Disease Clearance Research Articles

S1493 The Impact of Mirikizumab Induction, Maintenance, and Long-Term Treatment on Disease Clearance in Patients With Moderately to Severely Active Ulcerative Colitis: Post-Hoc Analysis of LUCENT Trials

S1493 The Impact of Mirikizumab Induction, Maintenance, and Long-Term Treatment on Disease Clearance in Patients With Moderately to Severely Active Ulcerative Colitis: Post-Hoc Analysis of LUCENT Trials

Clearance of P16-Positive Senescent Cells Delays Diabetic Kidney Disease (DKD) by Normalizing Glycolysis and Mitochondrial Metabolic Disorder

Clearance of P16-Positive Senescent Cells Delays Diabetic Kidney Disease (DKD) by Normalizing Glycolysis and Mitochondrial Metabolic Disorder

The Efficacy of Intense Pulsed Light and Laser Hair Removal in Hidradenitis Suppurativa Treatment.

Hidradenitis suppurativa (HS) is a multifactorial disease that presents with chronic cycles of inflammation, healing, and scarring and that elicits a profoundly negative impact on patient quality of life regarding self-image, fear of stigmatization, and social isolation. Patients commonly develop painful, odorous abscesses that evolve into draining sinus tracts and disfiguring scarring. While systemic medications and surgical therapies are often effective in reducing active lesion activity and inflammation, these therapies sometimes only provide modest success in the prevention of future recurrences and disease progression, warranting adjunctive therapies such as laser and light-based therapies.1 Herein, this systematic review has been conducted to assess the current level of evidence supporting intense pulsed light (IPL) and laser treatment for HS, with a focus on a decrease in the number of lesions with associated HS flares. GRADE assessments were performed using PubMed and Scopus. Of 428 studies identified, 10 studies (n= 235) evaluated IPL or laser hair removal treatment and their effectiveness in reducing HS flares. Significant reductions in the overall count of inflammatory lesions were observed in all studies, with percentages ranging from 50% to 75%, and in some cases, achieving complete resolution. However, durations of disease remission varied. These results provide a moderate level of evidence supporting the effectiveness of IPL and laser hair removal as adjunctive therapy in the treatment of HS; however, further long-term studies are required to provide future guidance on the most effective treatment duration and intervals for sustaining disease clearance. J Drugs Dermatol. 2024;23(11):926-930. doi:10.36849/JDD.8627.

Antibodies as key mediators of protection against Mycobacterium tuberculosis.

Tuberculosis (TB) is caused by infection with the bacterial pathogen Mycobacterium tuberculosis (M.tb) in the respiratory tract. There was an estimated 10.6 million people newly diagnosed with TB, and there were approximately 1.3 million deaths caused by TB in 2022. Although the global prevalence of TB has remained high for decades and is an annual leading cause of death attributed to infectious diseases, only one vaccine, Bacillus Calmette-Guérin (BCG), has been approved so far to prevent/attenuate TB disease. Correlates of protection or immunological mechanisms that are needed to control M.tb remain unknown. The protective role of antibodies after BCG vaccination has also remained largely unclear; however, recent studies have provided evidence for their involvement in protection against disease, as biomarkers for the state of infection, and as potential predictors of outcomes. Interestingly, the antibodies generated post-vaccination with BCG are linked to the activation of innate immune cascades, providing further evidence that antibody effector functions are critical for protection against respiratory pathogens such as M.tb. In this review, we aim to provide current knowledge of antibody application in TB diagnosis, prevention, and treatment. Particularly, this review will focus on 1) The role of antibodies in preventing M.tb infections through preventing Mtb adherence to epithelium, antibody-mediated phagocytosis, and antibody-mediated cellular cytotoxicity; 2) The M.tb-directed antibody response generated after vaccination and how humoral profiles with different glycosylation patterns of these antibodies are linked with protection against the disease state; and 3) How antibody-mediated immunity against M.tb can be further explored as early diagnosis biomarkers and different detection methods to combat the global M.tb burden. Broadening the paradigm of differentiated antibody profiling and antibody-based detection during TB disease progression offers new directions for diagnosis, treatment, and preventative strategies. This approach involves linking the aforementioned humoral responses with the disease state, progression, and clearance.

Intra-operative Measurement of Eustachian Tube Orifice, and Its Correlation With Post-operative Surgical Outcome in Chronic Suppurative Otitis Media Patients.

