative Re-resection to Achieve R0 Status on Survival in Patients With Pancreatic Cancer: A Single-center Experience With 483 Patients.

OBJECTIVE: The aim of this study was to test the hypothesis that intraoperative frozen section (FS) and re-resection results to achieve R0 status are associated with different long-term outcomes in pancreatic cancer patients. BACKGROUND: Recent data have challenged the survival benefit of additional resection in patients with pancreatic cancer in case of positive FS to achieve clear pathological section (PS). METHODS: Patients who underwent surgery for exocrine pancreatic malignancy with curative intent were identified from a prospective database. Data were stratified by resection margin (group I: FS-R0 → PS-R0; group II: FS-R1 → PS-R0; group III: FS-R1 → PS-R1). Associations with survival were analyzed by univariate and multivariate analyses. RESULTS: A total of 483 patients met the inclusion criteria. Of these, 61 patients were excluded due to R2 or Rx status. Three hundred seventeen (75%) patients were allocated to margin group I, 32 (8%) to group II, and 73 (17%) to group III. Median overall survival in group I, II, and III was 29, 36, and 12 months (P < 0.001). There was no significant difference in survival between patients in Group I and II (P = 0.849), whereas patients in group III had significantly poorer outcome than group I (P < 0.001) and II (P = 0.039). The prognostic value of margin group status was confirmed on multivariate analysis (hazard ratio = 1.694, 95% confidence interval 1.175-2.442). CONCLUSIONS: FS analysis with intraoperative re-resection should be performed routinely in patients undergoing pancreatic cancer surgery with the aim to achieve a R0 resection.

Inactivation of Zika virus by solvent/detergent treatment of human plasma and other plasma-derived products and pasteurization of human serum albumin.

BACKGROUND: In 2016 the World Health Organization declared the mosquito-borne Zika virus (ZIKV) a "public health emergency of international concern." ZIKV is a blood-borne pathogen, which therefore causes concerns regarding the safety of human plasma-derived products due to potential contamination of the blood supply. This study investigated the effectiveness of viral inactivation steps used during the routine manufacturing of various plasma-derived products to reduce ZIKV infectivity. STUDY DESIGN AND METHODS: Human plasma and intermediates from the production of various plasma-derived products were spiked with ZIKV and subjected to virus inactivation using the identical techniques (either solvent/detergent [S/D] treatment or pasteurization) and conditions used for the actual production of the respective products. Samples were taken and the viral loads measured before and after inactivation. RESULTS: After S/D treatment of spiked intermediates of the plasma-derived products Octaplas(LG), Octagam, and Octanate, the viral loads were below the limit of detection in all cases. The mean log reduction factor (LRF) was at least 6.78 log for Octaplas(LG), at least 7.00 log for Octagam, and at least 6.18 log for Octanate after 60, 240, and 480 minutes of S/D treatment, respectively. For 25% human serum albumin (HSA), the mean LRF for ZIKV was at least 7.48 log after pasteurization at 60°C for 120 minutes. CONCLUSION: These results demonstrate that the commonly used virus inactivation processes utilized during the production of human plasma and plasma-derived products, namely, S/D treatment or pasteurization, are effective for inactivation of ZIKV.

Treatment of tailgut cysts by extended distal rectal segmental resection with rectoanal anastomosis.

PURPOSE: Complete surgical resection is the treatment of choice for tailgut cysts, because of their malignant potential and tendency to regrow if incompletely resected. We report our experience of treating patients with tailgut cysts, and discuss diagnostics, surgical approaches, and follow-up. METHODS: We performed extended distal rectal segmental resection of the tailgut cyst, with rectoanal anastomosis. We report the clinical, radiological, pathological, and surgical findings, describe the procedures performed, and summarize follow-up data. RESULTS: Two patients underwent en-bloc resection of a tailgut cyst, the adjacent part of the levator muscle, and the distal rectal segment, followed by an end-to-end rectoanal anastomosis. There was no evidence of anastomotic leakage postoperatively. At the time of writing, our patients were relapse-free with no, or non-limiting, symptoms of anal incontinence, respectively. CONCLUSIONS: This surgical approach appears to have a low complication rate and good recovery outcomes. Moreover, as the sphincter is preserved, so is the postoperative anorectal function. This approach could result in a low recurrence rate.

