Balakrishnan, Karthik

Abstract Therapeutic resistance in ovarian cancer is frequently driven by persistent replication stress, yet the molecular mechanisms that convert replication stress into a therapeutically exploitable vulnerability remain incompletely understood. Here, we identify drug-induced nuclear cathepsin L (nCTSL) as a previously unrecognized regulator of replication stress and DNA repair. Clofarabine (CLF) combined with the ATR inhibitor AZD6738, or the CHK1 inhibitor prexasertib promoted nuclear accumulation of CTSL, where it remodeled the replication machinery through degradation of CCNE1, MCM3, MCM6, and geminin, accompanied by loss of RAD51 and 53BP1 and increased γH2AX and phospho-RPA2. DNA fiber analysis demonstrated marked inhibition of replication fork progression following CLF-based combinations, whereas CTSL depletion accelerated fork progression and abolished therapy-induced replication stress. Reconstitution with the nuclear M1F CTSL isoform restored replication restraint, confirming a direct role for nuclear CTSL in regulating replication dynamics. GFP-based DNA repair reporter assays further revealed that CLF-based combinations suppress DNA repair competence in a CTSL-dependent manner, indicating that nuclear CTSL couples replication stress amplification with functional inhibition of repair pathways. Functionally, CLF-based combinations selectively targeted transformed fallopian tube secretory epithelial cells while sparing non-transformed counterparts, demonstrated broad activity in patient-derived ovarian cancer ascites spheroids, and significantly inhibited tumor growth and prolonged survival in vivo . Collectively, our findings identify nuclear CTSL as a mechanistic driver of replication stress that remodels the replication machinery, impairs DNA repair, and creates a therapeutically exploitable vulnerability in ovarian cancer. We propose that nuclear CTSL promotes a transition from replication competence to replication catastrophe, thereby establishing a conceptual framework for biomarker-guided therapeutic strategies targeting CTSL-dependent replication stress.

Background: Access to high-quality airway equipment is critical for effective otolaryngological and emergency care. In sub-Saharan Africa (SSA), challenges in the procurement infrastructure may hinder equipment availability, impacting patient outcomes. Given the paucity of literature investigating equipment procurement in SSA, this study aims to map out the multilevel barriers to procurement of airway equipment in SSA to inform opportunities for improvement. Methods: A qualitative study design was employed using semi-structured interviews and open-ended survey responses. Participants included otolaryngologists in SSA, manufacturing company representatives and international policymakers, selected through purposive sampling to ensure representation of various roles in the procurement process. Six interviews, one focus group and six survey responses with regional healthcare providers (n = 13), manufacturing representatives (n = 3) and international policymakers (n = 2) explored supply chain dynamics, regulatory challenges, manufacturing capabilities, financial constraints and policy frameworks. Data were analysed using thematic analysis to identify recurrent themes and interrelationships. Results: Systemic barriers exist in the procurement process, including fragmented supply chains, inconsistent regulatory enforcement, limited local manufacturing capacity and insufficient funding mechanisms. Otolaryngologists emphasised frequent delays in equipment availability, while manufacturers reported logistical challenges and regulatory hurdles. Policymakers noted gaps in infrastructure and regional coordination. Emerging themes suggest opportunities for streamlining procurement processes, fostering local production and enhancing collaboration to improve supply chain efficiency. Conclusion: This study underscores the multifaceted challenges in airway equipment procurement in SSA and highlights the need for integrated approaches involving stakeholders across the supply chain. Contribution: Findings provide actionable insights to inform policy development and capacity-building initiatives with the goal of enhancing access to life-saving airway equipment and improving healthcare outcomes.