Background Chronic suppurative otitis media (CSOM) is the inflammation of the middle ear mucosa for more than two weeks, resulting in ear discharge. It is associated with hearing loss and the presence of a perforation in the tympanic membrane. Tympanoplasty is performed to place a graft and clear the disease in the middle ear. Despite adequate disease clearance and proper graft placement, graft failure and disease persistence occur due to Eustachian tube (ET) dysfunction. The ET plays a significant role in the ventilation of the middle ear. Hence, this study was conducted to determine the significance of ET size for post-operative graft uptake. Methodology A total of 55 patients with inactive CSOM were included in the study. Their demographic data were recorded. Patients previously operated on for CSOM, cases with traumatic perforation of the tympanic membrane, congenital anomalies (e.g., cleft lip/cleft palate), and atticoantral disease were excluded. Thorough history taking and examination, including otoscopy and examination of the nose, throat, and oropharynx, were conducted. Once the patient was deemed fit for surgery, they underwent tympanoplasty. Intraoperatively, the ET size was measured using the tip of the suction cannulas. They were followed up after three months to assess graft uptake. Results Out of 55 patients included in the study, 42 (76%) had good graft uptake, while 13 (24%) had defects in graft uptake. Graft uptake failed in patients with an ET diameter of <3 mm. Post-operative graft uptake was observed in the majority of patients with a wider ET diameter, ranging between 3 mm and 6 mm, with a statistically significant p-value of 0.00 (0.05), as determined by Pearson's Chi-square test. Conclusion In our study, we found that there is an association between the ET diameter and post-operative graft uptake. Hence, a wider ET may improve middle ear ventilation and play an important role in post-operative graft uptake.

Let it glow: Intraoperative visualization of pulmonary metastases using pafolacianine, a next-generation fluorescent agent, for young adults undergoing pulmonary metastasectomy.

A new generation of disease-specific molecular imaging agents is poised to revolutionize fluorescence-guided surgery. Pafolacianine has been approved for adult lung and ovarian cancers. We demonstrate a proof of concept for pediatric surgeons treating young adults with pulmonary metastatic sarcomas. Five successful fluorescence-guided pulmonary metastasectomy operations were performed in young adult patients with metastatic osteosarcoma or Ewing sarcoma following administration of pafolacianine. All osteosarcoma lesions identified using standard techniques were also markedly fluorescent in patients. Novel fluorescent molecular agents targeted to tumor-specific receptors have promise of increased sensitivity and specificity for detecting metastatic nodules and enhancing surgical clearance of disease.

Optimizing the Outcome of Pediatric Metastatic Neuroblastoma in a Nontransplant Setting in a Developing Country: Retrospective Study from a Tertiary Cancer Center in India

Abstract Objective This article estimates the survival of children over 1 year of age diagnosed with metastatic neuroblastoma (NB) and treated in a nontransplant facility and determines the factors affecting survival. Materials and Method Case records of children aged 1 to 14 years treated for metastatic NB in our center from January 2008 to December 2017 were studied. Patients received conventional chemotherapy followed by surgery, radiotherapy, and metronomic maintenance chemotherapy. Results Eighty-nine patients with metastatic NB received treatment. Mean age was 3.5 years and male:female ratio was 1.1:1. The most common primary site was suprarenal (55%) and the most common site of metastasis was bone marrow (76%). Forty percent patients had multiple metastatic sites. Mean baseline lactate dehydrogenase (LDH) was 3724 U/L (range 303–16609 U/L) and 65% patients had LDH &gt; 750 U/L. Fifty-three patients (59.6%) had good response to chemotherapy as evidenced by clearance of metastatic disease, but out of them, 43 patients (81%) progressed subsequently. Twenty-six patients underwent surgery and 12 patients received maintenance therapy. Seventy-four patients (86%) developed recurrence and all but one died. Median time to recurrence and death were 9 months (range 0–120 months) and 10 months (range 1–123 months), respectively. At a median follow-up of 72 months (range 15–135 months), 16 patients are alive, with 5-year disease-free survival and overall survival of 17.6 and 18.4%, respectively. Age, baseline LDH, chemotherapy regimen, and response to treatment significantly affected survival. Conclusion Younger age, lower baseline LDH, and good response to chemotherapy appear to confer survival advantage in pediatric metastatic NB, and may be used for optimization of treatment in the nontransplant setting in developing countries.