Impact of Bevacizumab on parenchymal damage and functional recovery of the liver in patients with colorectal liver metastases.

BACKGROUND: Little is known about the safety of the anti-VEGF antibody bevacizumab in patients undergoing resection for colorectal liver metastases (CLM). This meta-analysis evaluates the impact of bevacizumab on parenchymal damage and functional recovery in patients undergoing resection for CLM. METHODS: The Medline, Embase and Cochrane Library were systematically searched for studies on preoperative chemotherapy with and without bevacizumab prior to resection of CLM. Studies that reported histological and/or clinical outcomes were eligible for inclusion. Meta-analyses were performed using a random effects model. RESULTS: A total of 18 studies with a total sample size of 2430 patients (1050 patients with bevacizumab) were found. Meta-analyses showed a significant reduction in sinusoidal obstruction syndrome (SOS) (Odds ratio 0.50 [95% confidence interval 0.37, 0.67]; p < 0.001; I(2) = 0%) and hepatic fibrosis (0.61 [0.4, 0.86]; p = 0.004; I(2) = 7%) after preoperative chemotherapy with bevacizumab. The reduced incidence of posthepatectomy liver failure in patients with bevacizumab treatment just failed to reach statistical significance (0.61 [0.34, 1.07]; p = 0.08 I(2) = 6%). While there was no difference in perioperative morbidity and mortality, the incidence of wound complications was significantly increased in patients who received bevacizumab (1.81 [1.12, 2.91]; p = 0.02 I(2) = 4%). CONCLUSIONS: The combination of bevacizumab with cytotoxic chemotherapy is safe but increases the incidence of wound complications after resection of CLM. The reduction of SOS and hepatic fibrosis warrant further investigation and may explain the inverse association of bevacizumab administration and posthepatectomy liver failure.

Perioperative application of somatostatin analogs for pancreatic surgery-current status in Germany.

BACKGROUND: The most common major complication after pancreatic resection is the postoperative pancreatic fistula (POPF). Somatostatin analogs can reduce POPF, but the use of somatostatin analogs is still controversial. The aim of this study was to assess treatment algorithms for pancreatic surgery in Germany with a special focus on the application of somatostatin analogs. METHODS: A questionnaire evaluating the perioperative management-especially the use of somatostatin analogs-and postoperative complications after pancreatic surgery was developed and sent to 209 German hospitals performing >12 pancreatoduodenectomies per year (the requirement for certification as a pancreas center). Statistical analysis was carried out using SPSS 21. RESULTS: The final response rate was 77 % (160/209), 14.5 % of hospitals never, 37 % always, and 45 % occasionally apply somatostatin analogs after pancreatic surgery. A (standard) drug of choice was defined in 64 % of hospitals. When standard and occasional usage was analyzed, it appeared that hospitals favored somatostatin (69 %) > sandostatin (50 %) > pasireotide (5 %). A relation between the usage of the different somatostatin analogs and morbidity (POPF) or mortality (84 and 16 % of hospitals reported <5 and 5-10 %, respectively) was not seen. Eighty-seven percent of hospitals were interested in participating in future studies analyzing somatostatin use. CONCLUSION: This is the first national survey in Germany evaluating the perioperative application of somatostatin analogs for pancreatic surgery. Despite controversial results in the literature, the majority of German pancreas surgeons apply somatostatin analogs perioperatively. The ideal drug to reduce POPF is still unclear. This uncertainty has aroused significant interest and prompted surgeons to participate in future studies in order to elucidate this issue.

T2*-relaxivity contrast imaging: first results.

