Longitudinal Monitoring of Circulating Tumor DNA to Assess the Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Genitourinary Malignancies.

PURPOSE: Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker demonstrating improved assessment of treatment response in patients receiving immune checkpoint inhibitors (ICIs). Here, we performed a pilot study to support the role of ctDNA for longitudinal treatment response monitoring in patients with advanced genitourinary (GU) malignancies receiving ICIs. MATERIALS AND METHODS: Patients with histologically confirmed advanced GU malignancies were prospectively enrolled. All eligible patients received ICI treatment for at least 12 weeks, followed by serial collection of blood samples every 6-8 weeks and conventional scans approximately every 12 weeks until disease progression. ctDNA analysis was performed using Signatera, a tumor-informed multiplex-polymerase chain reaction next-generation sequencing assay. Overall, the objective response rate (ORR) was reported and its association with ctDNA status was evaluated. Concordance rate between ctDNA dynamics and conventional imaging was also assessed. RESULTS: ctDNA analysis was performed on 98 banked plasma samples from 20 patients (15 renal, four urothelial, and one prostate). The median follow-up from the time of initiation of ICI to progressive disease (PD) or data cutoff was 67.7 weeks (range, 19.6-169.6). The ORR was 70% (14/20). Eight patients ultimately developed PD. The overall concordance between ctDNA dynamics and radiographic response was observed in 83% (15/18) of patients. Among the three patients with discordant results, two developed CNS metastases and one progressed with extracranial systemic disease while ctDNA remained undetectable. CONCLUSION: In this pilot study, longitudinal ctDNA analysis for monitoring response to ICI in patients with advanced GU tumors was feasible. Larger prospective studies are warranted to validate the utility of ctDNA as an ICI response monitoring tool in patients with advanced GU malignancies.

Response and Outcomes of Maintenance Avelumab After Platinum-Based Chemotherapy (PBC) in Patients With Advanced Urothelial Carcinoma (aUC): "Real World" Experience.

BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC. MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR). RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown). CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.

Lutetium-177 PSMA for the treatment of metastatic castrate resistant prostate cancer: a systematic review.

INTRODUCTION: Metastatic castrate resistant prostate cancer (mCPRC) remains an aggressive form of prostate cancer that no longer responds to traditional hormonal treatment alone. Despite the advent of novel anti-androgen medications, many patients continue to progress, and as a result, there is a growing need for additional treatment options. AREAS COVERED: Lutetium-177 (177Lu) - PSMA-617 has become one of the new frontline treatment options for refractory metastatic castrate resistant prostate cancer after the failure of novel anti-androgen therapy and chemotherapy. Lu-177 has been used in real-world prospective trials and is now becoming utilized in newer phase III clinical trials. Here, we present a comprehensive overview of the current literature, covering retrospective studies, prospective studies, and clinical trials that established Lutetium-177-PSMA-617 (177Lu-PSMA-617) for the treatment of mCRPC. EXPERT OPINION: 177Lu - PSMA-617 has been approved for treatment of mCRPC based on positive phase III studies. While this treatment is tolerable and effective, biomarkers are necessary to determine which patients will benefit. In the future, radioligand treatments will likely be utilized in earlier lines of therapy and potentially in combination with other prostate cancer treatments.

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma.

Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1,2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing ß2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation.

Treatment with neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) is associated with clinical benefit in urothelial carcinoma. While extensive research evaluating role of tumor mutational expression profiles and clinicopathologic factors into chemoresponse has been published, the role of gut microbiome (GM) in bladder cancer in chemoresponse has not been thoroughly evaluated. A working knowledge of the microbiome and its effect on all forms of cancer therapy in BC is critical. Here we examine gut microbiome of bladder cancer patients undergoing NAC. Overall, there was no significant difference in alpha and beta diversity by responder status. However, analysis of fecal microbiome samples showed that a higher abundance of Bacteroides within both institutional cohorts during NAC was associated with residual disease at the time of radical cystectomy regardless of chemotherapy regimen. Group community analysis revealed presence of favorable microbial subtypes in complete responders. Finally, fecal microbial composition outperformed clinical variables in prediction of complete response (AUC 0.88 vs AUC 0.50), however, no single microbial species could be regarded as a fully consistent biomarker. Microbiome-based community signature as compared to single microbial species is more likely to be associated as the link between bacterial composition and NAC response.

