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Introduction: The severe acute respiratory syndrome coronavirus 2 caused a pandemic of coronavirus disease 2019 (COVID-19). Unprecedented public health actions were introduced, including social distancing, travel restrictions and quarantine. The Belgian government announced a national emergency plan, thereby postponing all non-urgent medical consultations and operations. This report analyses the impact of these measures on cancer screening, through assessment of the workload of a laboratory for histopathology and cytopathology. Methods: Data on monthly numbers of histological and cytological samples, immunohistochemistry and molecular tests were extracted from the laboratory information management system. Results: The global histopathological and cytological workload was substantially reduced. The impact on oncology-related surgical procedures was rather limited. The anti-COVID-19 measures significantly diminished all screening-related samples, such as colon biopsies, breast biopsies and cervical cytology, and strongly reduced the number of samples related to “functional” pathology, such as thyroidectomies and gastric biopsies. Conclusions: Since many health care interventions are reflected in the workload of a pathology laboratory, this study enabled us to identify areas for “deconfinement” health care actions. Our findings indicate that various areas in medicine were affected, but the impact seemed largest for cancer screening. Health care professionals should assure that consultations related to cancer screening are postponed instead of cancelled.

In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients.

Background Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency. Methods Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature. Results Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models. Conclusions Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients.

Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing’s sarcoma resection surgery. Chronic infection by Clostridium hathewayi, Proteus mirabilis and Finegoldia magna was worsened by methicillin-susceptible Staphylococcus aureus exhibiting an inducible Macrolides-Lincosamides-Streptogramin B resistance phenotype (iMLSB). After failure of conventional conservative treatment, combination of in situ anti-S. aureus PT with surgical debridement and intravenous antibiotic therapy led to marked clinical and microbiological improvement, yet failed to prevent a recurrence of infection on the midterm. This eventually led to surgical graft replacement. Multiple factors can explain this midterm failure, among which incomplete coverage of the polymicrobial infection by PT. Indeed, no phage therapy against C. hathewayi, P. mirabilis or F. magna could be administered. Phage-antibiotic interactions were investigated using OmniLog® technology. Our results suggest that phage-antibiotic interactions should not be considered “unconditionally synergistic”, and should be assessed on a case-by-case basis. Specific pharmacodynamics of phages and antibiotics might explain these differences. More than two years after final graft replacement, the patient remains cured of her sarcoma and no further infections occurred.

Objective Rheumatoid Arthritis (RA) often exhibits suboptimal treatment response despite early diagnosis and treatment. This study aimed to analyze Early Rheumatoid Arthritis (ERA) synovial biopsies through histology and immunohistochemistry (IHC) to identify predictive factors for treatment response to Methotrexate (MTX). Methods 140 ERA patients from the UCLouvain Arthritis Cohort underwent synovial biopsy and were monitored after initiating Disease-Modifying Antirheumatic Drug (DMARD) therapy. Histological features [Synovial Hyperplasia, Fibrinoid Necrosis (FN), Hypervascularization and Inflammatory Infiltrate] and IHC (CD3, CD20, CD138, CD68) were each semi-quantitatively assessed on a 0–3 scale with 7 levels. Results A strong association was observed between synovial CD68 and Fibrinoid Necrosis scores [ r  = 0.44 (0.27 − 0.56); p  < 0.0001]. CD68 correlated with C-Reactive Protein (CRP), DAS28, SDAI and CDAI. Fibrinoid Necrosis score correlated with CRP and DAS28. Patients were then categorized as CD68Necrosis HIGH (CD68 + Necrosis ≥ 3) and CD68Necrosis LOW (CD68 + Necrosis < 3). CD68Necrosis HIGH exhibited higher pre-treatment disease activity [5.48 (1.6) versus 4.8 (1.7); p  = 0.03] and a greater fall in DAS28 [1.99 (2.06) versus 1.1 (2.27), p  = 0.03], SDAI [21.45 (IQR 23.3) versus 11.65 (IQR 17.5); p  = 0.003] and CDAI [16 [14.9] versus 10.5 (20.1), p  = 0.04]. CD68Necrosis HIGH patients had a higher EULAR Moderate/Good Response rate. CD68Necrosis score was incorporated into a probability matrix model together with clinical features (SJC44 and DAS28) to predict achieving a Moderate/Good EULAR Response Criteria at 3 months with a good performance (AUC 0.724). Conclusion FN and CD68 + in ERA synovial biopsies identify patients with higher disease activity and predict a better treatment response at three months. A model including synovial CD68 and fibrinoid necrosis with baseline clinical features predicts EULAR response at 3 months.

Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics ( iLEC Kras mice). We found that iLEC Kras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLEC Kras mice. Because most iLEC Kras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLEC Kras mice. Notably, we found that trametinib suppressed this phenotype in iLEC Kras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.