In this study, T2*- relaxivity contrast imaging (RCI) is proposed for new contrast generation in MRI. The method produces images of relaxivities r*2,vasc and r*2,EES caused by susceptibility gradients across the vessel walls and cell membranes, respectively. The sensitivity to noise was assessed with a simulation study, and initial results are presented for five colorectal tumor xenografts in nude mice. Simulations show that the new relaxivity parameters are at least as accurate and precise as standard parameters such as plasma volume and interstitial volume. Mean values of both relaxivities were significantly different (r*2,vasc=10.9±2.9 mM(-1) s(-1) and r*2,EES=15.6±2.6 mM(-1) s(-1)). r*2,vasc (r=0.67) and r*2,EES (r=0.52) were weakly correlated with plasma volume and interstitial volume, respectively. Images of r*2,vasc and r*2,EES reveal a different tumor structure than plasma volume and interstitial volume maps. These results suggest that relaxivity contrast imaging is practically feasible and might offer supplementary information compared to dynamic contrast-enhanced-MRI.

Radial multigradient-echo DCE-MRI for 3D K(trans) mapping with individual arterial input function measurement in mouse tumor models.

The purpose of this study was to provide proof of concept for a new three-dimensional (3D) radial dynamic contrast enhanced MRI acquisition technique, called "Radial Entire Tumor with Individual Arterial input function dynamic contrast-enhanced MRI" (RETIA dynamic contrast-enhanced MRI), which allows for the simultaneous measurement of an arterial input function in the mouse heart at 2 s temporal resolution and coverage of the whole tumor. Alternating 2D and 3D projections contribute to the 2D heart image or 3D tumor data with a 3-cm field of view. Sixty-four 2D images of the heart are obtained during acquisition of each 3D tumor dataset. In a pilot study, global K(trans) and ve values were measured in four mice, in a respiratory motion-animated subcutaneously implanted breast tumor model. This technique is expected to be most useful for the characterization of microvasculature in motion-animated orthotopic tumors.

Lens epithelium-derived growth factor/p75 qualifies as a target for HIV gene therapy in the NSG mouse model.

Lens epithelium-derived growth factor (LEDGF/p75) is an essential cofactor of HIV integration. Both stable overexpression of the C-terminal part of LEDGF/p75 (LEDGF(325-530)) containing the integrase (IN)-binding domain (IBD) and stable knockdown (KD) of LEDGF/p75 are known to inhibit HIV infection in laboratory cell lines. Here, primary human CD(4)(+) T-cells were transduced with lentiviral vectors encoding LEDGF(325-530), the interaction-deficient mutant LEDGF(325-530)D366N, or a hairpin depleting LEDGF/p75 and challenged with HIV. Maximal protection of primary T-cells from HIV infection was obtained after LEDGF(325-530) overexpression reducing HIV replication 40-fold without evidence of cellular toxicity. This strategy was subsequently evaluated in the NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mouse model. Threefold reduction in mean plasma viral load was obtained in mice engrafted with CD(4)(+) T-cells expressing LEDGF(325-530) in comparison with engraftment with LEDGF(325-530)D366N cells. Four weeks after transplantation with LEDGF(325-530)D366N cells, 70% of the CD(4)(+) cells were lost due to ongoing HIV replication. However, in mice transplanted with LEDGF(325-530) cells only a 20% decrease in CD(4)(+) cells was measured. Liver and spleen sections of LEDGF(325-530) mice contained less HIV than LEDGF(325-530)D366N mice as measured by p24 antigen detection. LEDGF(325-530) overexpression potently inhibits HIV replication in vivo and protects against HIV mediated cell killing of primary CD(4)(+) T-cells.

Comparison of three humanized mouse models for adoptive T cell transfer.

