Biopsies Of Patients Research Articles

Detecting Monkeypox Virus by Immunohistochemistry.

Mpox (formerly known as monkeypox), a zoonotic disease caused by Monkeypox virus (MPXV), has become an international outbreak since May 2022. Mpox often presents with a mild systemic illness and a characteristic vesiculopustular skin eruption. In addition to molecular testing, histopathology of cutaneous lesions usually showsdistinctive findings, such as epidermal necrosis, balloon degeneration, papillary dermal edema, and focal dermal necrosis, which have proven helpful in the diagnosis of mpox. Viral cytopathic changes with areas of multinucleation, smudging of the nuclei, and intracytoplasmic inclusions have also been described. Although useful, these features are relatively nonspecific. The use of a monoclonal antibody for immunohistochemical (IHC) staining of MPXV may be a useful tool in confirming mpox infection. Three cases of PCR-confirmed mpox were biopsied and subjected to IHC staining with a monoclonal MPXV-specific antibody targeting viral envelope protein A29. As controls, cell lines transduced to express other MPXV viral antigens and samples of cutaneous viral infections involving Molluscum contagiosum, Herpes simplex, Herpes zoster, or Cytomegalovirus were also subjected to IHC staining with this antibody. All three mpox patient biopsies performed on lesional skin subjected to MPXV IHC staining reliably detected viral infection in lesional skin with a diffuse cytoplasmic and focally nuclear staining pattern. No staining was seen in transduced cell lines expressing off-target MPXV viral antigens and in lesional skin of other common viral infections listed above. The monoclonal MPXV-specific antibody may be used as an adjunct tool to confirm mpox infection.

Tumor-derived G-CSF induces an immunosuppressive microenvironment in an osteosarcoma model, reducing response to CAR.GD2 T-cells

Sarcomas are rare, mesenchymal tumors, representing about 10–15% of all childhood cancers. GD2 is a suitable target for chimeric antigen receptor (CAR) T-cell therapy due to its overexpression in several solid tumors. In this preclinical study, we investigated the potential use of iCasp9.2A.GD2.CAR-CD28.4–1BBζ (CAR.GD2) T-cells as a treatment option for patients who have GD2-positive sarcomas and we sought to identify factors shaping hostile tumor microenvironment in this setting. GD2 expression was evaluated by flow-cytometry on primary tumor biopsies of pediatric sarcoma patients. GD2 expression in sarcoma cells was also evaluated in response to an enhancer of zeste homolog 2 (EZH2) inhibitor (Tazemetostat). The antitumor activity of CAR.GD2 T-cells was evaluated both in vitro and in vivo preclinical models of orthotopic and/or metastatic soft-tissue and bone sarcomas. GD2 expression was detected in 55% of the primary tumors. Notably, the Osteosarcoma and Alveolar Rhabdomyosarcomas subtypes exhibited the highest GD2 expression levels, while Ewing sarcoma showed the lowest. CAR.GD2 T-cells show a significant tumor control both in vitro and in vivo models of GD2-expressing tumors. Pretreatment with an EZH2 inhibitor (Tazemetostat) upregulating GD2 expression, sensitizes GD2dim sarcoma cells to CAR.GD2 T-cells cytotoxic activity. Moreover, in mouse models of disseminated Rhabdomyosarcomas and orthotopic Osteosarcoma, CAR.GD2 T-cells showed both a vigorous anti-tumor activity and long-term persistence as compared to un-transduced T-cells. The presence of immunosuppressive murine myeloid-derived suppressor (MDSC) cells significantly reduces long-term anti-tumour activity of infused CAR.GD2 T-cells. Tumor-derived G-CSF was found to be one of the key factors driving expansion of immunosuppressive murine and human MDSC, thus indirectly limiting the efficacy of CAR.GD2 T-cells. Our preclinical data strongly suggest that CAR.GD2 T-cells hold promise as a potential therapeutic option for the treatment of patients with GD2-positive sarcomas. Strategies to tackle hostile immunosuppressive MDSC are desirable to optimize CAR.GD2 T-cell activity.

