SD Patients Research Articles

Perceptual and semantic deficits in face recognition in semantic dementia

State of the artSemantic dementia (SD) patients including semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) patients show semantic difficulties identifying faces and known people related to right anterior temporal lobe (ATL) atrophy. However, it remains unclear whether they also have perceptual deficits in face recognition. MethodologyWe selected 74 SD patients (54 with svPPA and predominant left ATL atrophy and 20 with sbvFTD and predominant right ATL atrophy) and 36 cognitively healthy controls (HC) from UCSF Memory and Aging Center. They underwent a perceptual face processing test (Benton facial recognition test-short version; BFRT-S), and semantic face processing tests (UCSF Famous people battery – Recognition, Naming, Semantic associations – pictures and words subtests), as well as structural magnetic resonance imaging (MRI). Neural correlates with the task’s performance were conducted with a Voxel-based morphometry approach using CAT12. ResultssvPPA and sbvFTD patients were impaired on all semantic face processing tests, with sbvFTD patients performing significantly lower on the famous faces’ recognition task in comparison to svPPA, and svPPA performing significantly lower on the naming task in comparison to sbvFTD. These tasks predominantly correlated with gray matter (GM) volumes in the right and left ATL, respectively. Compared to HC, both svPPA and sbvFTD patients showed preserved performance on the perceptual face processing test (BFRT-S), and performance on the BFRT-S negatively correlated with GM volume in the right posterior superior temporal sulcus (pSTS). ConclusionOur results suggest that early in the disease, with the atrophy mostly restricted to the anterior temporal regions, SD patients do not present with perceptual deficits. However, more severe SD cases with atrophy in right posterior temporal regions might show lower performance on face perception tests, in addition to the semantic face processing deficits. Early sparing of face perceptual deficits in SD patients, regardless of hemispheric lateralization, furthers our understanding of clinical phenomenology and therapeutical approaches of this complex disease.

Evaluation of an in-house pan-Malassezia quantitative PCR in human clinical samples.

Althought Malassezia spp. have been involved in various pathologies, they are an integral part of the cutaneous, gut, oral, ears, nose and throat (ENT) mycobiota. Since Malassezia are difficult to grow in culture, unexhaustive molecular biology methods have been developed to detect them. The aim of the study was to evaluate an in-house pan-Malassezia quantitative polymerase chain reaction (panM-qPCR) on various clinical human samples and determine Malassezia burden in various human mycobiota. The panM-qPCR was designed to target the repeated 28S rDNA gene from all Malassezia species. We used the assay to quantify the Malassezia burden on 361 samples from 161 subjects (80 skin swabs from 10 healthy volunteers (HV), 13 samples from 2 seborrheic dermatitis patients (SD), 90 skin samples from 19 burned patients, 119 stool samples from 89 immunocompromised patients, 59 ENT samples from 41 patients). For HV, the amount of Malassezia was different according to the swabbed areas. Quantification cycle (Cq) in SD is lower than in HV. In burned patients, Cq was significantly lower compared to HV. In stool samples, 6.7% were positive for Malassezia spp. with a high Cq. For the ENT area, a higher proportion of positive specimens were detected in ear samples than in nose samples. Our findings emphasized the importance of qPCR, confirming elevated Malassezia spp. levels on individuals' faces and scalps, increased burden in SD patients and in severely burnt patients than in HV. The pan-MqPCR appears to be a promising tool for studying Malassezia in various human mycobiota.

Rituximab, chidamide, and zanubrutinib (ZCR) ± CHOP as a regimen for treatment naive (TN) double-expressor DLBCL (DE-DLBCL).

e19053 Background: DLBCL patients with co-expression of MYC (≥40%) and BCL2 (≥50%) by immunohistochemistry are considered as DE-DLBCL. The prognosis of DE-DLBCL is usually worse than DLBCL-NOS. The Smart Start trial had established the feasibility of chemotherapy-free targeted therapy before 1L chemotherapy. The BTK inhibitor Zanubrutinib (Z) or epigenetic drug Chidamide (C) with R-CHOP regimen has a potential synergistic effect in the treatment of DE-DLBCL. Under the inspiration of Smart Start, this trial aim to explore the feasibility of ZCR±CHOP regimen in TN DE-DLBCL. Methods: This is a multicenter, open-label, single-arm phase 2 study (NCT05527912) conducted in China. If patients achieve complete response (CR) after cycle-2 (C2), ZCR will be continued for up to 8 cycles. Otherwise, ZCR-CHOP will be given for another 6 cycles. The primary endpoint is CR rate at the end of treatment (CRR-EOT); secondary endpoints included ORR (overall response rate) ,2y-PFS, and 2y-OS. Plasma samples were collected at baseline, C2 and the EOT. In evaluable samples, circulating tumor DNA (ctDNA) assays were performed. Results: From February 2023 till now, 34 TN DE-DLBCL patients were enrolled, with 32 patients evaluable. The median age was 52y (range: 22-68), 55.9% were male, 79.4% were Non-GCB (Table 1). 12 patients who achieved CR by C2 were continued with RCZ chemo-free therapy, and CHOP were added to the 14 PR and 3 SD patients. In the 32 evaluable patients, ORR after C2 of RCZ was 81.25% (26/32, CR 37.5%, PR 43.75%, SD 9.4%, PD 9.4%). Up to now, 12 patients have completed 8 courses (C8) and all of them have achieved CR, both ORR and CR are 100% (12/12). 3 patients withdrew due to PD. For safety information in the trial, 64.3% patients reported grade (G)-3/4 AEs. In the Chemo-Free subgroup, only 4 patients (36.4%, 4/11) reported G-3/4 AEs. the majority of G-3/4 AEs is hematological events, including leukopenia, neutropenia and thrombocytopenia. The CR rate at C2 was 66.7% (6/9) in patients with negative baseline ctDNA results. The patients with BCL6 fusion of ctDNA at baseline were more prone to PD (3/4, 75.0%). Compared to baseline, plasma ctDNA levels decreased significantly after C2. 29 patients were evaluable for ctDNA after C2, 100% (12/12) of C2-CR patients and 58.8% (10/17) of non-C2-CR patients were negative, P=0.023. Compared with Non-C2-CR patients, the number of detected mutations and average VAF level were decreased in C2-CR patients. Conclusions: This trial demonstrates ZCR±CHOP could be a promising regimen with active antitumor effect and acceptable toxicity in TN DE-DLBCL patients. Clinical trial information: NCT05527912 .

