Evaluation of BAFF, APRIL and CD40L in Ocrelizumab-Treated pwMS and Infectious Risk

simple summary Since B cells have been linked to multiple sclerosis (MS) and its progression as well as T cells, the second-generation anti-CD20 recombinant humanized monoclonal antibody ocrelizumab has been approved for MS treatment. although ocrelizumab efficiently depletes B cells in peripheral blood, some B cells and CD20 negative plasma cells persist in lymphatic organs, and their survival is regulated by the B-cell-activating factor (BAFF)/a proliferation-inducing ligand (APRIL) system. moreover, ocrelizumab may result in higher infectious risk. herein, we investigated plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated people with (pw) MS at baseline, at 6 months and at 12 months after starting the treatment, comparing the above-mentioned findings with a control group. at baseline, plasma levels of all three cytokines were higher compared to the control group. In pwMS, the longitudinal assessment showed a significant increase in plasma BAFF levels and a significant reduction in plasma APRIL and CD40L. moreover, when stratifying pwMS according to the onset of an infectious event during the 12-month follow-up period, significantly higher plasma BAFF levels were found at all time-points in the group with an infectious event than in the group without an infectious event. hence, BAFF may have a role as a marker of immune dysfunction and infectious risk. background: the anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). however, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L. methods: the aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. as a control group, healthy donors (HD) were enrolled too. results: a total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF (p < 0.0001), APRIL (p = 0.0223) and CD40L (p < 0.0001) levels compared to HD. compared to T0, plasma BAFF levels were significantly increased at both T6 and T12 (p < 0.0001 and p < 0.0001, respectively). whereas plasma APRIL and CD40L levels were decreased at T12 (p = 0.0003 and p < 0.0001, respectively). when stratifying pwMS according to the development of an infectious event during the 12-month follow-up period in two groups-with (14) and without an infectious event (24)-higher plasma BAFF levels were observed at all time-points; significantly, in the group with an infectious event compared to the group without an infectious event (T0: p < 0.0001, T6: p = 0.0056 and T12: p = 0.0400). conclusions: BAFF may have a role as a marker of immune dysfunction and of infectious risk

Multiple sclerosis-disease modifying therapies affect humoral and T-cell response to mRNA COVID-19 vaccine

The mRNA vaccines help protect from COVID-19 severity, however multiple sclerosis (MS) disease modifying therapies (DMTs) might affect the development of humoral and T-cell specific response to vaccination

Longitudinal virological and immunological profile in a case of human monkeypox infection

In a male with severe proctitis, monkeypox virus DNA was detected in skin lesions, blood, nasopharynx, and rectum, underlying the generalized viral spreading. Rectal involvement was still found when skin lesions disappeared. At the early-stage, increase of cytotoxic and activated T-cells, while reduction of CD56dimCD57+NK cells compared to recovery time-point was observed

Screening and diagnostic breast MRI:how do they impact surgical treatment? Insights from the MIPA study

Objectives: To report mastectomy and reoperation rates in women who had breast MRI for screening (S-MRI subgroup) or diagnostic (D-MRI subgroup) purposes, using multivariable analysis for investigating the role of MRI referral/nonreferral and other covariates in driving surgical outcomes. Methods: The MIPA observational study enrolled women aged 18-80 years with newly diagnosed breast cancer destined to have surgery as the primary treatment, in 27 centres worldwide. Mastectomy and reoperation rates were compared using non-parametric tests and multivariable analysis. Results: A total of 5828 patients entered analysis, 2763 (47.4%) did not undergo MRI (noMRI subgroup) and 3065 underwent MRI (52.6%); of the latter, 2441/3065 (79.7%) underwent MRI with preoperative intent (P-MRI subgroup), 510/3065 (16.6%) D-MRI, and 114/3065 S-MRI (3.7%). The reoperation rate was 10.5% for S-MRI, 8.2% for D-MRI, and 8.5% for P-MRI, while it was 11.7% for noMRI (p ≤ 0.023 for comparisons with D-MRI and P-MRI). The overall mastectomy rate (first-line mastectomy plus conversions from conserving surgery to mastectomy) was 39.5% for S-MRI, 36.2% for P-MRI, 24.1% for D-MRI, and 18.0% for noMRI. At multivariable analysis, using noMRI as reference, the odds ratios for overall mastectomy were 2.4 (p < 0.001) for S-MRI, 1.0 (p = 0.957) for D-MRI, and 1.9 (p < 0.001) for P-MRI. Conclusions: Patients from the D-MRI subgroup had the lowest overall mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). This analysis offers an insight into how the initial indication for MRI affects the subsequent surgical treatment of breast cancer. Key points: • Of 3065 breast MRI examinations, 79.7% were performed with preoperative intent (P-MRI), 16.6% were diagnostic (D-MRI), and 3.7% were screening (S-MRI) examinations. • The D-MRI subgroup had the lowest mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). • The S-MRI subgroup had the highest mastectomy rate (39.5%) which aligns with higher-than-average risk in this subgroup, with a reoperation rate (10.5%) not significantly different to that of all other subgroups

