Efficacy of Depatuxizumab Mafodotin (ABT-414) in preclinical models of head and neck cancer.

Epidermal growth factor receptor (EGFR) is highly expressed in 80-90% of head and neck squamous cell carcinomas (HNSCCs), making it an ideal target for antibody-drug conjugates (ADCs). Depatuxizumab mafodotin (ABT-414), is an EGFR-targeting ADC comprised of the monoclonal antibody (mAb) ABT-806 conjugated to monomethyl auristatin F, a tubulin polymerization inhibitor. This study assessed the in vivo efficacy of ABT-414 in HNSCC. The effects of ABT-414 on HNSCCs were determined using in vitro cytotoxicity assays and in vivo flank xenograft mouse models. The distribution of ABT-414 was assessed ex vivo via optical imaging methods using a conjugate of ABT-414 to the near-infrared agent IRDye800. In vitro treatment of high EGFR-expressing human HNSCC cell lines (UMSCC47 and FaDu) with ABT-414 (0-3.38 nM) resulted in dose-dependent cell death (IC50 values of 0.213 nM and 0.167 nM, respectively). ABT-414 treatment of the FaDu mouse xenografts displayed antitumor activity (p= 0.023) without a change in body mass (p= 0.1335), whereas treatment of UMSCC47 did not generate a significant response (p = 0.1761). Fluorescence imaging revealed ABT-414-IRDye800 accumulation in the tumors of both FaDu and UMSCC47 cell lines, with a signal-to-background ratio of >10. ABT-414 treatment yielded antitumor activity in FaDu tumors, but not in UMSCC47, highlighting the potential for ABT-414 efficacy in high EGFR-expressing tumors. While ABT-414-IRDye800 localized tumors in both cell lines, the differing antitumor responses highlight the need for further investigation into the role of the tumor microenvironment in drug delivery.

Same-Day Discharge for Pediatric Hemithyroidectomy Patients: Evaluating Safety and Barriers to Discharge.

OBJECTIVE: Hemithyroidectomy is often performed in the pediatric population for indeterminate or benign thyroid nodules. Prior studies confirmed the safety of same-day discharge for adults undergoing hemithyroidectomy or total thyroidectomy, but this has not been studied thoroughly in the pediatric population. Our goal was to determine differences in pediatric patients undergoing hemithyroidectomy who were admitted versus discharged for complications or factors to support same-day discharge. STUDY DESIGN: Retrospective cohort. SETTING: Pediatric tertiary care hospital. METHODS: This was a retrospective study of pediatric patients (0-18 years of age) undergoing hemithyroidectomy at a pediatric tertiary care hospital from 2003 to 2022. Perioperative variables and outcomes were gathered via manual chart review. RESULTS: One hundred five pediatric patients who underwent hemithyroidectomy were identified. Ninety (86%) patients were admitted postoperatively, and 15 (14%) were discharged the same day. There were no differences in patient demographics, including age (P = 0.29) distance from the hospital (P = 0.08) or benign versus malignant pathology (P = 0.93). Surgical time in same-day discharges was significantly shorter (P = 0.0001; 138.6 minutes, SD = 66.0) versus admitted patients (204.2 minutes, SD = 48.6) Hemostatic agents were used more in same-day discharges at 53.3% versus 4.5% (P = 0.0001). Perioperative complications occurred in 2 (2.2%) admitted patients compared to none in the same-day discharge (P = 1.0). There were no readmissions within 30 days for same-day discharges. CONCLUSION: In pediatric patients undergoing uncomplicated hemithyroidectomy, same-day discharge appears appropriate for those with shorter surgical times and intraoperative use of hemostatic agents with no readmissions or complications in those discharged the same day.

Identification of Optimal Tissue-Marking Dye Color for Pathological Evaluation in Fluorescence Imaging Using IRDye800CW.

PURPOSE: Fluorescence-guided surgery using a tumor-specific antibody-dye conjugate is useful in various cancer types. Fluorescence imaging is a valuable tool both intraoperatively and postoperatively for ex vivo imaging. The color of inks used for tumor specimens during ex vivo specimen processing in pathology is an important consideration for fluorescence imaging since the absorption/emission of the dyes may interfere with the fluorescent dye. This study assesses suitable ink colors for use specifically with IRDye800CW fluorescence imaging. PROCEDURES: Eight tissue-marking inks or dyes (TMDs) commonly used for pathological evaluation were assessed. Agarose tissue-mimicking phantoms containing Panitumumab-IRDye800CW were used as an initial model. Mean fluorescence intensity was measured at 800 nm using both Pearl Trilogy as a closed-field fluorescence imaging system and pde-neo II as an open-field fluorescence imaging system before and after TMD application. An in vivo mouse xenograft model using the human head and neck squamous cell carcinoma FaDu cell line was then used in conjunction with TMDs. RESULTS: The retained IRDye800CW fluorescence on Pearl Trilogy was as follows: yellow at 91.0 ± 4.5%, red at 90.6 ± 2.7%, orange at 88.2 ± 2.2%, violet at 56.6 ± 1.1%, lime at 40.9 ± 1.8%, green at 19.3 ± 2.8%, black at 13.3 ± 0.6%, and blue at 8.1 ± 0.2%. The retained IRDye800CW fluorescence on pde-neo II was as follows: yellow at 86.5 ± 6.4%, red at 77.0 ± 6.2%, orange at 76.9 ± 2.8%, lime at 72.5 ± 9.5%, violet at 59.7 ± 0.4%, green at 30.1 ± 6.9%, black at 17.0 ± 2.7%, and blue at 6.7 ± 1.7%. The retained IRDye800CW fluorescence in yellow and blue TMDs was 42.1 ± 14.9% and 0.2 ± 0.2%, respectively in the mouse experiment (p = 0.039). CONCLUSION: Yellow, red, and orange TMDs should be used, and blue and black TMDs should be avoided for evaluating tumor specimens through fluorescence imaging using IRDye800CW.

