Overcoming Resistance to Standard-of-Care Therapies for Head and Neck Squamous Cell Carcinomas.

Although there have been some advances during in recent decades, the treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging. Resistance is a major issue for various treatments that are used, including both the conventional standards of care (radiotherapy and platinum-based chemotherapy) and the newer EGFR and checkpoint inhibitors. In fact, all the non-surgical treatments currently used for HNSCC are associated with intrinsic and/or acquired resistance. Herein, we explore the cellular mechanisms of resistance reported in HNSCC, including those related to epigenetic factors, DNA repair defects, and several signaling pathways. This article discusses these mechanisms and possible approaches that can be used to target different pathways to sensitize HNSCC to the existing treatments, obtain better responses to new agents, and ultimately improve the patient outcomes.

Panitumumab-IRDye800 Improves Laryngeal Tumor Mapping During Transoral Laser Microsurgery.

Transoral laser microsurgery represents the primary surgical modality for early laryngeal cancers with oncologic outcomes equivalent to radiotherapy. Accurate tumor mapping and margin assessment can be difficult, however, particularly during piecemeal or ablative resections, and for tumors with a wider geographic footprint. Tumor-targeted fluorescence-guided surgery in patients with head and neck cancer has empirically improved tumor and margin identification; this case details, for the first time, a fluorescence-guided surgical resection of a T2N0M0 transglottic tumor using panitumumab-IRDye800, an epidermal growth factor receptor monoclonal antibody covalently linked to near-infrared (NIR) dye. Laryngoscope, 134:1837-1841, 2024.

89Zr-panitumumab PET imaging for preoperative assessment of ameloblastoma in a PDX model.

Accurate assessment of tumor margins with specific, non-invasive imaging would result in the preservation of healthy tissue and improve long-term local tumor control, thereby reducing the risk of recurrence. Overexpression of epidermal growth factor receptor (EGFR) has been used in other cancers as an imaging biomarker to identify cancerous tissue. We hypothesize that expression of EGFR in ameloblastomas may be used to specifically visualize tumors. The aims of this study are to measure the specificity of radiolabeled 89Zr-panitumumab (an EGFR antibody) in vivo using patient-derived xenograft (PDX) models of ameloblastoma and positron emission tomography/computed tomography (PET/CT) scans. In PDX of ameloblastomas from four patients (AB-36, AB-37, AB-39 AB-53), the biodistribution of 89Zr-panitumumab was measured 120 h post-injection and was reported as the injected dose per gram of tissue (%ID/g; AB-36, 40%; AB-37, 62%; AB-39 18%; AB-53, 65%). The radiolabeled %ID/g was significantly greater in tumors of 89Zr-panitumumab-treated mice that did not receive unlabeled panitumumab as a blocking control for AB-36, AB-37, and AB-53. Radiolabeled anti-EGFR demonstrates specificity for ameloblastoma PDX tumor xenografts, we believe 89Zr-panitumumab is an attractive target for pre-surgical imaging of ameloblastomas. With this technology, we could more accurately assess tumor margins for the surgical removal of ameloblastomas.

Delivery of therapeutic agents and cells to pancreatic islets: Towards a new era in the treatment of diabetes.

Pancreatic islet cells, and in particular insulin-producing beta cells, are centrally involved in the pathogenesis of diabetes mellitus. These cells are of paramount importance for the endocrine control of glycemia and glucose metabolism. In Type 1 Diabetes, islet beta cells are lost due to an autoimmune attack. In Type 2 Diabetes, beta cells become dysfunctional and insufficient to counterbalance insulin resistance in peripheral tissues. Therapeutic agents have been developed to support the function of islet cells, as well as to inhibit deleterious immune responses and inflammation. Most of these agents have undesired effects due to systemic administration and off-target effects. Typically, only a small fraction of therapeutic agent reaches the desired niche in the pancreas. Because islets and their beta cells are scattered throughout the pancreas, access to the niche is limited. Targeted delivery to pancreatic islets could dramatically improve the therapeutic effect, lower the dose requirements, and lower the side effects of agents administered systemically. Targeted delivery is especially relevant for those therapeutics for which the manufacturing is difficult and costly, such as cells, exosomes, and microvesicles. Along with therapeutic agents, imaging reagents intended to quantify the beta cell mass could benefit from targeted delivery. Several methods have been developed to improve the delivery of agents to pancreatic islets. Intra-arterial administration in the pancreatic artery is a promising surgical approach, but it has inherent risks. Targeted delivery strategies have been developed based on ligands for cell surface molecules specific to islet cells or inflamed vascular endothelial cells. Delivery methods range from nanocarriers and vectors to deliver pharmacological agents to viral and non-viral vectors for the delivery of genetic constructs. Several strategies demonstrated enhanced therapeutic effects in diabetes with lower amounts of therapeutic agents and lower off-target side effects. Microvesicles, exosomes, polymer-based vectors, and nanocarriers are gaining popularity for targeted delivery. Notably, liposomes, lipid-assisted nanocarriers, and cationic polymers can be bioengineered to be immune-evasive, and their advantages to transport cargos into target cells make them appealing for pancreatic islet-targeted delivery. Viral vectors have become prominent tools for targeted gene delivery. In this review, we discuss the latest strategies for targeted delivery of therapeutic agents and imaging reagents to pancreatic islet cells.