BACKGROUND: Humanized mouse models for adoptive T cell transfer are important for preclinical efficacy and toxicity studies. However, common xenograft models using immunodeficient mice have so far failed to efficiently support the homing of human T cells to secondary lymphoid tissues. METHODS: We established a new mouse model for the adoptive transfer of genetically-modified (gm) T cells using conditioned BALB/c mice. Conditioning involved cyclophosphamide injections, lethal irradiation and radioprotection with bone marrow from immunodeficient mice. We compared repopulation kinetics and the quality of grafts in these modified Trimera (mT3) mice with immunodeficient BALB/c Rag2(-/-) interleukin (IL)2 receptor gamma (rg) knockout (DKO) and NOD/LtSz-scid IL2rg(-/-) (NSG) recipient mouse strains. RESULTS: DKO mice showed only marginal engraftment until onset of graft-versus-host disease, whereas mT3 and NSG were repopulated with comparable kinetics. However, T cell repertoire and human cytokine profiles suggest a xenoreactivity-driven gm T cell expansion in mT3 mice, whereas NSG mice were characterized by an initial homeostatic proliferation. Morphological analysis revealed high levels of human gm T cell infiltration in the spleen and liver of all three mouse strains. However, mT3 mice provided the strongest homing of human gm T cells to mucosal sites. Additionally, mT3 mice were the only model with macroscopically visible superficial inguinal lymph nodes. These lymph nodes strongly supported the homing of gm T cells. CONCLUSIONS: In the present study, we give proof-of-concept that wild-type mice can accept gm T cell grafts while providing secondary lymphoid structures. Despite limitations, mT3 mice are a valid alternative for applications that specifically rely on improved secondary lymphoid structures.

Secreted antiviral entry inhibitory (SAVE) peptides for gene therapy of HIV infection.

Gene therapeutic strategies for human immunodeficiency virus type 1 (HIV-1) infection could potentially overcome the limitations of standard antiretroviral drug therapy (ART). However, in none of the clinical gene therapy trials published to date, therapeutic levels of genetic protection have been achieved in the target cell population for HIV-1. To improve systemic antiviral efficacy, C peptides, which are efficient inhibitors of HIV-1 entry, were engineered for high-level secretion by genetically modified cells. The size restrictions for efficient peptide export through the secretory pathway were overcome by expressing the C peptides as concatemers, which were processed into monomers by furin protease cleavage. These secreted antiviral entry inhibitory (SAVE) peptides mediated a substantial protective bystander effect on neighboring nonmodified cells, thus suppressing virus replication even if only a small fraction of cells was genetically modified. Accordingly, these SAVE peptides may provide a strong benefit to AIDS patients in future, and, if applied by direct in vivo gene delivery, could present an effective alternative to antiretroviral drug regimen.

SARS-CoV-2 Neutralization in Convalescent Plasma and Commercial Lots of Plasma-Derived Immunoglobulin.

INTRODUCTION: Patients with primary or secondary immunodeficiency (PID or SID) face increased insecurity and discomfort in the light of the COVID-19 pandemic, not knowing if and to what extent their comorbidities may impact the course of a potential SARS-CoV-2 infection. Furthermore, recently available vaccination options might not be amenable or effective for all patients in this heterogeneous population. Therefore, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG). Whether the ongoing COVID-19 pandemic and/or the progress in vaccination programs lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated (e.g., for humoral immunodeficiency) remains a pressing question for this patient population. PURPOSE: We investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/SCIG products from the end of 2020 until June 2021 as well as in convalescent plasma (CP) from May 2020 to August 2020 to determine whether potentially neutralizing antibody titers may be present. METHODS: Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for anti-SARS-CoV-2 S1-receptor binding domain (RBD) IgG as well as microneutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate. Neutralization capacities of 313 single plasma donations and 119 plasma-derived IVIG/SCIG lots were determined. Results obtained from both analytical methods were normalized against the WHO International Standard. Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations. RESULTS: CP donations presented with high variability with regards to anti-SARS-CoV-2 reactivity in ELISA as well as in neutralization testing. While approximately 50% of convalescent donations were not/low neutralizing, approximately 10% were at or above 600 IU/mL. IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities for SARS-CoV-2. Lots produced between December 2020 and June 2021 entailing plasma donations after the emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time. While lot-to-lot variability was substantial, neutralization capacity increased from a mean of 21 IU/mL in December 2020 to 506 IU/mL in June 2021 with a maximum of 864 IU/mL for the most recent lots. Pharmacokinetic extrapolations, based on non-compartmental superposition principles using steady-state reference profiles from previously published pharmacokinetic investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/mL of neutralizing SARS-CoV-2 IgG based on the average final container concentration from May 2021 of 216 IU/mL. Maximum extrapolated trough levels could reach 64 IU/mL based on the latest maximal final container potency tested in June 2021. CONCLUSIONS: SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from US plasma rapidly and in part exponentially increased in the first half of 2021. The observed increase of final container potencies is likely trailing the serological status of the US donor population in terms of COVID-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until Fall 2021. In summary, the data support rapidly increasing levels of anti-SARS-CoV-2 antibodies in IVIG/SCIG products, implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients. Nevertheless, more research is still needed to confirm which plasma levels are needed to provide protection against SARS-CoV-2 infection in immune-compromised patients.