AML-197 QuANTUM-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD)–Specific Measurable Residual Disease (MRD) Clearance Assessed Through Induction and Consolidation Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (ND) FLT3-ITD+ AML Patients

AML-197 QuANTUM-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD)–Specific Measurable Residual Disease (MRD) Clearance Assessed Through Induction and Consolidation Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (ND) FLT3-ITD+ AML Patients

QuANTUM-First Trial: FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD)–Specific Measurable Residual Disease (MRD) Clearance Assessed Through Induction and Consolidation Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (ND) FLT3-ITD+ AML Patients

QuANTUM-First Trial: FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD)–Specific Measurable Residual Disease (MRD) Clearance Assessed Through Induction and Consolidation Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (ND) FLT3-ITD+ AML Patients

IVAC-XS15-CLL01: personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients undergoing BTK-inhibitor-based regimens.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton's tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured "peptide warehouse" based on the patient's individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.

The surgical management of axillary lymph node disease in breast cancer patients

The precise assessment and management of the axillary lymph nodes in breast cancer is crucial for regional control, disease staging, selection of adjuvant chemotherapy strategies, and prediction of prognosis, with a general downward trend in surgical management. For early breast cancer with negative axillary lymph node metastases, sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as the criterion for axillary status measurement. Patients can be exempted from ALND if they have negative SLNB results. However, it remains to be carefully decided in China whether patients with one or two positive nodes in SLNB can be spared from ALND. However, consensus has been met that patients who meet the criteria of the Z0011 study can be exempted from ALND. For breast cancer patients with positive axillary lymph nodes metastases at the beginning of treatment, the clearance of lymph node disease can be achieved by neoadjuvant therapy, with a reduced rate of complications related to ALND. In particular, there are still many debates associated with SLNB after neoadjuvant therapy, such as whether patients who remain axillary lymph node positive can be spared from ALND. Exploratory and validation studies related to the SLNB avoidance criteria are still controversial. In the future, clinicians should consider the characteristics of patients, the risk of recurrence, and adjuvant treatment regimens to develop individualized axillary lymph node management.

Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

The safety and efficacy of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia in children

To explore the safety and efficacy of blinatumomab in the treatment of CD19 positive (CD19+) B-cell acute lymphoblastic leukemia (B-ALL) in children. A retrospective analysis was conducted on the clinical data of pediatric B-ALL patients who received blinatumomab treatment from Hematology & Blood Diseases Hospital of Chinese Academy of Medical Sciences from August 2021 to October 2023. Based on their disease status, the patients were divided into refractory/relapsed(RR) group, minimal residual disease clearance (MC) group, and chemotherapy intolerance (IC) group. Clinical data of the children were collected to evaluate the adverse drug reactions, therapeutic efficacy and survival of the children. In total, 35 patients were included, with 20 males and 15 females, aged from 0.6 to 16.4 (9.9±4.2) years old. There were 10 cases in the RR group, 20 cases in the MC group and 5 cases in the IC group. A total of 56 cycles of infusion were completed, with one cycle in 24 cases, two cycles in 5 cases, three cycles in 2 cases and four cycles in 4 cases. The median infusion time [M (Q1, Q3)] from the first to the fourth cycle was 14 (14, 28) days, 28 (28, 28) days, 28 (28, 28) days and 28 (26, 28) days, respectively. In terms of adverse reactions, the incidence of grade 1-2 cytokine release syndrome(CRS) was 57.1% (32/56), with grade 1 CRS accounting for 84.4% (27/32). The incidence rate of immune effector cell-associated neurotoxicity syndrome(ICANS) (grade 4) was 1.8% (1/56). In the RR group, 6 cases were treated effectively, and minimal residual disease(MRD) turned negative, before treatment, MRD levels were all less than 20%. Among them, 3 cases had MRD turning positive again 14 to 42 days after discontinuation of Belintoumab. Four cases were treated ineffectively, with MRD >20% before treatment. All MRD positive cases in MC group turned negative and all MRD negative cases in the IC group remained negative after treatment. The median follow-up time of RR group was 5.7 (3.8, 9.4) months, and 1 year median survival rate and event-free survival rate were 40.0%±21.9% and 33.3%±19.2%, respectively. The median follow-up time for MC and IC group patients was 6.7 (5.2, 12.5) months and 7.1 (5.1, 7.6) months, respectively, with an event free survival rate of 100%. The safety and efficacy of using belintoumab in partial RR, MRD clearance, and chemotherapy intolerance are good.