Infrared Fluorescence-guided Surgery for Tumor and Metastatic Lymph Node Detection in Head and Neck Cancer.

In patients with head and neck cancer (HNC), surgical removal of cancerous tissue presents the best overall survival rate. However, failure to obtain negative margins during resection has remained a steady concern over the past 3 decades. The need for improved tumor removal and margin assessment presents an ongoing concern for the field. While near-infrared agents have long been used in imaging, investigation of these agents for use in HNC imaging has dramatically expanded in the past decade. Targeted tracers for use in primary and metastatic lymph node detection are of particular interest, with panitumumab-IRDye800 as a major candidate in current studies. This review aims to provide an overview of intraoperative near-infrared fluorescence-guided surgery techniques used in the clinical detection of malignant tissue and sentinel lymph nodes in HNC, highlighting current applications, limitations, and future directions for use of this technology within the field. Keywords: Molecular Imaging-Cancer, Fluorescence © RSNA, 2024.

Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer.

PURPOSE: Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment. EXPERIMENTAL DESIGN: We performed high-dimensional single-cell RNA sequencing (scRNA-seq) on four patient tumors pretreatment and posttreatment from a neoadjuvant trial of patients with advanced-stage head and neck squamous cell carcinoma that were treated with the αPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes. RESULTS: Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFß-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells. CONCLUSIONS: Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. In addition, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.

A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital of Karachi, Pakistan.

INTRODUCTION: Responsible for at least one in nine pediatric deaths, diarrheal diseases are the leading, global cause of death. Further abetted by improper antibiotic use in a hospital setting, children with acute watery diarrhea can see prolonged hospital stays, and unwanted adverse effects such as antibiotic resistance. Hence, this study is aimed to identify the association between antibiotic usage for the treatment of acute watery diarrhea in children, and the impact this line of management has on the duration of their hospital stay. METHODS: A retrospective review was conducted at the department of Pediatric of Aga Khan University Hospital (AKUH) in Karachi. A total of 305 records of children aged 6 months to 5 years who were admitted with a diagnosis of acute watery diarrhea from June 2017 -December 2018 was screened, of which 175 fulfilled the eligibility criteria. A predesigned questionnaire was used to collect demographic information, comorbidities, and clinical features, severity of dehydration, clinical examination, treatment received, and laboratory investigations. The primary outcome of this study was the length of hospital stay measured against the number of hours a child stayed in hospital for treatment of acute watery diarrhea. The statistical analysis was carried out using STATA version 14 to reach conclusive results. RESULTS: 175 patients presented with acute watery diarrhea, out of which 106 (60.6%) did not receive antibiotics. The median (IQR) age of the group that did not receive antibiotics was 12.0 (12.0) months compared to 15.0 (12.0) months for the group that did receive antibiotics. In both groups, there were more males than females, less than 15% of the patients were severely malnourished (WHZ score -3SD) and less than 10% of the patients were severely dehydrated. The median (IQR) length of hospital stay (hours) was 32.0 (19.0) respectively for the group that did not receive antibiotic and 41.0 (32.0) for the group that did receive antibiotic therapy. The expected length of hospital stay for the group that received antibiotic therapy was 0.22 hours higher than the group that did not. Finally, as compared to females, hospital stay for males was longer by 0.25 hours. CONCLUSION: In conclusion, antibiotic use was associated with a prolonged hospital stay in children with acute watery diarrhea as compared to children who did not receive antibiotics. Large scale robust prospective studies are needed to establish this association using this observational data.

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan.

BACKGROUND: Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods. METHODS: A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children's Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH. RESULTS: A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons. CONCLUSION: PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality.

Response of extensively drug resistant Salmonella Typhi to treatment with meropenem and azithromycin, in Pakistan.

INTRODUCTION: Salmonella Typhi is one of the leading health problems in Pakistan. With the emergence of extensively drug resistant (XDR) Salmonella Typhi, treatment options are limited. Here we report the clinical manifestations and the response to treatment of patients with XDR Typhoid fever. The patients were treated with either Meropenem or Azithromycin or a combination of both. METHODS: We reviewed the records of culture confirmed XDR typhoid who visited Aga Khan University Hospital (AKUH), Karachi and Aga Khan Secondary Care Hospital, Hyderabad from April 2017 to June 2018. Symptoms developed during disease, unplanned treatment extension and complications developed while on antimicrobials was recorded. Means with standard deviation were calculated for duration of treatment, time to defervescence, and cost of treatment. RESULTS: Records of 81 culture confirmed XDR typhoid patients admitted at the AKU hospitals were reviewed. Most, (n = 45; 56%) were male. Mean age of the cases was 8.03 years with range (1-40). About three quarter (n = 66) of the patients were treated as inpatient. Fever and vomiting were the most common symptoms at the time of presentation. Oral azithromycin alone (n = 22; 27%), intravenous meropenem alone (n = 20; 25%), or a combination of azithromycin and meropenem (n = 39; 48%) were the options used for treatment. Average (95% confidence interval) time to defervescence was 7.1(5.5-8.6), 6.7(4.7-8.7), and 6.7(5.5-7.9) days for each treatment option respectively whereas there were 1,0 and 3 treatment failures in each treatment option respectively. Average cost of treatment per day for azithromycin was US$5.87 whereas it was US$88.46 for meropenem. CONCLUSION: Patients treated with either Azithromycin, Meropenem alone or in combination showed similar time to defervescence. Because of the lower cost of azithromycin, it is preferable in lower socio-economic areas. Background estimates for power calculation can be made for more robust clinical trials using this observational data.