Magnetic resonance imaging before breast cancer surgery: results of an observational multicenter international prospective analysis (MIPA).

Funder: Bayer AGFunder: Università degli Studi di MilanoOBJECTIVES: Preoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue. METHODS: This observational study enrolled women aged 18-80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases. RESULTS: Of 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p < 0.001 for all comparisons). Mastectomy was planned based on conventional imaging in 22.4% (MRI group) versus 14.4% (noMRI group) (p < 0.001). The additional planned mastectomy rate in the MRI group was 11.3%. The overall performed first- plus second-line mastectomy rate was 36.3% (MRI group) versus 18.0% (noMRI group) (p < 0.001). In women receiving conserving surgery, MRI group had a significantly lower reoperation rate (8.5% versus 11.7%, p < 0.001). CONCLUSIONS: Clinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup. KEY POINTS: • In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes. • The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate. • Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making

The Challenge of Imaging Dense Breast Parenchyma Is Magnetic Resonance Mammography the Technique of Choice? A Comparative Study With X-Ray Mammography and Whole-Breast Ultrasound

Purpose: To establish the value of magnetic resonance imaging (MRI) of the breast in comparison to x-ray mammography and ultrasound for breast cancer evaluation in women with dense breast parenchyma. Materials and Methods: Two hundred thirty-eight women with dense breast parenchyma who were suspicious for breast cancer or inconclusive for the presence of breast lesions based on clinical examination, ultrasound or x-ray mammography, and who underwent breast MRI at 1.5 T before and after administration of 0.1 mmol/k., gadobenate dimeglumine were evaluated. Lesions considered malignant (Breast Imaging Reporting and Data System (BI-RADS) 4 or 5) on x-ray mammography and/or ultrasound and as BI-RADS 3, 4, or 5 on MRI were evaluated histologically. Other lesions were followed up at 6 and/or 18 months. The diagnostic performance (sensitivity, specificity, accuracy, and positive and negative predictive values) of each technique was determined and compared using a general linear mixed model with appropriate correction for multiplicity. Results: At final diagnosis 121 of 238 (50.8%) women had one or more confirmed malignant lesions, whereas 117 (49.2%) had benign lesions or no lesions. Among 97 women who underwent all 3 techniques more lesions (malignant and benign) were detected with breast MRI to (n = 135) than with x-ray mammography (n = 85) or ultrasound (n = 107) and diagnostic confidence was greater. In terms of patient-based diagnostic accuracy breast M RI was significantly (P[r] < 0.0001) superior to both x-ray mammography and ultrasound (96.9% accuracy for MRI vs. 60.8% for mammography and 66.0% for US). Malignant lesions were histologically confirmed in 55 of 97 women who underwent all 3 techniques. Breast MRI detected more cases of multifocal, multicentric, and contralateral disease and fewer misdiagnoses occurred. Overall, breast MRI led to a modification of the surgical approach for 28 (23.1%) of the 121 women with diagnosed malignant disease. Conclusion: Breast MRI should be considered for routine breast cancer evaluation in women with dense breast parenchyma

Contrast-enhanced magnetic resonance mammography: does it affect surgical decision-making in patients with breast cancer?