A Modified Floxuridine Reduced-Dose Protocol for Patients with Unresectable Colorectal Liver Metastases Treated with Hepatic Arterial Infusion.

Most patients treated with the standard dosing protocol (SDP) of hepatic arterial infusion (HAI) floxuridine require dose holds and reductions, thereby limiting their HAI therapy. We hypothesized that a modified dosing protocol (MDP) with a reduced floxuridine starting dose would decrease dose holds, dose reductions, and have similar potential to convert patients with unresectable colorectal liver metastases (uCRLM) to resection. We reviewed our institutional database of patients with uCRLM treated with HAI between 2016 and 2022. In 2019, we modified the floxuridine starting dose to 50% (0.06 mg/kg) of the SDP (0.12 mg/kg). We compared treatment related outcomes between the SDP and MDP cohorts. Of n = 33 patients, 15 (45%) were treated on the SDP and 18 (55%) with our new institutional MDP. The MDP cohort completed more cycles before a dose reduction (mean 4.2 vs. 2), received more overall cycles (median 7.5 vs. 5), and averaged 39 more days of treatment (all P < 0.05). The SDP experienced more dose reductions (1.4 vs. 0.61) and dose holds (1.2 vs. 0.2; both P < 0.01). Of the patients in each group potentially convertible to hepatic resection, three patients (23%) in the SDP and six patients (35%) in the MDP group converted to resection (P = 0.691). Overall, four patients (27%) in the SDP developed treatment ending biliary toxicity compared with one patient (6%) in the MDP. A 50% starting dose of HAI floxuridine provides fewer treatment disruptions, more consecutive floxuridine cycles, and a similar potential to convert patients with initially uCRLM for disease clearance.

Endoscopic, Histologic, and Composite Endpoints in Patients With Ulcerative Colitis Treated With Etrasimod

Histologic remission, a potentially important treatment target in ulcerative colitis (UC), is associated with favorable long-term outcomes. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post-hoc analysis of the ELEVATE UC program evaluated the efficacy of etrasimod according to histologic and composite (histologic/endoscopic/symptomatic) endpoints and examined their prognostic value. Patients with moderately to severely active UC were randomized 2:1 to once-daily oral etrasimod 2 mg or placebo. Histologic and composite endpoints, including disease clearance (endoscopic/histologic/symptomatic remission), were assessed at Weeks 12 (ELEVATE UC 52; ELEVATE UC 12) and 52 (ELEVATE UC 52). Logistic regressions examined associations between baseline and Week 12 histologic/composite endpoints and Week 52 outcomes. At Weeks 12 and 52, significant improvements with etrasimod vs placebo were observed in histologic/composite outcomes, including endoscopic improvement-histologic remission and disease clearance. The proportion of patients treated with etrasimod achieving clinical remission at Week 52 was higher among those with disease clearance at Week 12 vs those without disease clearance (73.9% [17/23] vs 28.3% [71/251]). Histologic improvement and endoscopic improvement at Week 12 were moderately and strongly associated with clinical remission at Week 52 (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.27-4.41; and OR, 6.36; 95% CI, 3.47-11.64, respectively). Histologic remission and endoscopic improvement at Week 12 were strongly associated with endoscopic improvement-histologic remission at Week 52 (OR, 3.21; 95% CI, 1.70-6.06 and OR, 5.47; 95% CI, 2.89-10.36, respectively). Etrasimod was superior to placebo for achievement of stringent histologic and composite endpoints. gov, Number: NCT03945188; ClinicalTrials.gov, Number: NCT03996369.

Immune responses associated with mpox viral clearance in men with and without HIV in Spain: a multisite, observational, prospective cohort study