Beyond the AJR: Prostate Cancer Screening-Safe Omission of Biopsy in Patients With Negative MRI and the Need for High-Quality Imaging Standards.

Beyond the AJR: Prostate Cancer Screening-Safe Omission of Biopsy in Patients With Negative MRI and the Need for High-Quality Imaging Standards.

Tolerability of Transperineal Prostate Biopsy Under Local Anaesthetic Using Pre-Emptive Over-the-Counter Analgesia: An Interventional Study in Patients with Abnormal Clinical Prostate Findings

Objective: Transperineal prostate (TP) biopsy is the key diagnostic tool for evaluating prostate cancer and is feasible under local anaesthetic (LA) alone. However, concerns about its tolerability encourage use of a multimodal analgesia approach. Pre-emptive over-the-counter analgesia with LA may provide a simple and low-risk option. The objective of this study was to investigate the effects of over-the-counter analgesia on TP biopsies conducted under LA. Methods: This interventional single-centre study investigated 160 participants who undertook a TP biopsy under LA, with and without pre-emptive analgesia (1 g of paracetamol and 400 mg of ibuprofen). Pain tolerability was measured using a visual analogue scale (VAS) at three procedural points (probe insertion, LA infiltration, and biopsy); an overall average VAS score was subsequently calculated. The abstracted secondary variables include patient details (age, prostate size, and PSA level), biopsy details (number of cores and volume of LA used), and preferability for LA use in future TP biopsies. An inferential statistical analysis was performed using Wilcoxon’s Rank Sum non-parametric test, Pearson’s test of correlation, and Pearson’s Chi-squared test. Results: The groups were comparable in age, prostate size, and PSA level. Median VAS scores were consistently lower in the intervention cohort, but without statistical significance. A higher volume of LA was associated with lower overall VAS (p = 0.03). LA was strongly preferred over GA for hypothetical future TP biopsies in both cohorts. Conclusions: Pre-emptive analgesia does not significantly improve tolerability of TP biopsy under LA. Our study substantiates evidence that TP biopsy is generally well tolerated under LA and preferred over GA.

Can Broadening the Kidney Biopsy Criteria Reduce Misleading Diagnoses in Young Patients with End-Stage Renal Diseases? A Survey on the Sicilian Registry of Nephrology, Dialysis, and Transplantation

Audits allow analysis of the delivery of care and the prevalence of diseases. This study investigated kidney diseases’ impact on end-stage renal disease (ERSD) in patients younger than 30 years. Methods: This analysis is retrospectively conducted on young dialysis-dependent patients included in the Sicilian Registry of Nephrology, Dialysis and Transplantation Participants. It evaluated patients who started dialysis before the age of 30 retrieved in the mentioned registry. The sample was divided into two groups, according to the presence or absence of a specific diagnosis. Baseline features were reported as mean ± sd, median [IQR] and n (%). A Student T-test, Mann–Whitney test or Pearson Chi-Square test was performed. Logistic regression analysis detected the association between the variables and the unknown diagnosis, and variables with a p-value < 0.2 were added to the multivariate model. ROC curves were drawn including this multivariate prediction. Results: In total, 145 patients started dialysis before the age of 30 years. Between patients with and without a diagnosis, the intake of renin–angiotensin–aldosteron system inhibitors (RAASIs) and blood pressure differed enough to be considered as possibly confounding. Logistic regression showed that blood pressure and RAASIs seemed to be related to the unknown diagnosis. ROC curves adjusted for RAASIs and blood pressure provided an AUC = 0.689. Conclusions: Although Kidney Disease Improving Global Outcomes (KDIGO) did not include hypertension among biopsy indications, our data suggest that performing renal biopsy in young patients with hypertension and worsening renal function could improve kidney diagnosis management.

Outcome of lupus nephritis patients treated with an anti-CD40 monoclonal antibody according to kidney biopsy features.