Long-term mandibular growth in patients with airway obstruction treated with mandibular distraction

Congenital craniofacial malformations play an important role in upper airway obstruction. One of the main causes is mandibular hypoplasia which is present in the pierre robin sequence. Mandibular distraction osteogenesis (MDO) is one of the most commonly used treatments for the resolution of upper airway obstruction in patients that do not respond to a conservative treatment. We performed a long term follow up of syndromic and non-syndromic patients with pierre robin sequence where the lateral xrays were studied before surgery (T1), after MDO (T2) and long-term follow-up (T3, at least 5 years). Possible complications of the surgery were also studied through panoramic x-rays and clinical controls. The results evidenced an increase of mandibular length comparing T1-T2 and a good stability during the long-term follow-up. The Sd patients presented smaller mandible dimensions. We had not found any complications during the follow-up. The scars outcomes are modest, but none of the patients requested a surgical correction. Mandibular distraction osteogenesis is a treatment to be considered in patients with upper airway obstruction that do not respond to conservative treatments. The results of the surgery are stable and the complications in experienced hands are low.

Functional brain alterations in symptomatic dermographism patients-An exploratory magnetoencephalography study.

Symptomatic dermographism (SD) is a common form of urticaria, which is triggered by stroking the skin. Brain involvement in its aetiology was investigated by means of magnetoencephalography (MEG) after provocation with histamine and dermography. Wheals were induced by histamine skin prick test and dermography in twelve SD patients and fourteen controls. Itch severity was scored on a Visual Analogue Scale (VAS). Relative power and functional connectivity (FC) were measured using a 306-channel whole-head MEG system at baseline and 10 min after histamine and dermography, and contrasted between groups and conditions. Furthermore, wheal diameter and itch scores after these procedures were correlated with the MEG values. SD patients had higher itch scores after histamine and dermography. No significant group-differences were observed in relative power or FC for any condition. In both groups, power decreases were mostly observed in the beta band, and power increases in the alpha bands, after provocation, with more regions involved in patients compared to controls. Increased FC was seen after histamine in patients, and after dermography in controls. In patients only, dermography and histamine wheal size correlated with the alpha2 power in the regions of interest that showed significant condition effects after these procedures. Our findings may be cautiously interpreted as aberrant itch processing, and suggest involvement of the central nervous system in the aetiology of SD.

Differences in prefrontal cortex activation in Chinese college students with different severities of depressive symptoms: A large sample of functional near-infrared spectroscopy (fNIRS) findings

BackgroundPrevious studies proposed that functional near-infrared spectroscopy (fNIRS) can be used to distinguish between not only different severities of depressive symptoms but also different subgroups of depression, such as anxious and non-anxious depression, bipolar and unipolar depression, and melancholia and non-melancholia depression. However, the differences in brain haemodynamic activation between depression subgroups (such as confirmed depression [CD] and suspected depression [SD]) with different symptom severities and the possible correlation between symptom severity and haemodynamic activation in specific brain regions using fNIRS have yet to be clarified. MethodsThe severity of depression symptoms was classified using the Hospital Anxiety and Depression scale (HADS) and the Mini International Neuropsychiatric Interview by psychiatrists. We recruited 654 patients with depression who had varying severities of depressive symptoms, including 276 with SD and 378 with CD, and 317 with HCs from among Chinese college students. The 53-channel fNIRS was used to detect the cerebral hemodynamic difference of the three groups during the VFT (verbal fluency task). ResultsCompared with the HC, region-specific fNIRS leads indicate CD patients had significant lower haemodynamic activation in three particular prefrontal regions: 1) right dorsolateral prefrontal cortex (DLPFC), 2) bilateral frontopolar cortex (FPC), and 3) right Broca's area (BA). SD vs. HC comparisons revealed only significant lower haemodynamic activation in the right FPC area. Compared to SD patients, CD patients exhibited decreased hemodynamic activation changes in the right DLPFC and the right BA. Correlation analysis established a significant negative correlation between the hemodynamic changes in the bilateral FPC and the severity of depressive symptoms. ConclusionsThe right DLPFC and right BA are expected to be physiological mechanisms to distinguish depression subgroups (CD, SD) with different symptom severities. The haemodynamic changes in the bilateral FPC was nagatively associated with the symptom severity of depression.