Background Combining immune checkpoint inhibitors (ICI) with neoadjuvant chemotherapy (NACT) has been the standard of care for stage II and III triple negative breast cancer (TNBC) since 2021. For Luminal B/HER2(-) breast cancers (BC) recent results from randomized phase 3 clinical trials demonstrated an improvement in pathological complete response (pCR) when ICI are combined with overall NACT. Emerging real-life data on TNBC reveal rates of ICI-related toxicities higher than expected, raising questions about the possibility of reducing ICI exposure during NACT while maintaining an efficacy advantage. The B-IMMUNE study explored the safety and efficacy of short-course durvalumab combined with EC during NACT in locally advanced BC. Patients and methods The prospective phase 1b/2 trial included patients with locally advanced Luminal B/HER2(-) or TNBC who were treated with paclitaxel 80mg/m2 weekly from weeks 1–12, followed by 4 cycles of dose-dense epirubicin 90mg/m2 and cyclophosphamide 600mg/m2 biweekly (ECdd), in a neoadjuvant setting. Phase 1b evaluated a single infusion of durvalumab 1500mg combined with the 3rd cycle of ECdd and phase 2 evaluated two infusions with the 1st and 3rd cycles of ECdd respectively. The primary endpoints were safety and pathological complete response (pCR) rate versus historical control. Based on Simon’s two-stage design, the trial was considered positive if > 8/20 pCRs were observed among TNBC patients and > 5/22 for luminal B HER2(-) BC patients. Results Fifty patients were considered for safety analyses and 34% of them experienced grade 3–4 adverse events (AEs) and 8% immunity-related AEs. Of the 47 patients treated with durvalumab in phase 2, 46 (22 TNBC and 24 Luminal B/HER2(-) BC) were considered for efficacy analyses. A pCR was observed in 12/22 TNBC patients (55%) and 8/24 Luminal B/HER2(-) BC patients (33%). Conclusions The B-IMMUNE study achieved its primary objective by showing that the addition of only 2 doses of durvalumab to NACT seems to improve the pCR rate compared to a historical control without ICI, for both TNBC and Luminal B/HER2(-) BC, while maintaining an acceptable safety profile. De-escalation of ICI in the neoadjuvant setting should be further investigated in phase 3 trials. Trial registration EudraCT: 2016–003998-1 date: 19 January 2017.

Epithelial–mesenchymal transition (EMT) and tumor‐infiltrating lymphocytes (TILs) play a central role in early‐stage breast cancer (BC) and are associated with chemoresistance, stemness, and invasion. The objective of this study was two fold: (a) by investigating the predictive value of EMT and TILs, we aimed to estimate the chance of achieving a response after neoadjuvant chemotherapy (NAC) and (b) to evaluate the potential changes of EMT and TILs in BC upon NAC. Using bulk RNA sequencing and immunofluorescence (IF) for EMT (E‐cadherin and vimentin) and lymphocyte markers (CD3, CD8, FOXP3), we analyzed pre‐ and post‐NAC tumor samples from 100 early‐BC patients treated with NAC. For each BC molecular subtype, we compared the expression of EMT and TILs, at the RNA and protein level, between responding and non‐responding tumors. Paired analysis of pre‐ and post‐NAC samples was performed for patients with residual disease after NAC. RNA sequencing of pre‐ and post‐NAC samples identified significant differences in EMT‐related and inflammation‐related gene expression between non‐responding (RCB‐II/III) and responding (RCB‐0/I) tumors. Increased EMT‐related marker expression was observed after NAC in cases with residual disease, in particular in the luminal subtype. Characterization of TILs in pre‐NAC samples showed substantially more CD3 + CD8‐FOXP3‐lymphocytes in responding HER2+ tumors compared with non‐responding. Paired analyses of pre‐ and post‐NAC samples demonstrated higher levels of CD3 + CD8 + FOXP3‐lymphocytes in residual luminal and triple‐negative BC and higher levels of CD3 + CD8‐FOXP3‐lymphocytes in residual triple‐negative BC compared with other subtypes of lymphocytes. We found that there is an unmet clinical need for reliable biomarkers to predict response to NAC in BC. Our results suggest that an upregulation of the EMT gene signature in diagnostic biopsies is associated with poor response to NAC in early BC, across all subtypes. Additionally, changes in EMT and in the TIL population occur in residual tumors after NAC. These findings could help to personalize future NAC and adjuvant treatment regimens. Epithelial–mesenchymal transition (EMT) and tumor‐infiltrating lymphocytes (TILs) are associated with early breast cancer response to neoadjuvant chemotherapy (NAC). This study evaluated EMT and TIL shifts, with immunofluorescence and RNA sequencing, at diagnosis and in residual tumors as potential biomarkers associated with treatment response. Our findings highlight the need for reliable biomarkers to guide personalized NAC regimens across BC subtypes.

Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab. Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3 , CD20 , and CD68 cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR. Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders. We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.