A phase II trial tested different doses of the anti-CD40 monoclonal antibody BI655064 as add-on therapy to the standard of care in class III or IV Lupus Nephritis (LN) patients with active disease. A post-hoc analysis showed a potential benefit of the higher tested doses (180mg/240mg) versus low dose (120mg)/placebo. We investigated whether the treatment effect of BI655064 on kidney outcomes may be modified by the presence of glomerular monocytes, a target for this drug with a well-known role in LN pathogenesis. 101 renal biopsies of LN patients enrolled in the BI655064 trial were scored centrally. eGFR and spot urine protein/urine creatinine ratio (UP/UC) and Complete Renal Response (CRR) were evaluated over 52 weeks. Patients were divided according to a "Better" or "Worse" performance than the average of all patients in the cohort, predicted by a mixed model for repeated measurements. Logistic regression models adjusted for potential confounders assessed the association between different treatment doses and outcomes according to the presence or absence of monocytes. A higher BI655064 dose (180/240mg) was associated with better outcomes of UP/UC and CRR when glomerular monocytes were present in kidney biopsies (OR 3.66[1.09-12.3], P=0.04; OR 4.58[1.24-16.9], P=0.02). A trend toward improved eGFR was also observed in these patients (P 52-weeks=0.08). In LN kidney biopsies with glomerular monocytes, high-dose BI655064 treatment improved proteinuria at 52 weeks and resulted in a higher CRR compared to biopsies without glomerular monocytes. Histologic features may guide the choice of treatment for individual LN patients.

LIBELULE: a randomized phase III study to evaluate the clinical relevance of early liquid biopsy in patients with suspicious metastatic lung cancer.

Genomic profiling is a major component for first-line treatment decisions in patients with non-small cell lung cancer (NSCLC) and the timeliness of biomarker testing is essential to improve time to treatment initiation (TTI) or avoid inappropriate treatment. The phase III LIBELULE trial (NCT03721120) included patients with radiological suspicion of advanced lung cancer. They were randomized (1:1), the control arm receiving diagnostic procedures according to each center's practice and the liquid biopsy arm with additional testing performed at the first visit using the InVisionFirst®-Lung assay. Treatment initiation and type were defined according to ESMO guidelines. Primary endpoint was the time from randomization to initiation of appropriate treatment based on informative genomic and pathological results in the intention-to-treat population. 319 patients were enrolled (LB: 161; control: 158). Median age was 68 years, 28.8% were non-smokers, 18.1% had PS≥2 and 56.7% had adenocarcinoma. In LB arm, 81% of patients had circulating tumor DNA findings. The mean TTI was not significantly reduced (LB: 29.0 days (d); control 34d (p=0.26)). Sensitivity analyses showed a shorter TTI in patients from the LB arm who received systemic treatment (LB: 29.1d; control: 38.8d, p=0.01), in patients with advanced non-squamous NSCLC (LB: 29.5d; control: 40.3d, p=0.01), and in patients with first-line targetable alterations (LB: 21d; control 37.4d) (p=0.004). Time to contributory genomic results was significantly reduced (LB: 17.9d; control 25.6d, p<0.001). Early liquid biopsy testing did not significantly shorten the TTI in unselected patients referred for suspected advanced lung cancer. Nevertheless, it could reduce the TTI in patients eligible for systemic treatment, particularly for those with actionable alterations.

Role of Stool for H. Pylori Antigen and Upper GI Endoscopy in Diagnosis Among Patients with Dyspepsia – A Single Centre Study

Objective: The objective of our study was to compare the efficacy of stool for H. pylori antigen test with endoscopic biopsy in patients with dyspepsia. Methodology: The study was conducted at the department of Gastroenterology, Pak Emirates Military Hospital, Rawalpindi during the time period of 10 months i.e. from August 2023 to May 2024. It was a prospective observational study. Sampling was done via non- probability consecutive sampling technique. Our study consisted of 202 patients. We included all the dyspeptic patients over 18 years of age while excluding those above 60 years of age, with comorbidities or taking PPIs and antibiotics. Demographic variables like age, gender and socioeconomic status were recorded. Data was be analysed by using statistical package for social sciences version 23 (SPSS ver 23). Quantitative variables were summarized as mean ± SD and qualitative variables were summarized as frequency and percentages. Sensitivity, specificity, Positive predictive value (PPV) and Negative predictive value (NPV) were calculated using Chi-square test. Values with P&lt; 0.05 were considered significant at Confidence Interval (CI) 95%. Results: The results of our study showed that the sensitivity of the H.Pylori Antigen test was 86.86%, specificity was 81.54 %, positive predictive value (PPV) was 90. 84% and negative predictive value (NPV) was 74. 65%. The diagnostic accuracy of the test came out to be &gt;85%. Conclusion: The test proved to be a beneficial diagnostic tool in terms of cost - effectiveness, with an additional benefit of being non-invasiveness. It can be used in the centers where endoscopy is not available and can also decrease the workload of endoscopy setups. Key Words: H. pylori antigen test, endoscopic biopsy, sensitivity, specificity, stool test