Since the emergence of the global mpox outbreak in May, 2022, more than 90 000 cases have been diagnosed across 110 countries, disproportionately affecting people with HIV. The durability of mpox-specific immunity is unclear and reinfections have been reported. We aimed to compare mpox immune responses up to 6months after diagnosis in participants with and without HIV and assess their effect on disease severity and viral clearance dynamics. This study was embedded within a prospective, observational, multicentre cohort study of viral clearance dynamics among people with mpox in Spain (MoViE). We included women and men aged 18 years or older, who had signs of mpox, and reported having symptom onset within the previous 10 days at the moment of mpox diagnosis from three sex clinics of the Barcelona metropolitan area. Samples from skin ulcers were collected weekly to estimate the time to clear monkeypox virus (MPXV) from skin lesions. Blood samples were taken at diagnosis, 29, 91, and 182days later for immune analysis. This included quantifying IgG and IgA against three mpox antigens by ELISA, evaluating in-vitro neutralisation, and characterising mpox-specific T-cell responses using interferon γ detecting enzyme-linked immunospot (ELISpot) assay and multiparametric flow cytometry. Of the 77 originally enrolled participants, we included 33 participants recruited between July 19, and Oct 6, 2022. Participants without HIV (19 [58%] participants) and participants with HIV (14 [42%] participants) had similar clinical severity and time to MPXV clearance in skin lesions. Participants with HIV had a CD4+ T-cell count median of 777 cells per μL (IQR 484-1533), and 11 (78%) of 14 were virally suppressed on antiretroviral therapy. Nine (27%) of 33 participants were age 49 years or older. 15 (45%) of 33 participants were originally from Spain, and all participants were men. Early humoral responses, particularly concentrations and breadth of IgG and IgA, were associated with milder disease and faster viral clearance. Orthopoxvirus-specific T cells count was also positively correlated with MPXV clearance. Antibody titres declined more rapidly in participants with HIV, but T-cell responses against MPXV were sustained up to day 182 after diagnosis, regardless of HIV status. Higher breadth and magnitude of B-cell and T-cell responses are important in facilitating local viral clearance, limiting mpox dissemination, and reducing disease severity in individuals with preserved immune system. Antibodies appear to contribute to early viral control and T-cell responses are sustained over time, which might contribute to milder presentations during reinfection. Fundació Lluita contra les Infeccions, IrsiCaixa, and Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación e Universidades.

Indications and outcomes of subtotal petrosectomy: our experience and review of literature

BackgroundSubtotal petrosectomy (STP) has attracted massive interest over last two decades. The aim is to present our experience of this uncommon surgery. The indications, outcomes, and our variation in surgical technique would be presented and literature reviewed.MethodsA retrospective observational study of all patients who underwent STP at a tertiary care center in India was analyzed.ResultsA total of 9 ears (in 8 patients) underwent STP over last 5 years at our center. The pathological conditions for which STP was done included chronic otitis media squamous (four ears), middle ear tumors (three ears), petrous apicitis (one ear), and traumatic cerebrospinal fluid (CSF) otorhinorrhea (one ear). The indication of STP included disease clearance (eight ears), unserviceable hearing (seven ears), hearing rehabilitation with otological implants (six ears), and intraoperative CSF gusher (one ear). Intraoperative indications included CSF gusher, large tegmen defect with erosion of apical turn of cochlea, and erosion of anterior bony wall of external auditory canal. The mean follow-up period was 36 months (range of 6 months to 60 months). None of the patients had any dehiscence of blind sac closure or secondary acquired cholesteatoma on imaging.ConclusionsSTP facilitates disease clearance by providing unmatchable exposure in difficult otological scenarios and additionally isolates middle ear cleft from external environment, thereby eliminating problems of mastoid cavity. Furthermore, it also prepares ear for second stage otological implants. It is a safe surgery with minimal complications.

Personalized cell-free tumor DNA analysis for patients with HNSCC: Liquid biopsy for minimal residual disease detection in head and neck squamous cell carcinoma (LIONESS).