Internal carotid artery position to characterize risk for vessel injury in pediatric intraoral trauma.

OBJECTIVE: The internal carotid artery (ICA) lies in close anatomic proximity to the oropharynx and is at risk for injury in the instance of intraoral trauma. The objectives of this study are to describe the position of the ICA relative to the oropharynx and identify patient risk factors related to its position. METHODS: A total of 100 patients aged 12 months to 7 years 11 months who received computed tomography (CT) of the neck were randomly selected. The position of the ICA was determined by measuring its angular location relative to the center of the oropharynx (ICA angle) and the shortest distance from the oropharyngeal surface (OP-ICA distance). RESULTS: Indication for imaging was controlled for in all reported data. Patient age was related to ICA angles on both the left (F = 8.06; P = 0.01; η2 = 0.08, 95% CI: 0.01-0.19) and right (F = 18.62; P < 0.001; η2 = 0.17, 95% CI: 0.05-0.29). Patient weight also was related to ICA angles on both the left (F = 7.08; P = 0.01; η2 = 0.07, 95% CI: 0.01-0.18) and right (F = 11.86; P < 0.001; η2 = 0.11, 95% CI: 0.02-0.24). Patient age was related to the left OP-ICA distance (F = 7.36; P = 0.01; η2 = 0.07, 95% CI: 0.01-0.19), as was patient weight (F = 4.82; P = 0.03; η2 = 0.05, 95% CI: 0.00-0.15). Across all measurements, no significant relationship was identified between ICA position and other patient variables, including sex and race/ethnicity. CONCLUSION: The ICA of younger patients and those with lower body weight may be located more medially within the neck and closer to the oropharyngeal surface. This vessel position may place these children at greater anatomic susceptibility for ICA injury in the event of intraoral trauma.

Cervical Necrotizing Fasciitis and Shock in the Post-Operative Pediatric Patient.

Cervical necrotizing fasciitis (CNF) is a rare infection that can quickly lead to devastating patient outcomes. Considering the vital importance of surrounding neck structures, rapid control of the infection is essential. Infection is most frequently polymicrobial and occurs in the adult patient in the context of certain medical comorbidities. Complications are typically limited to tissue destruction in the form of necrosis. There are no current reports describing CNF complicated by acute shock in the post-operative pediatric patient. Here, we present a pediatric case of CNF complicated by acute shock following Sistrunk procedure for removal of a supposed thyroglossal duct cyst. This case illustrates a potential post-operative complication that can be seen within the pediatric patient. Although most reported examples of CNF are polymicrobial and result from odontogenic infection, providers should be aware of other potential sources of disease. It is important for the pediatric surgeon to rapidly identify CNF and consequent shock, as prompt medical and surgical interventions are critical to offering the best chance of patient survival.

Site-specific cancer risk following cobalt exposure via orthopedic implants or in occupational settings: A systematic review and meta-analysis.

In 2020, the European Commission up-classified metal cobalt as Class 1B Carcinogen (presumed to have carcinogenic potential) based primarily on data from rodent inhalation carcinogenicity studies. This up-classification requires an assessment under the Medical Device Regulations of cobalt cancer risk from medical devices. We performed a systematic review and meta-analysis to evaluate site-specific cancer risks with cobalt exposure from either total joint replacement (TJR) or occupational exposure (OC). Results were stratified by exposure type (OC or TJR), exposure level (metal-on-metal (MoM) or non-MoM), follow-up duration (latency period: <5, 5-10 or >10 years), and cancer incidence or mortality (detection bias assessment). From 30 studies (653,104 subjects, average 14.5 years follow-up), the association between TJR/OC and cancer risk was null for 22 of 27 cancer sites, negative for 3 sites, and positive for prostate cancer and myeloma. Significant heterogeneity and large estimate ranges were observed for many cancer sites. No significant increase in estimates was observed by exposure level or follow-up duration. The current evidence, including weak associations, heterogeneity across studies and no increased association with exposure level or follow-up duration, is insufficient to conclude that there exists an increased risk for people exposed to cobalt in TJR/OC of developing site-specific cancers.