Platelet derived exosomes disrupt endothelial cell monolayer integrity and enhance vascular inflammation in dengue patients.

Thrombocytopenia is the most notable phenomenon in dengue. Activation status of platelets and interaction of platelets with endothelium contribute towards dengue disease pathogenesis. Platelets are the major cell types known to release extracellular vesicles, especially exosomes in circulation. However, the role of platelet derived exosomes (PLT-EXOs) in endothelial dysfunction during dengue infection remains unknown. In this study, we recruited 28 healthy subjects and 69 dengue patients categorized as WS- (n=31), WS+ (n=29) and SD (n=9). Platelets were isolated from platelet rich plasma of dengue patients and their activation was assessed by flow cytometry. PLT-EXOs were isolated by ultracentrifugation method. Western blot analyses were performed to characterize the exosomes. Exosome uptake experiment was carried out to see the internalization of exosomes inside endothelial cells (HUVECs). To observe the effect of exosomes on endothelial cells, exosomes were added on HUVECs and expression of adherens and tight junctional proteins were examined by immunofluorescence assay and western blot. Expression levels of vascular injury markers were measured in the culture supernatants of Exosome-HUVEC coculture and sera of dengue patients by MSD-multiplex assay. As compared to healthy subjects, CD41/CD61 expression was significantly reduced (p<0.0001) and CD62p expression was significantly increased (p<0.0001) on platelets in dengue patients. PLT-EXOs isolated from the dengue patients showed higher expression of CD63 and CD9 proteins than the healthy subjects. With in-vitro immunofluorescence assays, we illustrated the internalization of PLT-EXOs by the HUVECs and observed disruption of endothelial cell monolayer integrity in the presence of PLT-EXOs from WS+ and SD patients. Furthermore, the significant reduction in the expressions of ZO-2, VE-Cadherin and CD31 in endothelial cells following exposure to PLT-EXOs from the dengue patients provide direct evidence of PLT-EXOs mediated vascular permeability. PLT-EXOs stimulated the release of inflammatory markers CRP, SAA, sVCAM-1 and sICAM-1 in the supernatants of HUVEC cells. Importantly, significantly higher levels of CRP, sVCAM-1 and sICAM-1 in the sera of severe than mild dengue patients (p<0.0001) suggest their role in disease severity. In summary, our data suggest that PLT-EXOs promote vascular leakage via release of proinflammatory mediators and compromise vascular barrier integrity in dengue patients.

Comparison of CT-Guided needle biopsy versus percutaneous endoscopic debridement and drainage in pathogen identification and pain outcomes for spondylodiscitis patients: A systematic review and literature review

IntroductionSpondylodiscitis (SD) is an infection of the intervertebral disc with involvement of the adjacent vertebral bodies. Diagnostic tests with CT-guided biopsy only provide a positive yield in 14%–48% of cases. Percutaneous endoscopic debridement and drainage (PEDD) has recently shown promise in the treatment of spondylodiscitis. Research questionThe purpose of this study is to determine differences in pathogen identification and clinical outcomes for PEDD versus CT-guided needle biopsy in SD patients. Materials and methodsWe conducted a systematic review of the literature using PRISMA guidelines to determine differences in positive microbiology results, perioperative complications, pain control, and long-term clinical outcomes for PEDD vs. CT-guided needle biopsy in SD patients. Results1078 studies were evaluated, 87 of which underwent full review. 15 studies met the inclusion and exclusion criteria, including 7 PEDD, 7 CT-guided biopsy, and 1 CT-guided biopsy vs. PEDD article, for a total of 192 PEDD patients and 604 CT-guided biopsy patients. We found 36.59% of CT-guided biopsy patients had positive microbiology results, compared to 84.38% of PEDD patients. No major perioperative complications occurred as a result of the PEDD procedure. Of the five PEDD studies that reported pain outcomes, greater than 80% of patients experienced relief after intervention. Discussion and conclusionThese results suggest that PEDD may improve pathogen identification while simultaneously reducing pain compared to CT-guided needle biopsy in SD. Although current treatment guidelines recommend CT-guided biopsy, in patients with severe back pain and suspected SD, PEDD can be considered an alternative intervention.