People with deficiencies in their immune system often have an insufficient antibody response to antigens such as bacteria, viruses, or vaccines. These patients therefore often receive antibodies from healthy people to replace the missing antibodies and build a first line of defense against infections. These antibodies (also called immunoglobulins [Ig]) are prepared from plasma, the liquid fraction of the blood without cells, of healthy donors. This plasma is then split up during pharmaceutical production into its protein components. One of these is immunoglobulin G (IgG), which is the protein family that neutralizes/inactivates infectious agents as well as marks these infectious agents so they can be recognized by other parts of the immune system. With the ongoing COVID-19 pandemic and the severe to fatal outcomes for certain patient groups, especially people with impaired immunity, these patients and their physicians are interested in whether their antibody replacement therapy also confers protection against SARS-CoV-2 infection. We analyzed the capability of plasma-derived Ig lots to (i) recognize SARS-CoV-2 protein by ELISA method as well as (ii) neutralize SARS-CoV-2 by neutralization studies using the actual virus under biosafety level 3 (BSL-3) conditions. Here we show increasing anti-SARS-CoV-2 activity over time of manufactured Ig lots produced between December 2020 and June 2021. The most recent lots had a neutralizing activity of up to 864 IU/mL. Considering that the US represents Octapharma's main plasma source, the progress in vaccination levels together with the evolution of the COVID-19 pandemic in this country suggests that the intravenous or subcutaneous immunoglobulin (IVIG/SCIG) neutralization capacities against SARS-CoV-2 might still increase and could potentially reach a level where antibody plasma concentrations in the patient confer immune protection.

From Dose Reduction to Contrast Maximization: Can Deep Learning Amplify the Impact of Contrast Media on Brain Magnetic Resonance Image Quality? A Reader Study.

OBJECTIVES: The aim of this study was to evaluate a deep learning method designed to increase the contrast-to-noise ratio in contrast-enhanced gradient echo T1-weighted brain magnetic resonance imaging (MRI) acquisitions. The processed images are quantitatively evaluated in terms of lesion detection performance. MATERIALS AND METHODS: A total of 250 multiparametric brain MRIs, acquired between November 2019 and March 2021 at Gustave Roussy Cancer Campus (Villejuif, France), were considered for inclusion in this retrospective monocentric study. Independent training (107 cases; age, 55 ± 14 years; 58 women) and test (79 cases; age, 59 ± 14 years; 41 women) samples were defined. Patients had glioma, brain metastasis, meningioma, or no enhancing lesion. Gradient echo and turbo spin echo with variable flip angles postcontrast T1 sequences were acquired in all cases. For the cases that formed the training sample, "low-dose" postcontrast gradient echo T1 images using 0.025 mmol/kg injections of contrast agent were also acquired. A deep neural network was trained to synthetically enhance the low-dose T1 acquisitions, taking standard-dose T1 MRI as reference. Once trained, the contrast enhancement network was used to process the test gradient echo T1 images. A read was then performed by 2 experienced neuroradiologists to evaluate the original and processed T1 MRI sequences in terms of contrast enhancement and lesion detection performance, taking the turbo spin echo sequences as reference. RESULTS: The processed images were superior to the original gradient echo and reference turbo spin echo T1 sequences in terms of contrast-to-noise ratio (44.5 vs 9.1 and 16.8; P < 0.001), lesion-to-brain ratio (1.66 vs 1.31 and 1.44; P < 0.001), and contrast enhancement percentage (112.4% vs 85.6% and 92.2%; P < 0.001) for cases with enhancing lesions. The overall image quality of processed T1 was preferred by both readers (graded 3.4/4 on average vs 2.7/4; P < 0.001). Finally, the proposed processing improved the average sensitivity of gradient echo T1 MRI from 88% to 96% for lesions larger than 10 mm ( P = 0.008), whereas no difference was found in terms of the false detection rate (0.02 per case in both cases; P > 0.99). The same effect was observed when considering all lesions larger than 5 mm: sensitivity increased from 70% to 85% ( P < 0.001), whereas false detection rates remained similar (0.04 vs 0.06 per case; P = 0.48). With all lesions included regardless of their size, sensitivities were 59% and 75% for original and processed T1 images, respectively ( P < 0.001), and the corresponding false detection rates were 0.05 and 0.14 per case, respectively ( P = 0.06). CONCLUSION: The proposed deep learning method successfully amplified the beneficial effects of contrast agent injection on gradient echo T1 image quality, contrast level, and lesion detection performance. In particular, the sensitivity of the MRI sequence was improved by up to 16%, whereas the false detection rate remained similar.