Background: The incidence of pediatric thyroid cancer has been increasing, and care varies due to socioeconomic disparities or differing practice patterns. Clinical guidelines call for care in multidisciplinary teams to minimize variance and provide protocols. Based on expert opinion, we hope to describe the form and function of such multidisciplinary teams for pediatric thyroid programs. Methods: A modified Delphi method to reach consensus statements over two rounds. Twenty-one experts with varying backgrounds responded to each statement on a 9-point Likert scale. Upon completion of the survey, the panel reviewed and shared the results and comments from participants and modified the statements accordingly. This process was repeated such that statements reached consensus, were deemed no consensus, or had no change in the mean. Results: There was an 88% and 83% completion rate for Rounds 1 and 2, respectively. A consensus was observed that there is a distinct definable model of care for pediatric thyroid patients. No consensus was reached for the age range of patients, but programs should care for children with medullary thyroid cancer, differentiated thyroid cancer, and patients with genetic predisposition syndromes. A comprehensive team includes, but is not limited to, a thyroid surgeon, a pediatric endocrinologist, a high-volume fine-needle aspiration (FNA) proceduralist, an oncologist, a nuclear medicine physician, a pediatric pathologist, a pediatric radiologist, and a nurse coordinator. Necessary support services involve care coordination, access to a multidisciplinary tumor board, ability to perform ultrasound-guided FNA, and access to molecular testing. The panel emphasized cross-institutional collaborative research prioritizing guidelines development, disease-specific outcomes, treatment toxicity, and the molecular landscape of thyroid cancer. Conclusions: These consensus statements can be beneficial in improving multidisciplinary care, by describing which elements of pediatric thyroid programs should be consistent across institutions. Overall, the panel agreed that pediatric thyroid centers should provide integrated care with defined team members, services, resources, and research priorities. This model has the potential to standardize various aspects of clinical care and enhance our ability to study patient outcomes, improve health care delivery, and increase scholarly collaboration.

Objectives/HypothesisThis study defines essential data elements to be recorded during an aerodigestive “triple endoscopy” to form the foundation of a standardized multicenter registry and to clearly define measurement of each consensus item.Study DesignModified Delphi process.MethodsModified Delphi consensus with six survey rounds. Twenty‐four expert pediatric otolaryngology, pulmonology, and gastroenterology aerodigestive clinicians from eight large academic pediatric aerodigestive programs formed the Delphi panel. After achieving consensus through the Delphi process, outside validation was performed at 2019 national Aerodigestive Society conference. Consensus, near‐consensus, or exclusion was obtained for each proposed data element. Concordance was then measured between expert panel conclusions and validation group conclusions.ResultsOverall response rate was 94.4%. 73/167 proposed items reached consensus in six domains (flexible bronchoscopy, bronchoalveolar lavage, microdirect laryngoscopy and bronchoscopy, esophagogastroduodenoscopy with biopsies, and esophageal impedance and pH probe). Measurement of all items was defined; classification/grading systems were selected for 11 items. Validation group endorsed importance of 82/167 data items; compared to expert consensus, overall, inclusion, and exclusion concordance rates were 94.5%, 98.7%, and 90.9%.ConclusionTriple endoscopy is a central component of aerodigestive care. This study identifies and defines data elements to be recorded for all triple endoscopy procedures. The list is of usable length, and clear definitions were created for all items, with explicit classification/grading systems selected for 11 items. Face validity was confirmed with an independent multispecialty sample of aerodigestive providers. This consensus provides the foundation for a triple endoscopy registry but also is immediately applicable to standardize clinical documentation in aerodigestive care.Level of Evidence5 Laryngoscope, 132:2251–2258, 2022

ObjectiveTo identify social determinants of health care that are associated with poorer pediatric well‐differentiated thyroid cancer (WDTC) outcomes and increased stage at presentation.Study DesignUsing the SEER database (Surveillance, Epidemiology, and End Results), we retrospectively gathered data on pediatric WDTC across the United States between 1973 and 2015.SettingAll patients between 0 and 19 years old with a diagnosis of WDTC were included.MethodsPatient variables were analyzed for relationships to AJCC stage at presentation (American Joint Committee on Cancer), overall survival, and disease‐specific survival.ResultsAmong 3913 patients with pediatric thyroid cancer, 3185 were female (81.4%), 3366 had papillary thyroid cancer (85.3%), and 367 had follicular thyroid cancer (9.4%). Two‐ and 5‐year overall and disease‐specific survival approached 100%. However, when outcomes were analyzed by specific populations, male sex, non‐Caucasian race, poverty, and language isolation were linked to worse overall survival. Male sex and poverty were associated with poorer disease‐specific survival. Regarding overall AJCC stage at presentation, male sex and Black race were related to higher overall presenting AJCC stage. Later AJCC T stage at presentation was seen in male, Hispanic, Asian, and Black patients. There were no variables significantly related to following through with recommended surgery.ConclusionPediatric WDTC continues to carry an excellent prognosis in the United States. However, when we consider specific populations, the social determinants of health care affect survival and disease burden at presentation: male sex, poverty, language isolation, and race affected survival and/or AJCC stage at presentation in pediatric WDTC.