Abatacept use for 24 weeks has a limited effect on salivary gland inflammation in Sjögren's disease patients.

This study aimed to assess (1) effects of abatacept on salivary gland histology of Sjögren's disease (SjD) patients, (2) the predictive value of salivary gland histopathological characteristics at baseline for clinical response to abatacept treatment. Patients (n=41) who participated in the Dutch ASAP-II and ASAP-III trials and international abatacept trial (IM101603) from whom a labial (n=13) or parotid (n=28) salivary gland biopsy was obtained at baseline and after 24 weeks of treatment with abatacept were included. Biopsies were analysed for SjD related histopathological features before and after abatacept (n=25) or placebo (n=16) treatment. Histopathological data at baseline were compared between clinical responders and non-responders to abatacept treatment. Comparison between abatacept- and placebo-treated patients revealed virtually no differences in histopathological parameters of parotid and labial salivary gland biopsies of SjD patients at baseline and 24 weeks after therapy. In labial glands, only the number of IgA plasma cells/mm2 differed between the two groups over time (p=0.034). Correspondingly in parotid glands, the number of IgA plasma cells increased in the abatacept group (p=0.049) after 24 weeks. The number of CD20+ B-cells/mm2 in parotid glands of the placebo group increased compared to baseline (p=0.021). There were no evident differences in baseline histopathological parameters between CRESS or ClinESSDAI responders and non-responders treated with abatacept. Abatacept has limited effects on salivary gland histology in SjD patients after 24 weeks of treatment. Besides possibly affecting numbers of IgA plasma cells and preventing increases in B-lymphocyte infiltration, salivary gland histopathology could not predict response to abatacept treatment in SjD patients.

ASO Author Reflections: Investigating the Role of Sentinel Lymph Node Biopsy in Older Patients with Triple-Negative Breast Cancer.

ASO Author Reflections: Investigating the Role of Sentinel Lymph Node Biopsy in Older Patients with Triple-Negative Breast Cancer.

Multiphoton Microscopy: A Feasability Study to Explore the Potential Intraoperative Tool for TURBT Diagnosis

Background: Multiphoton microscopy (MPM) is a nonlinear optical imaging technology, allowing process-free imaging of fresh tissue up to a depth of 0.5 mm, with a combined signal of autofluorescence and second harmonic generation. The absence of bladder muscle in a transurethral resection of bladder tumor (TURBT) increases risk of residual disease, recurrence, and understaging, and an intraoperative assessment of resection depth and margins may avoid unnecessary second TURBTs. Objective: The objective of this study was to test the feasibility of MPM in the real-time detection of bladder muscle in cold cup biopsies of patients undergoing TURBT. Methods: This was a prospective feasibility study. Cold cup biopsies were taken intraoperatively from the resection bed during TURBT. Tissue was stored in phosphate buffered saline solution combined with fluorescent dyes (orange acridine and rhodamine). MPM imaging of the tissue was performed first, with z stack images of 100 µm maximum depth for 3D imaging. After MPM imaging, tissue was fixed in formalin and sent to the biorepository for standard histopathology. A descriptive analysis was performed between MPM tissue detection and final histopathology results. Results: Ten patients were included in this pilot study. Tissue was properly imaged for all patients, although 3 of them had artifacts, and we detected 5 times muscularis propria on MPM imaging. MPM average procedure time from biopsy to formalin fixation (MPM imaging) was 16.2 minutes (12-20 minutes). On final pathology, resection depth was correctly performed for only 4 patients of 10 (resection including bladder muscle). We found an 80% sensitivity on resection depth between first layer identified on MPM and final pathology (8/10 patients) and 100% correlation with final histopathology in specimens for the assessment of detrusor muscle. Conclusions: This study supports the use of MPM as a novel intraoperative tool which can evaluate cold cup biopsies during TURBT for resection depth and potentially avoid unnecessary second look procedure.