Diagnostic imaging in women with suspected breast cancer should accurately detect and diagnose malignant tumors and facilitate the correct choice of therapy. Contrast-enhanced magnetic resonance mammography (CE-MRM) is potentially the imaging modality of choice for accurate patient management decisions. A total of 164 women with suspected breast cancer based on clinical examination, conventional mammography and/or ultrasound each underwent preoperative bilateral CE-MRM using an axial 3D dynamic T1-weighted gradient-echo sequence and gadobenate dimeglumine as contrast agent. Images were evaluated by two readers in consensus. Histological evaluation of detected lesions was performed on samples from core biopsy or surgery. Determinations were made of the sensitivity, accuracy and positive predictive value of CE-MRM compared to mammography/ultrasound for the detection of malignant lesions and of the impact of CE-MRM for surgical decision-making. Conventional mammography/ultrasound detected 175 lesions in the 164 evaluated patients. CE-MRM revealed 51 additional lesions in 34/164 patients; multifocal and multicentric cancer was detected in 7 and 4 additional patients, respectively, contralateral foci in 21 additional patients and pectoral muscle infiltration in 2 additional patients. CE-MRM also confirmed the absence or benignity of 3 and 1 lesions suspected of malignancy on mammography/ultrasound. The sensitivity and accuracy for malignant lesion detection and identification was 100% and 93.4%, respectively, for CE-MRM compared to 77.3% and 72.1% for mammography/ultrasound, respectively. Patient management was altered for 32/164 (19.5%) patients as a result of CE-MRM. CE-MRM positively impacts patient management decisions and should be performed in all women with suspected breast cancer based on clinical examination, mammography and/or ultrasound

Contrast-enhanced MR mammography: Improved lesion detection and differentiation with gadobenate dimeglumine

OBJECTIVE. The objective of our study was to intraindividually compare 0.1 mmol/kg doses of gadobenate dimeglumine and gadopentetate dimeglumine for contrast-enhanced breast MRI. SUBJECTS AND METHODS. Forty-seven women (mean age ± SD, 50.8 ± 12.9 years) with breast lesions classified as BI-RADS category 3, 4, or 5 for suspicion of malignancy underwent two identical MR examinations at 1.5 T separated by 48-72 hours. T1-weighted gradient-echo images were acquired before contrast administration and at 2-minute intervals after the randomized injection of gadopentetate dimeglumine or gadobenate dimeglumine at 2 mL/s. Two blinded readers evaluated randomized image sets for lesion detection and differentiation as benign or malignant compared with histology. The McNemar exact test and the generalized estimating equation (GEE) were used to compare lesion detection rates and diagnostic performance in terms of sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). RESULTS. Histopathology data were available for 78 lesions. Significantly more lesions overall (75/78 [96%] vs 62/78 [79%], respectively; p = 0.0002) and significantly more malignant lesions (49/50 [98%] vs 38/50 [76%]; p = 0.0009) were detected with gadobenate dimeglumine than gadopentetate dimeglumine. All detected malignant lesions were correctly diagnosed with both agents. More detected benign lesions were correctly diagnosed with gadobenate dimeglumine than with gadopentetate dimeglumine (20/26 [77%] vs 17/24 [71%], respectively). Differentiation of lesions was significantly (p = 0.0001) better with gadobenate dimeglumine. Significantly better diagnostic performance was noted with gadobenate dimeglumine than with gadopentetate dimeglumine, respectively, for sensitivity (98.0% vs 76.0%; p = 0.0064), accuracy (88.5% vs 69.2%; p = 0.0004), PPV (86.0% vs 76.0%; p = 0.0321), and NPV (95.2% vs 57.1%; p = 0.0003). CONCLUSION. Lesion detection and malignant-benign differentiation is significantly better with 0.1 mmol/kg gadobenate dimeglumine than 0.1 mmol/kg gadopentetate dimeglumine. © American Roentgen Ray Society