Transcriptomic Signature and Functional Abnormalities of Bone Marrow Mesenchymal Stromal Cells Mediate Disease Progression of Myelodysplastic/Myeloproliferative Neoplasms

Background Mesenchymal stromal cells (MSC) are vital components of the bone marrow (BM) microenvironment niche and regulate hematopoietic stem and progenitor cell (HSPC) activity. While HSPC harbor primary disease driver mutations, MSC in myelodysplastic syndrome and myeloproliferative neoplasm (MDS/MPN) have been shown to influence the emergence and selection of leukemic clones and disease progression. However, it remains unclear if there are specific functional characteristics or genetic signals of MSC that interact with HSPC at different stages of disease progression. We examined BM samples from MDS/MPN patients with high rate of leukemic transformation in less than 2 years (HR) versus those with stable disease for 5 years (SD), to investigate the phenotypic differentiation, functional characteristics, and transcriptomic profiles of MSC and the HSPC counterparts. Methods We obtained BM samples at diagnosis and follow-up from MDS/MPN patients including chronic myelomonocytic leukemia (CMML) treated at Singapore General Hospital. We studied 5 HR and 13 SD patient samples to compare against 5 healthy donor samples. MSC were derived in MesenCult-ACF media (StemCell Technologies), and phenotypic characterization was done after 1-2 passages. HSPC were subjected to co-culture expansion with MSC in MyeloCult-H5100 for 7 days, and long-term culture-initiating cell assays (LTC-IC) using MSC as feeder cells for 6 weeks. Total RNA extracted from MSC and HSPC were subjected to bulk and single-cell RNA sequencing (scRNA-Seq) (10X Genomics platform). Principal component analysis (PCA) was used for the uniform manifold approximation and projection (UMAP). Gene set enrichment analysis (GSEA) was performed on differentially expressed genes to examine canonical signaling pathways. Cellchat algorithm was applied to predict intercellular communication between MSC and HSPC using scRNA-Seq data. Results Baseline clinical variables for the international prognostic scoring system (IPSS) including age at diagnosis, myeloblast percentage and cytogenetics were not significantly different between HR and SD patients. Decreased osteogenic and chondrogenic differentiation, but relatively preserved adipogenic differentiation capacity was observed in all MDS/MPN MSC samples. A significantly lower yield of CD34+ CD38- primitive HSPC with myeloid skewing was observed in the co-culture experiments with MDS/MPN MSC, compared to healthy MSC. Pre-treatment of SD-MSC feeder with the hypomethylating agent 5-azacytidine improved the clonogenic potential of the corresponding co-cultured HSPC, but did not restore the HSPC colony yield with HR-MSC feeder. Unbiased PCA of bulk RNA-Seq data demonstrated greater clustering of HR-MSC, while SD and healthy MSC overlapped significantly. Genes associated with mesenchymal multipotency and differentiation (PODXL20, FOXQ122, SERPINA923) were generally downregulated in MDS/MPN MSC, likely attributed to promoter hypermethylation. Significant differential upregulation of CD74 and IL-6 expression was observed in HR-MSC, which suggested a uniquely enriched inflammatory signature. GSEA results showed that pathways associated with G2M cell cycle checkpoint, DNA repair, glycolysis, and response to azacytidine were suppressed in HR-MSC. UMAP on scRNA-Seq data of longitudinal MSC samples identified distinct clustering of HR-MSC at disease progression. Cell-cell interaction analysis predicted a strong communication between collagen-encoding genes (COL1A1 and COL1A2) in HR-MSC at diagnosis and CD44, a negative regulator of HSPC proliferation, and the interaction was further enhanced at disease progression (Figure 1). Ongoing analysis of downstream gene expression changes and secretome profile of HSPC in MDS/MPN MSC-based in-vivo scaffold models will be presented. Conclusion Together, our data point towards a degree of co-development and communication between MSC and HSPC during disease progression of MDS/MPN. Further characterization of the unique functional and transcriptomic signatures in MSC may help to optimize disease prognostication and identify novel therapeutic targets in MDS/MPN patients.

Using machine learning to forecast symptom changes among subclinical depression patients receiving stepped care or usual care

BackgroundSubclinical depression (SD) is a mental health disorder characterized by minor depressive symptoms. Most SD patients are treated in the primary practice, but many respond poorly to treatment at the expense of provider resources. Stepped care approaches are appealing for tiering SD care to efficiently allocate scarce resources while jointly optimizing patient outcomes. However, stepped care can be time inefficient, as some persons may respond poorly and be forced to suffer with their symptoms for prolonged periods. Machine learning can offer insight into optimal treatment paths and inform clinical recommendations for incident patients. MethodsAs part of the Step-Dep trial, participants with SD were randomized to receive stepped care (N=96) or usual care (N=140). Machine learning was used to predict changes in depressive symptoms every three months over a year for each treatment group. ResultsTree-based models were effective in predicting PHQ-9 changes among patients who received stepped care (r=0.35–0.46, MAE=0.14–0.17) and usual care (r=0.34–0.49, MAE=0.15–0.18). Patients who received stepped care were more likely to reduce PHQ-9 scores if they had high PHQ-9 but low HADS-A scores at baseline, a low number of chronic illnesses, and an internal locus of control. LimitationsModels may suffer from potential overfitting due to sample size limitations. ConclusionOur findings demonstrate the promise of machine learning for predicting changes in depressive symptoms for SD patients receiving different treatments. Trained models can intake incident patient information and predict outcomes to inform personalized care.