3010 Background: Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). We conducted LIONESS, a single-center prospective cohort study to assess ctDNA in plasma and saliva from 76 patients with HNSCC receiving primary surgery with curative intent. Our objectives were to determine whether postoperative ctDNA detection can act as a biomarker for surgical tumor clearance and detection of molecular residual disease (MRD) and to evaluate the potential of tumor-informed ctDNA analysis for early molecular-level detection of relapse or prior to clinically confirmed recurrence. Methods: Plasma and saliva samples from 76 HNSCC patients (37% stage I/II, 63% stage III/IV; 93% p16-negative) were collected pre- and postoperatively and during clinical follow-up. Whole exome sequencing was performed on FFPE tumor tissue. Tumor-specific variants for personalized assay design (RaDaR, NeoGenomics Laboratories) were selected and used in the analysis of serial samples for evidence of MRD. ctDNA levels were correlated to tumor volumes from staging CT, as well as pathological and other clinical parameters. Results: 617 longitudinal plasma and 128 saliva samples were collected pre- and postoperatively and during clinical follow-up (median follow-up time of 805 days). In plasma, ctDNA was detected at a median estimated variant allele frequency (eVAF) of 0.036% (0.000327% - 18.43%). 34% of positive samples had ctDNA levels detected at an eVAF of ≤0.01%. Increased plasma ctDNA levels were detected postoperatively in 96% of cases with confirmed clinical recurrences (21/22) with a median lead time of 160 days (6 – 763 days). Of the remaining 54 patients with no clinically confirmed relapse, ctDNA was detected immediately postop in 7 of them. In 5 patients, adjuvant therapy resulted in persistent ctDNA clearance, while 2 patients are deceased. ctDNA was also detected in baseline saliva samples from patients with HNSCC of various anatomical locations with a 74% overlap with the corresponding plasma ctDNA profiles. There was a strong linear correlation between larger tumor volumes and higher eVAF and a trend towards higher eVAF in cases with regional and distant recurrences in comparison to local relapse. Pathological tumor stage and lymph node involvement were both strongly correlated with preoperative ctDNA shedding. Conclusions: The use of ctDNA detection in surgically treated patients with HNSCC has significant potential to guide treatment decisions, improve disease outcome and potentially spare patients unnecessary, partially invasive interventions during clinical follow-up. Our work demonstrates the feasibility of tumor-informed ctDNA assays for detection of MRD postoperatively and for monitoring for early detection of relapse.

Recent Insights into the Molecular Mechanisms of the Toll-like Receptor Response to Influenza Virus Infection.

Influenza A viruses (IAVs) pose a significant global threat to human health. A tightly controlled host immune response is critical to avoid any detrimental effects of IAV infection. It is critical to investigate the association between the response of Toll-like receptors (TLRs) and influenza virus. Because TLRs may act as a double-edged sword, a balanced TLR response is critical for the overall benefit of the host. Consequently, a thorough understanding of the TLR response is essential for targeting TLRs as a novel therapeutic and prophylactic intervention. To date, a limited number of studies have assessed TLR and IAV interactions. Therefore, further research on TLR interactions in IAV infection should be conducted to determine their role in host-virus interactions in disease causation or clearance of the virus. Although influenza virus vaccines are available, they have limited efficacy, which should be enhanced to improve their efficacy. In this study, we discuss the current status of our understanding of the TLR response in IAV infection and the strategies adopted by IAVs to avoid TLR-mediated immune surveillance, which may help in devising new therapeutic or preventive strategies. Furthermore, recent advances in the use of TLR agonists as vaccine adjuvants to enhance influenza vaccine efficacy are discussed.

The oncologic burden of residual disease in incidental gallbladder cancer: An elastic net regression model to profile high-risk features

IntroductionIncidental Gallbladder Cancer (IGBC) following cholecystectomy constitutes a significant portion of gallbladder cancer diagnoses. Re-exploration is advocated to optimize disease clearance and enhance survival rates. The consistent association of residual disease (RD) with inferior oncologic outcomes prompts a critical examination of re-resection's role as a modifying factor in the natural history of IGBC. MethodsAll patients diagnosed with gallbladder cancer between 2012 and 2022 were included. An elastic net regularized regression model was employed to profile high-risk predictors of RD within the IGBC group. Survival outcomes were assessed based on resection margins and RD. ResultsAmong the 181 patients undergoing re-exploration for IGBC, 133 (73.5 %) harbored RD, while 48 (26.5 %) showed no evidence. The elastic net model, utilizing a selected λ = 0.029, identified six coefficients associated with the risk of RD: aspiration from cholecystectomy (0.141), hepatic tumor origin (1.852), time to re-exploration >8 weeks (1.879), positive margin status (2.575), higher T stage (1.473), and poorly differentiated tumors (2.241). Furthermore, the study revealed a median overall survival of 44 months (CI 38–60) for IGBC patients with no evidence of RD, compared to 31 months (23–42) for those with RD (p < 0.001). ConclusionRe-resection revealed a high incidence of RD (73.5 %), significantly correlating with poorer survival outcomes. The preoperative identification of high-risk features provides a reliable biological disease profile. This aids in strategic preselection of patients who may benefit from re-resection, underscoring the need to consolidate outcomes with tailored chemotherapy for those with unfavorable characteristics.