A cluster randomized trial to determine the effectiveness of a novel, digital pendant and voice reminder platform on increasing infant immunization adherence in rural Udaipur, India.

BACKGROUND: Five hundred thousand children under the age of 5 die from vaccine preventable diseases in India every year. More than just improving coverage, increasing timeliness of immunizations is critical to ensuring infant health in the first year of life. Novel, culturally appropriate community engagement strategies are worth exploring to close the immunization gap. In our study, a digital NFC (Near Field Communication) pendant worn on black thread and voice call reminder system was tested for the effectiveness in improving DTP3 adherence within 2 monthly camps from DTP1 administration. METHOD: A cluster randomized controlled trial was conducted in which 96 village health camps were randomized to 3 arms: NFC sticker, NFC pendant, and NFC pendant with voice call reminder in local dialect. Randomization was done across 5 blocks in the Udaipur District serviced by Seva Mandir from August 2015 to April 2016. RESULTS: In terms of our three primary outcomes related to DTP3 adherence, point estimates show conflicting results. Two outcomes presented adherence in the control. DTP3 completion within two camps after DTP1 showed higher adherence in the Control (Sticker) (74.2%) arm compared to the Pendant (67.2%) and Pendant and Voice arms (69.3%). Likewise, the estimate for DTP3 completion within 180 days of birth in the Control (Sticker) (69.4%) arm was higher than estimates in the Pendant (57.4%) and Pendant and Voice arms (58.7%). However, one outcome displayed higher adherence in the intervention. DTP3 completion within two months from the time of registration was higher in the Pendant (37.7%) and Pendant and Voice arms (38.7%) compared to the Control (Sticker) arm (27.4%). In all primary outcomes, differences in adherence were statistically insignificant both before and after controlling for confounding factors. In terms of secondary outcomes, our results suggest that providing a necklace generated significant community discussion (H = 8.8796, df = 2, p = .0118), had strong satisfaction among users (χ2=26.039, df = 4, p < .0001), and resulted in increased visibility within families (grandmothers:χ2=34.023, df = 2, p < .0001, fathers: χ2=34.588, df = 2, p < .0001). CONCLUSION: Neither the NFC necklace nor the necklace with additional voice call reminders in the local dialect directly resulted in an increase in infant immunization timeliness through DTP3, the primary outcome. Still our process outcomes suggest that our culturally symbolic necklace has potential to be an assistive tool in immunization campaigns. Follow-on work will seek to examine whether positive behavior change towards vaccines can be fostered with earlier engagement of this platform beginning in the prenatal stage, under a continuum of care framework.

Gonadotropin-releasing hormone agonist trigger increases the number of oocytes and embryos available for cryopreservation in cancer patients undergoing ovarian stimulation for fertility preservation.

OBJECTIVE: To compare the oocyte and embryo yield associated with GnRH-agonist triggers vs. hCG triggers in cancer patients undergoing controlled ovarian stimulation (COS) for fertilization preservation. DESIGN: Retrospective cohort study. SETTING: Academic center. PATIENT(S): Cancer patients undergoing COS with letrozole and gonadotropins or gonadotropin-only protocols for oocyte or embryo cryopreservation. INTERVENTION(S): Gonadotropin-releasing hormone agonist or hCG trigger. MAIN OUTCOME MEASURE(S): Number of metaphase II (MII) oocytes or two-pronuclei (2PN) embryos available for cryopreservation were primary outcomes. Separate multivariate linear regression models were used to assess the effect of trigger type on the primary outcomes, after controlling for confounders of interest. RESULT(S): A total of 341 patients were included, 99 (29.0%) in the GnRH-agonist group and 242 (71%) in the hCG group. There was no difference in the baseline demographics of patients receiving GnRH-agonist or hCG triggers. Within the letrozole and gonadotropins group (n = 269), the number (mean ± SD, 11.8 ± 5.8 vs. 9.9 ± 6.0) and percentage of MII oocytes (89.6% vs. 73.0%) available for cryopreservation was higher with GnRH-agonist triggers compared with hCG triggers. Similar results were noted with GnRH-agonist triggers in the gonadotropin-only group (n = 72) (i.e., a higher number [13.3 ± 7.9 vs. 9.3 ± 6.0] and percentage of MII oocytes [85.7% vs. 72.8%] available for cryopreservation). Multivariate linear regression demonstrated approximately three more MII oocytes and 2PN embryos available for cryopreservation in the GnRH-agonist trigger group, irrespective of cancer and COS protocol type. CONCLUSION(S): Utilization of a GnRH-agonist trigger increases the number of MII oocytes and 2PN embryos available for cryopreservation in cancer patients undergoing COS for fertility preservation.