Salivary miRNA Profiles in COVID-19 Patients with Different Disease Severities

The oral mucosa is the first site of SARS-CoV-2 entry and replication, and it plays a central role in the early defense against infection. Thus, the SARS-CoV-2 viral load, miRNAs, cytokines, and neutralizing activity (NA) were assessed in saliva and plasma from mild (MD) and severe (SD) COVID-19 patients. Here we showed that of the 84 miRNAs analyzed, 8 were differently expressed in the plasma and saliva of SD patients. In particular: (1) miRNAs let-7a-5p, let-7b-5p, and let-7c-5p were significantly downregulated; and (2) miR-23a and b and miR-29c, as well as three immunomodulatory miRNAs (miR-34a-5p, miR-181d-5p, and miR-146) were significantly upregulated. The production of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-9, and TNFα) and chemokines (CCL2 and RANTES) increased in both the saliva and plasma of SD and MD patients. Notably, disease severity correlated with NA and immune activation. Monitoring these parameters could help predict disease outcomes and identify new markers of disease progression.

Systematic Review of Naloxone Dosing and Adverse Events in the Emergency Department

BackgroundExperts recommend using the lowest effective dose of naloxone to balance the reversal of opioid-induced respiratory depression and avoid precipitated opioid withdrawal, however, there is no established dosing standards within the emergency department (ED). ObjectivesThe aim of this review was to determine current naloxone dosing practice in the ED and their association with adverse events. MethodsWe conducted a systematic review by searching PubMed, Cochrane, Embase, and EBSCO from 2000–2021. Articles containing patient-level data for initial ED dose and patient outcome had data abstracted by two independent reviewers. Patients were divided into subgroups depending on the initial dose of i.v. naloxone: low dose ([LD], < 0.4 mg), standard dose ([SD], 0.4–2 mg), or high dose ([HD], > 2 mg). Our outcomes were the dose range administered and adverse events per dose. We compared groups using chi-squared difference of proportions or Fisher's exact test. ResultsThe review included 13 articles with 209 patients in the results analysis: 111 patients in LD (0.04–0.1 mg), 95 in SD (0.4–2 mg), and 3 in HD (4–12 mg). At least one adverse event was reported in 37 SD patients (38.9%), compared with 14 in LD (12.6%, p < 0.0001) and 2 in HD (100.0%, p = 0.16). At least one additional dose was administered to 53 SD patients (55.8%), compared with 55 in LD (49.5%, p < 0.0001), and 3 in HD (100.0%, p = 0.48). ConclusionsLower doses of naloxone in the ED may help reduce related adverse events without increasing the need for additional doses. Future studies should evaluate the effectiveness of lower doses of naloxone to reverse opioid-induced respiratory depression without causing precipitated opioid withdrawal.

Influence of modified Lugano criteria by pre-infusion tumor kinetics on early survival prediction for patients with lymphoma under chimeric antigen receptor T-cell therapy.

e19500 Background: Chimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed (r/r) lymphoma with prolongation of survival. We aimed to improve the prediction of Lugano criteria for overall survival (OS) at 30-day follow-up (FU1) by including the pre-infusion tumor growth rate (TGRpre-BL) and its early change to 30-day FU1 imaging (TGRpost-BL). Methods: Consecutive patients with pre-baseline (pre-BL), baseline (BL) and FU imaging around day 30 with CT or PET/CT before CART were included. TGR was defined as change of Lugano criteria-based tumor burden between pre-BL, BL and FU examinations in relation to days between imaging exams. Overall response and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of TGR with OS. For survival analysis, OS was analyzed using Kaplan-Meier survival curves. Results: 59 out of 81 patients met the inclusion criteria. At 30-day FU 8 patients (16%) had a CR, 25 patients (42%) a PR, 15 patients (25%) a SD, and 11 patients (19%) a PD according to Lugano criteria. The Median TGRpre-BL was -0.6 mm2/d, 24.4 mm2/d, -5.1 mm2/d, and 18.6 mm2/d and the median TGRpost-BL was -16.7 mm2/d, -102.0 mm2/d, -19.8 mm2/d and 8.5 mm2/d in CR, PR, SD, and PD patients, respectively. PD patients could be subclassified into a cohort with an increase in TGR (7 of 11 patients [64%], PD TGRpre-to-post-BL INCR) and a cohort with a decrease in TGR (4 of 11 patients [36%], PD TGRpre-to-post-BL DECR) from pre- to post-BL. PD TGRpre-to-post-BL DECR patients exhibited similar OS to patients classified as SD, while PD TGRpre-to-post-BL INCR patients had significantly shorter OS (65 days vs 471 days, p &lt; 0.001). Conclusions: In the context of CART, the additional use of TGRpre-BL and its change to TGRpost-BL determined at 30-day FU1 showed better OS prognostication for patients with overall progressive disease according to Lugano criteria. Therefore, this modification of the Lugano classification should be explored as a potential novel imaging biomarker of early response. [Table: see text]

Phase I first-in-human trial of ABT-301, an oral pan-HDAC inhibitor, in patients with advanced solid tumors.