Current Barriers in Pursuing Otolaryngology as an Osteopathic Applicant and Proposed Goals for the Future.

The osteopathic (DO) medical profession has seen a substantial increase in popularity, evident by the drastic increase in the DO physician workforce and increasing number of DO graduates in the United States. Osteopathic medical schools have historically been primary care focused, resulting in a majority of their graduates pursuing practice in those specialties. This focus may be inadvertently creating a disadvantageous environment for DO students who aim to pursue specialized or traditionally competitive fields in medicine. Otolaryngology is a prime example of osteopathic underrepresentation, as there is currently a significantly low percentage of DO residents in otolaryngology residency programs and practicing DO otolaryngologists. Given the recent American Council on Graduate Medical Education (ACGME) and American Osteopathic Association (AOA) merger between osteopathic and allopathic (MD) residency programs, it is of great value to further discuss avenues for progress and mitigation of barriers.

Development of the National Otolaryngology Interest Group: Conception to Implementation.

Otolaryngology is a small and highly sought-after surgical subspecialty with sparse residency positions, making it competitive to match into. Allopathic (MD) students without home otolaryngology residency programs, osteopathic (DO) medical students, and underrepresented minorities have historically faced additional challenges in matching into otolaryngology. These specific populations generally experience limited opportunities in establishing mentors, engaging in scholarly activity, and gaining early exposure to clinical settings. Even though the American Osteopathic Association and the Accreditation Council for Graduate Medical Education merger was in part established to create equity among applicants, there remains a substantial disparity among the match rates of medical students of various educational and cultural backgrounds. The National Otolaryngology Interest Group is a student-led interest group created to provide all medical students, especially those facing barriers, with the resources needed to best prepare for matching into an otolaryngology residency program and ultimately a career in otolaryngology.

Anatomy and physiology of the palatine tonsils, adenoids, and lingual tonsils.

OBJECTIVE: This review aims to discuss the basic anatomy and physiology of the palatine and pharyngeal tonsils, with reference to how this foundational understanding may affect patient management and surgical procedures in these regions of the upper airway. METHODS: A literature search was performed using PubMed and Google Scholar using the MeSH terms tonsils, adenoids, anatomy, physiology, and adenotonsillectomy. Primary sources were excluded if they were abstracts only, non-English language, or non-human studies. Thirty-five sources were included in this review. RESULTS AND CONCLUSIONS: The pharyngeal and palatine tonsils are compact yet physiologically complex mucosa-associated lymphoid tissues that make up a portion of Waldeyer's ring. As part of the mucosal immune system, these structures function in exogenous antigen sampling and stimulation of immune responses. Aberrant immune activation and/or regulation can lead to a myriad of pathologies, with adenotonsillar hypertrophy, chronic tonsillitis/adenoiditis, and recurrent otitis media among the most commonly encountered conditions by otolaryngologists. While the pathophysiology of these conditions is still incompletely understood, current evidence and future investigations may reveal patterns amenable to targeted medical management. When medical management fails, tonsillectomy and/or adenoidectomy may be indicated for patient care. Though routine procedures, the execution of tonsil and/or adenoid removal requires a thorough understanding of the anatomy of these lymphoepithelial organs so as to minimize the risk for rare serious complications that can occur.

Carcinogenic assessment of cobalt-containing alloys in medical devices or cobalt in occupational settings: A systematic review and meta-analysis of overall cancer risk from published epidemiologic studies.