Can Deep Learning Replace Gadolinium in Neuro-Oncology?: A Reader Study.

MATERIALS AND METHODS: This monocentric retrospective study leveraged 200 multiparametric brain MRIs acquired between November 2019 and February 2020 at Gustave Roussy Cancer Campus (Villejuif, France). A total of 145 patients were included: 107 formed the training sample (55 ± 14 years, 58 women) and 38 the separate test sample (62 ± 12 years, 22 women). Patients had glioma, brain metastases, meningioma, or no enhancing lesion. T1, T2-FLAIR, diffusion-weighted imaging, low-dose, and standard-dose postcontrast T1 sequences were acquired. A deep network was trained to process the precontrast and low-dose sequences to predict "virtual" surrogate images for contrast-enhanced T1. Once trained, the deep learning method was evaluated on the test sample. The discrepancies between the predicted virtual images and the standard-dose MRIs were qualitatively and quantitatively evaluated using both automated voxel-wise metrics and a reader study, where 2 radiologists graded image qualities and marked all visible enhancing lesions. RESULTS: The automated analysis of the test brain MRIs computed a structural similarity index of 87.1% ± 4.8% between the predicted virtual sequences and the reference contrast-enhanced T1 MRIs, a peak signal-to-noise ratio of 31.6 ± 2.0 dB, and an area under the curve of 96.4% ± 3.1%. At Youden's operating point, the voxel-wise sensitivity (SE) and specificity were 96.4% and 94.8%, respectively. The reader study found that virtual images were preferred to standard-dose MRI in terms of image quality (P = 0.008). A total of 91 reference lesions were identified in the 38 test T1 sequences enhanced with full dose of contrast agent. On average across readers, the brain lesion SE of the virtual images was 83% for lesions larger than 10 mm (n = 42), and the associated false detection rate was 0.08 lesion/patient. The corresponding positive predictive value of detected lesions was 92%, and the F1 score was 88%. Lesion detection performance, however, dropped when smaller lesions were included: average SE was 67% for lesions larger than 5 mm (n = 74), and 56% with all lesions included regardless of their size. The false detection rate remained below 0.50 lesion/patient in all cases, and the positive predictive value remained above 73%. The composite F1 score was 63% at worst. CONCLUSIONS: The proposed deep learning method for virtual contrast-enhanced T1 brain MRI prediction showed very high quantitative performance when evaluated with standard voxel-wise metrics. The reader study demonstrated that, for lesions larger than 10 mm, good detection performance could be maintained despite a 4-fold division in contrast agent usage, unveiling a promising avenue for reducing the gadolinium exposure of returning patients. Small lesions proved, however, difficult to handle for the deep network, showing that full-dose injections remain essential for accurate first-line diagnosis in neuro-oncology.

Risk factors for morbidity and mortality after single-layer continuous suture for ileocolonic anastomosis.