Prevalence of Plasmid-Mediated Quinolone Resistance Genes in Escherichia coli Isolates From Colonic Biopsies of Iranian Patients With Inflammatory Bowel Diseases: A Cross-Sectional Study.

Emerging evidence suggests that ciprofloxacin and other quinolones can be effectively used as adjuncts to immunosuppressive therapy in managing inflammatory bowel disease (IBD). Clinical isolates of Enterobacterales frequently exhibit quinolone resistance. Additionally, increased IBD severity has been linked to the proliferation of Enterobacterales in the gut. This study aimed to explore the frequency of fluoroquinolone resistance and the presence of associated resistance genes in Escherichia coli isolates obtained from intestinal biopsies of patients with IBD in Iran. In this research, we conducted a study that involved the isolation and examination of E. coli bacteria from inflamed ileal and/or colonic tissues of patients diagnosed with IBD, specifically ulcerative colitis (UC) and Crohn's disease (CD), during colonoscopy procedures. We collected demographic and clinical information from the patients. To identify E. coli strains that were resistant to quinolone antibiotics, we performed both phenotypic and molecular analyses. From the colonic and ileal biopsies of 121 patients with IBD, we isolated 107 unique strains of E. coli. Among these strains, 18 (16.8%) were derived from patients with CD, and 89 (83.2%) came from those with UC. Antimicrobial susceptibility tests revealed that 61 out of 107 isolates (57%) of the isolates showed phenotypic resistance to at least one type of quinolone. Additionally, plasmid-mediated quinolone resistance (PMQR) genes, specifically oqxA, oqxB, and qnrS were detected in the E. coli strains linked to both UC and CD. Notably, there was a significant positive correlation observed between intestinal colonization by ciprofloxacin-resistant E. coli and the patients' history of extended ciprofloxacin antibiotic therapy. Our results reveal that a significant number of patients with IBD carry quinolone-resistant E. coli. This colonization may pose a risk factor that could affect disease progression and contribute to potential complications.

Optimizing prostate biopsy decision-making for patients with Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions: novel magnetic resonance imaging (MRI)-based nomograms.

Current protocols endorse biopsies for men with Prostate Imaging-Reporting and Data System (PI-RADS v2.1) scores ≥3. However, the subjective nature of PI-RADS can lead to increased false positives and unnecessary biopsies. Synthetic magnetic resonance imaging (MRI), which quantifies multiple relaxation parameters, and apparent diffusion coefficient (ADC), which is the most commonly used quantitative metric, have not yet been combined with a predictive tool. This study aimed to develop and validate novel nomograms using multiparametric MRI, including synthetic MRI, to forecast the risk of prostate cancer (PCa) and clinically significant prostate cancer (csPCa), and to assess the potential of these nomograms to reduce unnecessary biopsies in PI-RADS ≥3 cases. Between August 2020 and August 2022, 323 patients suspected of PCa were enrolled from two centers (cohort 1: 243; cohort 2: 80). All participants underwent multiparametric MRI, including synthetic MRI, before targeted biopsy. Univariable and multivariable logistic regression identified risk factors for PCa and csPCa. Internal validation was conducted using bootstrap resampling, and nomogram performance was evaluated through receiver operating characteristic (ROC) curve analysis, calibration plots, and decision curve analysis (DCA). External validation was performed with cohort 2 data. The impact of the nomograms on biopsy decisions was measured by the avoidance rate and the risk of missed diagnoses. The predictive nomogram for PCa incorporated four risk factors: age, quantitative transverse relaxation time (T2 value) from synthetic MRI, ADC value, and PI-RADS score. The csPCa nomogram included age, ADC value, and PI-RADS score. The nomograms showed high diagnostic accuracy with the area under the curves (AUCs) of 0.916 [95% confidence interval (CI): 0.901-0.974] and 0.947 (95% CI: 0.900-0.994) for PCa prediction in training and external datasets, and 0.884 (95% CI: 0.840-0.928) and 0.935 (95% CI: 0.871-0.998) for csPCa. Calibration curves confirmed the accuracy of predictions. DCA indicated that the nomograms possessed significant net benefit. For PCa detection, biopsy strategy combining our nomogram reduced biopsy procedures by 20.2% and 13.8% in the training and external cohorts, respectively, with a PCa miss rate of 4.5% for both cohorts. The csPCa-targeted biopsy strategy also provided clinical benefits, with biopsy avoidance rates of 20.2% and 10.0%, and csPCa miss rates of 4.8% and 1.7% for PI-RADS ≥3 patients in the two cohorts. The nomograms integrating multiparametric MRI and synthetic MRI are highly effective in predicting PCa and csPCa, concurrently, reducing unnecessary biopsies for patients with PI-RADS ≥3 lesion.