e15137 Background: ABT-301 (previously known as MPT0E028) is a novel, oral pan-histone deacetylases (HDAC) inhibitor with potent inhibitory activity for HDAC 1, 2, 3 (class I), HDAC 6, 10 (class IIb), modest activity for HDAC 8 (class I) and HDAC 11 (class IV), but no activity for HDAC 4, 5, 7, 9 (class IIa). Preclinical studies showed that ABT-301 had a stronger apoptotic activity and inhibited HDAC activity more potently than vorinostat. ABT-301 exerts antitumor activity as a monotherapy in human colorectal cancer and B-cell lymphoma xenografts and synergistic antitumor activity with immune checkpoint inhibitor in CT26 syngeneic tumor model. Methods: This was a 3+3 Phase 1 dose escalation study to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetic (PK) /pharmacodynamic (PD) profiles for the ABT-301 in patients with locally advanced or metastatic solid cancers. 5 cohorts of 3 or 6 patients received ABT-301 once daily at gradually escalating doses starting from 50 mg. Results: 23 subjects (6 sarcomas and 17 carcinomas) were treated at 5 dose levels (3 at 50, 100, and 250 mg respectively, 6 at 150 mg, and 8 at 200 mg). Cycle 1 DLTs occurred in 5 subjects: 1 at 50 mg (G3 mucositis); 2 at 200 mg (G3 abdominal pain and G4 thrombocytopenia); 2 at 250 mg (G3 vomiting and G4 thrombocytopenia). The MTD was 150 mg. The most common treatment-related adverse events were thrombocytopenia (44%), anemia (18%), nausea (61%), vomiting (44%), anorexia (22%), hyperglycemia (22%), fatigue (18%), and mucositis (18%), which were generally G1 to G2 in severity. No cardiac abnormalities were observed. 1 had a partial response (PR), and 8 achieved SD, resulting in a disease control rate (DCR) of 39%. The PR (a patient with eccrine ductal carcinoma) lasted 24 weeks whereas 5/8 SD patients achieved a sustained condition of 16 to 53 weeks (hepatocellular carcinoma, 53 w; thymic cancer, 49 w; salivary gland carcinoma, 27 w; endometrial stromal carcinoma, 25 w; renal cell carcinoma, 16 w). DCR for 9 patients at MTD was 78% (7/9; 1 PR and 6 SD). Plasma PK showed a dose-dependent increase in ABT-301 exposure. Cmax is 5.5 µM and AUC0-inf is 11.5 µM*h at 150 mg. Increased acetylated histone 3 was observed across all cohorts. Conclusions: ABT-301 was well-tolerated at a daily dose of up to 150 mg and demonstrated objective responses and long-term SD across multiple tumor types at MTD. The safety profile of ABT-301 was superior to known HDAC inhibitors with only predictable HDAC inhibitor-related toxicities observed but no cardiac toxicity, neutropenia, nor lymphopenia elicited. Non-clinical and clinical results suggested the potential clinical development of ABT-301 in combination with myelosuppressive agents and immunotherapies. Phase 2 studies combining PD-1/PD-L1 blockade are being designed. Clinical trial information: NCT02350868 .

Lipolytic activity of Malassezia spp. on inflamed seborrheic areas increases after exposure to beta-endorphin

Annotation. The opiate system of the skin modulates inflammation and regeneration, while metabolic products of some bacteria and fungi disrupt the skin barrier and cause inflammation. Therefore, the study aimed to evaluate the effect of beta-endorphin (BE) on the lipolytic activity (LA) of Malassezia spp. isolated from both seborrheic areas and healthy skin of patients with seborrheic dermatitis. The study included 42 patients with moderate and severe forms of SD, with positive growth of Malassezia spp., and 17 medical workers without any skin diseases constituting the control group. Two smears were taken from the SD patients: from the face, specifically inflamed areas affected by SD, and intact skin of the sternum. Samples were transferred to MLNA (37°C; 72 h), colonies were suspended in Dixon broth, and 500 nmol/L human BE was added (3 days; 32 °C). 1 ml of the suspension was then applied to yolk agar (7 days; 35 °C). The precipitation zone was considered a sign of the presence of LA. The following statistical research methods were used: chi-square test, Mann-Whitney t-test, and Student’s test. Half of the Malassezia spp. isolated from healthy individuals did not show any LA before and after BE exposure. 69% of samples obtained from healthy areas and 95% of samples from inflamed skin areas from SD patients had LA. After BE stimulation, all samples from healthy areas of SD patients had LA. In healthy individuals, the average value of the LA did not show a significant difference after BE exposure (0.99 (0.99-1.00) vs 0.95 (0.92-0.97) p=0.358). In patients with SD, the intensity of lipolysis significantly increased. In samples obtained from healthy areas, the difference in LA was smaller than in samples from inflamed skin areas (0.06 p≤0.031; 0.22 p≤0.001). However, when comparing the intensity of LA in samples from healthy areas of SD patients and healthy individuals, no significant difference was found either before or after BE stimulation (0.91 (0.86-0.95) vs 0.95 (0.92-0.97) p=0.173). It was established that BE increases the LA of Malassezia spp., which colonizes the inflamed skin areas of patients with SD. Further research using opioid receptor blockers for the treatment of seborrheic dermatitis would be a logical next step.