AIM: The study was designed to determine the suitability of a single-layer continuous anastomosis for ileo-colonic anastomoses and to determine perioperative risk factors for morbidity and mortality in a teaching hospital. PATIENTS AND METHODS: Perioperative data of 463 patients undergoing colonic surgery with an ileocolonic anastomosis between 2000 and 2007 were retrospectively reviewed. Outcomes were compared using univariate and multivariate analyses to identify risk factors for morbidity, including anastomotic leakage, and mortality. RESULTS: The overall anastomotic leakage rate was 2.1%. In more than 50% right hemicolectomies were performed for colonic cancer. Univariate analysis showed a significant association of the underlying diagnosis with the leakage rate (ischemia 3.0% vs. carcinoma 1.3%). Multivariate analysis identified age, ASA score, diagnosis, and urgency as risk factors for morbidity; and an urgent operation setting (vital indications), a body mass index >25, diabetes mellitus, and a hypotensive circulation upon admission as predictors of anastomotic leakage. The mortality rate was 20% (2/10) among patients with anastomotic leakage and 2.9% (13/453) in those without anastomotic leakage. CONCLUSION: Single-layer continuous anastomoses for ileo-colonic surgery can be safely performed, even in a teaching setting. Four preoperative risk factors for morbidity and four different factors for anastomotic leakage could be identified in multivariate analysis. If feasible, these factors should have an impact on the preoperative decision-making progress.

Quantitative perfusion analysis of transabdominal contrast-enhanced ultrasonography of pancreatic masses and carcinomas.

BACKGROUND & AIMS: Preoperative differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) and focal masses in patients with chronic pancreatitis (CP) can be challenging. There are fine differences in the vascularization of these lesions; ultrasound contrast agents can aid in their differentiation. We evaluated the value of software-aided quantitative analysis of transabdominal contrast-enhanced ultrasonography for differential diagnosis of PDAC vs focal masses. METHODS: Sixty patients for whom it was not possible to differentiate between an inflammatory focal lesion of the pancreas and a pancreatic carcinoma underwent contrast-enhanced ultrasonography with a second-generation contrast agent. Time-intensity curves were obtained for all exams in 2 regions of interest within the lesion and within the normal pancreatic tissue. Images were processed using Axius ACQ software; the following parameters were obtained: maximum intensity, arrival time, time-to-peak, and area under the curve. Absolute values and differences between the lesion and the normal tissue were evaluated. RESULTS: Histology analysis revealed 45 PDACs and 15 inflammatory masses in patients with CP. Time-dependent parameters (arrival time and time to peak) were significantly longer in PDACs compared to focal masses. Although markedly lower than in healthy pancreata, the maximum intensity and area under the curve parameters were not significantly different between PDACs and focal lesions in patients with CP. CONCLUSIONS: In cases of CP, PDAC and focal masses exhibit different perfusion patterns at a capillary level that can be visualized using the small microbubbles of ultrasound contrast agents. Contrast quantification software supplements a subjective visual assessment with objective criteria to facilitate the differential diagnosis of focal lesions in pancreatic cancer and chronic pancreatitis.

2D and 3D radial multi-gradient-echo DCE MRI in murine tumor models with dynamic R*2-corrected R1 mapping.

Dynamic contrast-enhanced MRI is extensively studied to define and evaluate biomarkers for early assessment of vasculature-targeting therapies. In this study, two-dimensional and three-dimensional radial multi-gradient-echo techniques for dynamic R*(2)-corrected R(1) mapping based on the spoiled gradient recalled signal equation were implemented and validated at 4.7 T. The techniques were evaluated on phantoms and on a respiratory motion animated tumor model. R(1) measurements were validated with respect to a standard inversion-recovery spin-echo sequence in a four-compartment phantom covering a range of relaxation rates typically found in tumor tissue. In the range of [0.4, 3] sec(-1), R(1) differences were less than 10% for both two-dimensional and three-dimensional experiments. A dynamic contrast-enhanced MRI pilot study was performed on a colorectal tumor model subcutaneously implanted in mice at the abdominal level. Low motion sensitivity of radial acquisition allowed image recording without respiratory triggering. Three-dimensional K(trans) maps and significantly different mean K(trans) values were obtained for two contrast agents with different molecular weights. The radial multi-gradient-echo approach should be most useful for preclinical experimental conditions where the tissue of interest experiences physiologic motion, like spontaneous extracerebral tumors developed by transgenic mice, and where dynamic contrast-enhanced MRI is performed with high-relaxivity contrast agents.