Association between ABO blood type and live-birth outcomes in single-embryo transfer cycles.

OBJECTIVE: To investigate the association between ABO blood type and live-birth outcomes in patients undergoing IVF with day 5 single-embryo transfer (SET). DESIGN: Retrospective cohort study. SETTING: University-affiliated center. PATIENT(S): Normal responders, <40 years old, undergoing their first IVF cycle with fresh SET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate was the primary outcome. Secondary outcomes were birth weight and gestational age at delivery. Univariate and multivariable logistic regression was used to examine the association between blood type and live birth, while controlling for confounders. Odds ratios (OR) with 95% confidence intervals (CI) for live birth were estimated. RESULT(S): A total of 2,329 patients were included. The mean age of the study cohort was 34.6 ± 4.78 years. The distribution of blood types was as follows: A = 897 (38.5%); B = 397 (17.0%); AB = 120 (5.2%); and, O = 1,915 (39.3%) patients. There was no difference in the baseline demographics, ovarian stimulation, or embryo quality parameters between the blood types. The unadjusted ORs for live birth when comparing blood type A (referent) with blood types B, AB, and O were 0.96 (95% CI, 0.6-1.7), 0.72 (95% CI, 0.4-1.2), and 0.96 (95% CI. 0.6-1.7), respectively. The adjusted ORs for live birth remained not significant when comparing blood type A to blood types B, AB, and O individually. No difference in birth weight or gestational age at delivery was noted among the four blood types. CONCLUSION(S): Our findings suggest that ABO blood type is not associated with live-birth rate, birth weight, or gestational age at delivery in patients undergoing IVF with day 5 SET.

Replacing single frozen-thawed euploid embryos in a natural cycle in ovulatory women may increase live birth rates compared to medicated cycles in anovulatory women.

PURPOSE: The goal of this study was to compare pregnancy outcomes between natural frozen embryo transfer (FET) cycles in ovulatory women and programmed FET cycles in anovulatory women after undergoing in vitro fertilization with preimplantation genetic screening (IVF-PGS). METHODS: This was a retrospective cohort study performed at an academic medical center. Patients undergoing single FET IVF-PGS cycles between October 2011 and December 2014 were included. Patients were stratified by type of endometrial replacement: programmed cycles with estrogen/progesterone replacement and natural cycles. IVF-PGS with 24-chromosome screening was performed on all included patients. Those patients with euploid embryos had single embryo transfer in a subsequent FET. The primary study outcome was live birth/ongoing pregnancy rate. Secondary outcomes included implantation, biochemical pregnancy, and miscarriage rates. RESULTS: One hundred thirteen cycles met inclusion criteria: 65 natural cycles and 48 programmed cycles. The programmed FET group was younger (35.9 ± 4.5 vs. 37.5 ± 3.7, P = 0.03) and had a higher AMH (3.95 ± 4.2 vs. 2.37 ± 2.4, P = 0.045). The groups were similar for BMI, gravidity, parity, history of uterine surgery, and incidence of Asherman's syndrome. There was also no difference in embryo grade at biopsy or transfer, and proportion of day 5 and day 6 transfers. Implantation rates were higher in the natural FET group (0.66 ± 0.48 vs. 0.44 ± 0.50, P = 0.02). There was no difference in the rates of biochemical pregnancy or miscarriage. After controlling for age, live birth/ongoing pregnancy rate was higher in natural FETs with an adjusted odds ratio of 2.68 (95% CI 1.22-5.87). CONCLUSIONS: Natural FET in ovulatory women after IVF-PGS is associated with increased implantation and live birth rates compared to programmed FET in anovulatory women. Further investigation is needed to determine whether these findings hold true in other patient cohorts.