AbstractBackgroundSinonasal adenocarcinoma (SNAC) is a rare tumor. The impact of health disparities on survival, stage at presentation, and utilization of surgery is not well understood in patients with SNAC.MethodsThe Surveillance, Epidemiology, and End Results database was queried for cases of SNAC from 1973 to 2015. Cases were analyzed to assess for disparities in presentation, treatment, and survival.ResultsSNAC was identified in 630 patients. In a multivariate model of overall survival, an age increase of 10 years (Hazard Ratio (HR) = 1.37, p < 0.001), male sex (HR = 1.26, p = 0.045), and more recent decade of diagnosis (HR = 0.74, p < 0.001) were significantly related to time‐to‐death. There is a higher rate of SNAC‐related death in counties with more rural populations (p = 0.027).ConclusionFuture interventions targeting rural and less well‐educated populations may improve care with the goal of increasing the span of healthy life and reducing survival disparities related to SNAC.

Objectives/HypothesisThe purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality.Study DesignDelphi method‐based survey series.MethodsA multidisciplinary, multi‐institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work‐up.ResultsThe international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18).ConclusionThis consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best‐practice applications of systemic bevacizumab for patients with early‐onset or less‐severe disease phenotypes.Level of Evidence5 Laryngoscope, 131:E1941–E1949, 2021

ObjectiveThe mechanism by which recurrent croup occurs is unknown. Gastroesophageal reflux is commonly implicated, although this relationship is only loosely documented. We conducted a systematic review with a meta‐analysis component to evaluate the relationship between recurrent croup and gastroesophageal reflux disease (GERD), and to assess for evidence of improvement in croup symptoms when treated.Style DesignSystematic Review and Meta Analysis.MethodsWe searched five separate databases. Studies were included if they discussed the relationship between croup and GERD in children, >5 subjects, and available in English. Literature retrieved was assessed according to pre‐specified criteria. Retrieved articles were reviewed by two independent authors and decisions mediated by a third author. If there was a difference of opinion after first review, a second review was performed to obtain consensus. Heterogeneity was calculated and summarized in forest plots.ResultsOf 346 initial records, 15 met inclusion criteria. These were two retrospective cohort and 13 cross‐sectional studies. Thirteen of 15 articles support an association between recurrent croup and GERD. Although heterogeneity is high among studies that reported prevalence of GERD, there is less uncertainty in results for improvement to recurrent croup after GERD treatment. Most studies lacked a control group and all carry a moderate‐to‐high risk of bias.ConclusionThere is limited evidence linking GERD to recurrent croup; Further research is needed to assess for causality as most studies are retrospective, lack a control group, and have a study design exposing them to bias. Patients treated with reflux medication appear to demonstrate a reduced incidence of croup symptoms.Level of Evidence1 Laryngoscope, 131:209–217, 2021

We present the case of a 3-year-old female with multiple congenital anomalies, including postprandial otorrhea, who developed the inability to be mask ventilated secondary to a combination of velopharyngeal insufficiency and tympanic membrane perforation. When applied by mask, positive pressure ventilation was observed to preferentially escape the patient’s left ear, resulting in significant air leak, insufficient tidal volumes, hypoventilation, and severe hypoxemia. The problem was remedied by the insertion of a finger into the patient’s external auditory meatus, which controlled the air leak until the surgical team could provide definitive surgical correction of the velopharyngeal insufficiency and nasopharyngeal reflux.