Clinical Manifestations, Prognostic Factors, and Outcomes of Extranodal Natural Killer T-Cell Lymphoma: A Single-Center Experience in Thailand

Background/Objectives: The primary objective of this study was to investigate clinical manifestations, time to diagnosis, and number of biopsies in patients with extranodal natural killer T-cell lymphoma (ENKTL). The secondary objectives were to determine response rates, survival outcomes, prognostic factor for overall survival (OS), and validation of the Prognostic Index of Natural Killer Lymphoma (PINK), Ann Arbor staging system (AASS), and the CA system. Methods: This retrospective study included data pertaining to patients with newly diagnosed ENKTL in Chiang-Mai University Hospital from 2004 to 2020. Comparisons between the areas under the receiver operating characteristic curve (AUC) of prognostic models (PINK, AASS, and CA system) were made. Results: Sixty patients were enrolled (n = 60) with a mean age of 49.1 ± 13.4 years. The most frequent symptom of ENKTL was nasal obstruction (66%). The median time to diagnosis was 22 days (ranging from 3 to 84 days), with 36.7% requiring more than one biopsy for diagnosis. Most patients presented with limited stage disease (75%). The median OS was 49 months. Factors associated with increased mortality were advanced stage, bone marrow involvement, gastrointestinal tract involvement, and receiving chemotherapy. Following prognostic model validation, the CA system model scored the highest level of accuracy (AUC 0.61), followed by AASS (AUC 0.58) and PINK (AUC 0.54). Conclusions: Patients with ENKTL commonly presented with nasal obstruction, with 36.7% requiring more than one biopsy for diagnosis. An advanced stage, bone marrow involvement, or gastrointestinal tract involvement were associated with poor OS. The CA system model has the highest level of accuracy for prognostic determination.

Minimal residual disease as a target for liquid biopsy in patients with solid tumours.

Metastasis is the leading cause of cancer-related death in patients with solid tumours. Current imaging technologies are not sufficiently sensitive to detect minimal residual disease (MRD; also known as measurable or molecular residual disease) after initial surgery or chemotherapy, pointing to the need for more sensitive tests to detect remaining traces of cancer in the body. Liquid biopsy, or the analysis of tumour-derived or tumour-induced cells or cellular products in the blood or other body fluids, has opened a new diagnostic avenue to detect and monitor MRD. Liquid biopsy is already used in clinical decision making for patients with haematological malignancies. Here, we review current knowledge on the use of circulating tumour DNA (ctDNA) to detect and monitor MRD in patients with solid tumours. We also discuss how ctDNA-guided MRD detection and characterization could herald a new era of novel 'post-adjuvant therapies' with the potential to eliminate MRD and cure patients before terminal metastatic disease is evident on imaging.

An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naïve and longitudinal samples throughout neoadjuvant chemotherapy.

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial ( NCT02276443 ) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.

Seeding-competent TDP-43 persists in human patient and mouse muscle.

TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.

The Spectrum of Cutaneous Granulomatous Inflammation and Detection of Rubella Virus in Skin Biopsies of Patients With Common Variable Immune Deficiency.