Abstract CT197: Profiling of tumor infiltrating T cells in malignant pleural/peritoneal mesothelioma (MPM) and ovarian cancer patients as part of a Phase 1 clinical trial of gavo-cel (TC-210)

Abstract Gavocabtagene autoleucel (gavo-cel; TC-210) is a T cell receptor fusion construct (TRuC) cell therapy directed against mesothelin. As part of the phase 1 dose-escalation clinical trial (NCT03907852), patients with advanced solid tumors expressing mesothelin were administered a single infusion of gavo-cel. Thirty-two patients with late-stage disease (23 MPM, 8 ovarian and 1 cholangiocarcinoma) received gavo-cel at doses ranging from 5 × 107 - 5 × 108 TRuC cells/m2. The disease control rate (defined as achieving a response by RECISTv1.1 criteria or having stable disease [SD] for at least 12 weeks post-infusion) was 77%. Dose level 3 (1 × 108 TRuC cells/m2 following lymphodepletion with cyclophosphamide and fludarabine) was selected as the Recommended Phase 2 Dose (RP2D) for the ongoing phase 2 portion of the trial. Spatial distribution of immune cells, particularly T cells, in the tumor and stromal regions of tumor biopsies has been shown to identify patients that may respond to immunotherapies. To understand the tumor immune contexture, we profiled the T cell compartment in biopsies from five patients collected prior to and eight weeks post treatment using multiplexed immunofluorescence. We observed that the MPM patient with a partial response (PR) had a greater number of T cells at baseline in tumor biopsies when compared with the other SD patients. Notably, this patient with a PR, had a 3.6-fold increase in CD3+CD8+ T cell infiltrates into the tumor bed. In contrast, 2 SD patients with MPM had a minimal increase of T cells in the tumor compartment at 8 weeks post infusion. The density of TILs 8 weeks post infusion was much lower in the SD patients compared to the PR subject, indicating a potentially insufficient number of infiltrating T cells. Interestingly, 2/2 SD patients with ovarian cancer had a decrease in CD3+CD8+ T cells infiltrating into the tumor, consistent with an immune exclusion phenotype. The PR patient with MPM had minimal increase in PD-L1 and CD155 (a ligand for the inhibitory receptor, TIGIT) from negligible levels at baseline, whereas both SD patients with MPM had marked increases in PD-L1 and CD155, indicating potential resistance mechanisms. In summary, this preliminary data suggests although CD8+ TILs are increased following treatment with gavo-cel, the tumor regions in patients with SD show evidence of immune surveillance escape via PD-L1 and CD155 upregulation, thus acting as putative mechanisms of resistance. However, as seen in the PR patient with MPM there appears to be a critical number of TILs associating with response. We are currently evaluating the tumor immune contexture in phase 2, focusing on differences across tumor types with regards to TIL content, T cell influx, and correlations with response. We will also explore additional markers such as PD-1 and TIGIT, to profile the exhaustion state of immune cells and their spatial relationship with infiltrating gavo-cel T cells. Citation Format: Munisha Smalley, Michael Ross, Samantha F. Fowler, Lauren McLaughlin, Erin Jeter, Kevin Zikaras, Philip D. Bardwell, Alfonso Quintás-Cardama, Robert Tighe. Profiling of tumor infiltrating T cells in malignant pleural/peritoneal mesothelioma (MPM) and ovarian cancer patients as part of a Phase 1 clinical trial of gavo-cel (TC-210) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT197.

Abstract 4530: Single-cell analysis of oral squamous cell carcinoma (OSCC) from smoker vs. non-smoker patients highlights two groups of tumors with distinct immune microenvironments

Abstract Background and Rationale: OSCC is the most frequent head and neck cancer. While it is mainly affecting patients with a smoking and/or alcohol history (SD), 10% to 15% of OSCC are diagnosed in patients with not known risk factors (NSND). We and others have shown that OSCC from NSND patients are characterized by an enrichment in interferon gamma (IFNγ) response and PD-1 signaling pathways together with a higher intratumor T-cell infiltrate. Herein, we seek to gain more insights into the immune and non-immune tumor microenvironment (TME) of OSCC in SD vs. NSND patients. Material and Methods: We made use of single-cell RNA seq (10x Genomics) from non-sorted and CD45 negative enriched cell suspensions of OSCC biopsies from 11 treatment naïve patients, human papillomavirus negative, including 6 SD and 5 NSND patients. Results: All samples were characterized by a strong immune cell infiltrate. Consistent with our previous results, the analysis of 51,629 immune cells confirmed that NSND patients’ samples displayed a significantly higher proportion of T cells (p = 0.005) compared to SD patients. NK cells were also increased, with 2% in SD patients versus 6% in NSND patients (p = 0.008). T cells strongly expressed IFNγ and remarkably, both myeloid cells and tumor cells from NSND patients had an increased enrichment in IFNγ response pathway in NSND as compared to SD patients. The TME of SD patients was characterized by the presence of 15% of plasma cells vs. 3% in NSND patients (p = 0.003). Thus, tumors from NSND versus SD patients represent two distinct groups of tumors characterized by a different immune TME. Moreover, tumors from SD patients displayed 2% vs. 4% Cancer Associated Fibroblasts (CAFs) (p = 0.01). In addition, among CAFs subpopulations, myofibroblast CAFs, defined as the subpopulation producing extracellular matrix proteins were found only in tumors from SD patients, suggesting that distinct CAFs subpopulations may shape the immune TME by affecting the recruitment and function of adaptive immune cells in SD versus NSND patients. Finally, we analyzed tumor cells using non-negative matrix factorization to find Meta Programs (MP), which are set of genes coordinately upregulated. We identified 5 MP associated with different biological functions: epithelial differentiation, stress, cell cycle (G2/M), partial epithelial-to-mesenchymal transition, and epithelial senescence. While the epithelial differentiation MP was found in all patients, the remaining ones were more frequently found in SD patients. Conclusion: Our results show that the TME of OSCC from NSND vs. SD differs in terms of T, NK, and plasma cells composition, CAFs, and tumor cells MP. Integration with spatial transcriptomics is ongoing. Those biological differences may represent an opportunity to refine the therapeutic approaches in the two populations of patients. Citation Format: Yannick Le Meitour, Béatrice Vanbervliet, Sonia Canjura-Rodriguez, Cyril Degletagne, Laurie Tonon, Lucas Michon, Jebrane Bouaoud, Philippe Zrounba, Aude Excoffier, Karène Mahtouk, Pierre Saintigny. Single-cell analysis of oral squamous cell carcinoma (OSCC) from smoker vs. non-smoker patients highlights two groups of tumors with distinct immune microenvironments. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4530.