There is a known association between common variable immunodeficiency (CVID) and granulomas in multiple organ systems, including the skin, lung, liver, and spleen. Rubella virus has also been detected within cutaneous granulomas in both immunocompetent and immunocompromised hosts. We present a retrospective case series of patients with CVID and granulomatous skin disease and describe the spectrum of clinical and histopathologic features, including the status of rubella virus in the cutaneous granulomas. We retrospectively reviewed the clinical and histopathological characteristics of patients diagnosed with CVID at our institution, with cutaneous findings and skin biopsies available for review between 1990 and 2023, demonstrating granulomatous inflammation. Eight patients met the inclusion criteria. The most common histopathologic pattern was palisaded granulomatous inflammation, seen in five of eight cases. Three cases showed strictly sarcoidal granulomas. Background inflammation was peri-granulomatous (8/8) and the predominant background inflammatory cell type was lymphocytic (6/8). Rubella virus testing was performed for seven of eight cases and found to be positive in one case. Cutaneous granulomatous disease in CVID can present with a spectrum of clinical morphologies, granulomatous patterns, and variable rubella virus persistence. Dermatopathologists should be aware of the spectrum of findings when considering cutaneous CVID-related granulomatous disease in the differential diagnosis.

Comparison of Crohn’s disease-associated adherent-invasive Escherichia coli (AIEC) from France and Hong Kong: results from the Pacific study

ABSTRACT Association between ileal colonization by Adherent-Invasive Escherichia coli (AIEC) and Crohn’s disease (CD) has been widely described in high-incidence Western countries but remains unexplored in Asian countries with a fast increase in CD incidence. In the PACIFIC study, we compared the characteristics of AIEC pathobionts retrieved from ileal biopsies of CD patients enrolled in France (FR) and Hong Kong (HK). The prevalence of AIEC was similar in France (24.5%, 25/102) and Hong Kong (30.0%, 18/60) (p = 0.44). No difference was observed between the two populations of AIEC regarding adhesion and invasion levels. When tested for antibiotic resistance, the proportion of AIEC strains resistant to ampicillin, piperacillin, tobramycin, and gentamicin was significantly higher in HK AIEC strains compared to French strains. AIEC strains from FR or HK population were both able to persist in the mice intestine (DSS-treated CEABAC10 mice model). Moreover, genomic analysis of 25 FR and 17 hK AIEC strains using next-generation sequencing revealed the co-existence of several virulence factors associated with enteric E. coli pathotypes, although no single virulence factor was significantly associated with either country of origin or AIEC status. In vitro, all AIEC strains (FR and HK) were sensitive to the EcoActive™ phage cocktail, suggesting that it could be a promising option to target AIEC in CD across the world.

Dynamics in the Prostate Immune Microenvironment Induced by Androgen Deprivation Therapy.

The influence of testosterone on the prostate's immune microenvironment remains unclear. This study aims to elucidate the dynamics of immune cells in the prostate following androgen deprivation therapy (ADT). We retrospectively compared prostate needle biopsy and radical prostatectomy specimens from 33 patients who underwent both procedures, along with neoadjuvant ADT at a single institution. Immune cell infiltration in the cancer and stroma areas was assessed using multiplex fluorescence immunohistochemistry. Post-ADT, all immune cells, including CD4+ T cells, CD8+ T cells, Foxp3+ regulatory T cells, CD204+ macrophages, and CD20+ B cells, significantly increased in the prostatectomy specimen. However, few immune cells were detected in the biopsy of the same patients (p < 0.001). The number of CD20+ B cells in the cancer area was significantly lower post-ADT in high-risk cases according to the NCCN classification (p = 0.020). This difference was significantly associated with the Gleason Grade Group, rather than PSA levels or T classification (p < 0.001). However, no significant difference was observed in the recurrence rate between Grade Groups 1, 2, 3 and 4, 5 (p = 0.991). There was no significant difference in immune cells other than CD20+ B cells when divided into NCCN classifications. The marked increase in immune cells following ADT suggests an intensified immune response against prostate cancer.