Defining biomarkers in oral cancer according to smoking and drinking status.

Oral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis. Cells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay. Normal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p<0.05 for blood), of monocytes-macrophages (p<0.01 for blood) and of CD4+ T cells expressing CD45RO and CCR6 (p<0.001 for blood; p<0.0001 for TME) as well as higher levels of IL-6 (p<0.01 for sera, p<0.05 for tumor supernatant) were observed in SD patients as compared to NSND OSCC patients and HD. High percentages of CD4+ T cells expressing CD45RO and CCR6 cells in tumor tissue (p=0.05) and blood (p=0.05) of SD OSCC patients were also associated with a poorer prognosis while a high percentage of regulatory T cells (Treg) in tumor tissue was associated with a more favorable prognostic factor (p=0.05). Also, a higher percentage of blood CD8+ T lymphocytes among CD45+ cells in NSND patients was associated with a better disease-free survival (p=0.004). Granulocytes, monocytes-macrophages, and CD4+ T cells expressing CD45RO and CCR6 in blood and TME as well as serum IL-6 can therefore distinguish OSCC SD and NSND patients. Quantifying the proportion of CD4+ T cells expressing CD45RO and CCR6 and of Treg in SD patients and CD8+ T cells in NSND patients could help defining the prognostic of OSCC patients.

Comprehensive biomarker analysis from phase II study of nivolumab in patients with thymic carcinoma.

In a phase II trial of nivolumab in advanced thymic carcinoma (UMIN000022007), long SD (SD for more than 24 weeks) was seen in three patients and irAE (Gr2 or higher) was seen in four patients among 15 patients. Here, we report preplanned comprehensive biomarker analyses. We obtained tumor samples for immunohistochemistry, peripheral blood mononuclear cells (PBMCs), plasma and serum for pharmacokinetic analysis of nivolumab and cytokine evaluations, and whole blood for immuno pharmacogenomic (PGx) analysis. PD-L1 expression on tumor cells were not associated with therapeutic efficacy, but FOXP3 expression in tumor area and stroma, CD204 expression in stroma, and MHC class I in tumor area were all low among long SD patients. PBMC of long SD patients presented with larger number of naïve/memory cells prior to treatment, suggesting priming after nivolumab administration. Immuno-PGx analysis showed non-synonymous SNVs in ITGAX and PDCD1 had some correlation with PFS. Concentration of nivolumab in blood during the treatment was not related to PFS, with their overall trend towards decreased nivolumab concentration in patients with irAEs. Low immunogenicity of thymic carcinoma demonstrated in our study may require the activation of immune systems via a combination of immune checkpoint blockades.

MALASSEZIA COLONIZATION CORRELATES WITH THE SEVERITY OF SEBORRHEIC DERMATITIS.

The aim: To compare the number of fungi of the genus Malassezia on inflated and healthy areas of the skin and to correlate them with the severity of seborrheic dermatitis. Materials and methods: 168 patients with typical manifestations of seborrheic dermatitis on the scalp and face and 30 healthy individuals were recruited. SD severity was assessed by SEDASI. Samples from lesions on scalp, face and intact chest skin were cultivated and/or stained with methylene blue or cotton and inoculated onto Malassezia Leeming & Notman Agar Modified (MLNA). Results: A statistical difference in colonization intensity between all body zones (Dwass-Steel-Critchlow-Flinger pairwise comparisons p≤0,001). Face zone with lesions of SD patients was two times more colonized with funguses than in the control group (38,5 vs 16,5 p=0,003). The sternal area with no skin lesions was more colonized in the SD group (25,0 vs 9,0 p=0,013). The SEDASI was positively correlated with the amount of CFU on the face (Spearman's rho 0,849; p≤0,001) and trunk (0,714; p≤0,001). Conclusions: Our results demonstrate that inflamed seborrheic areas are more colonized with Malassezia fungi than intact areas. The intensity of Malassezia growth is correlated with the severity of the symptoms of seborrheic dermatitis. The level of colonization may be a potential biomarker to indicate the efficiency of new treatment approaches.