In 2020, the European Commission up-classified pure cobalt metal to a Category 1B hazard, based primarily on data from rodent inhalation carcinogenicity studies of metallic cobalt. The European Commission review did not evaluate cobalt-containing alloys in medical devices, which have very different properties vs. pure cobalt metal and did not include a systematic epidemiologic review. We performed a systematic review and meta-analysis of published, peer-reviewed epidemiologic studies evaluating the association between overall cancer risk and exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings. Study-specific estimates were pooled using random-effects models. Analyses included 20 papers on orthopedic implants and 10 occupational cohort papers (~1 million individuals). The meta-analysis summary estimates (95% confidence intervals) for overall cancer risk were 1.00 (0.96-1.04) overall and 0.97 (0.94-1.00) among high-quality studies. Results were also similar in analyses stratified by type of exposure/data sources (occupational cohort, implant registry or database), comparators (general or implant population), cancer incidence or mortality, follow-up duration (latency period), and study precision. In conclusion, meta-analysis found no association between exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings and overall cancer risk, including an analysis of studies directly comparing metal-on-metal vs. non-metal-on-metal implants.

Outlook into the future of front-line immune checkpoint inhibition in metastatic urothelial carcinoma.

Immune checkpoint inhibition has been approved for front-line treatment of metastatic bladder cancer in patients who are cisplatin-ineligible and demonstrate programmed death-ligand 1 (PD-L1) positivity. This approval followed the positive results of IMvigor210 and KEYNOTE-052 studies. Immunotherapy has also demonstrated efficacy as maintenance therapy patients for patients who initially respond to platinum-based chemotherapy. Other studies have investigated combinations of immunotherapy with chemotherapy, combinations between immunotherapies, and immunotherapy with novel agents. Although these combinations have demonstrated promise, further investigation is necessary to optimize the patients who would benefit from these approaches. Biomarkers beyond PD-L1 scoring can help predict response and resistance to immune checkpoint inhibition and will be integral to future studies.

The Potential of Circular RNAs as Cancer Biomarkers.

Circular RNA (circRNA) is a covalently closed RNA structure that has several proposed functions related to cancer development. Recently, cancer-specific and tissue-specific circRNAs have been identified by high-throughput sequencing and are curated in publicly available databases. CircRNAs have features that are ideal properties of biomarkers, including conservation, abundance, and stability in plasma, saliva, and urine. Many circRNAs with predictive and prognostic significance in cancer have been described, and functional mechanisms for some circRNAs have been suggested. CircRNA also has great potential as a noninvasive biomarker for early cancer detection, although further investigation is necessary before clinical application is feasible.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Improved 30 day heart failure rehospitalization prediction through the addition of device-measured parameters.

AIMS: This study aimed to improve in-person clinical evaluation on the day of heart failure (HF) hospitalization discharge by adding device-measured parameters to predict 30 day HF rehospitalization risk in cardiac resynchronization therapy-defibrillator (CRT-D) patients. METHODS AND RESULTS: In a cohort of Medicare patients with CRT-Ds, the independent prognostic value of four device-measured parameters was assessed relative to typical clinical parameters associated with rehospitalization risk. Medicare registry, claims, and Medtronic CareLink® Network data for these patients were analysed using logistic regression modelling and net reclassification methods. Among 1563 CRT-D patients, 411 patients had 607 HF hospitalization events during a median 6.3 years of follow-up. Compared with clinical variables alone, impedance measurements resulted in a 28% improvement between the predicted probabilities of having vs. not having a 30 day HF rehospitalization (relative integrated discrimination improvement = 0.28) and a net 42% improvement in the classification of 30 day HF rehospitalization events and non-events after an index HF hospitalization (net reclassification index = 0.42; 95% CI: 0.10, 0.74). CONCLUSIONS: In CRT patients, intrathoracic impedance measurements improve prediction of 30 day HF rehospitalization over clinical characteristics alone. The present study provides supportive data for the routine evaluation of intrathoracic impedance prior to discharge in patient with CRT devices. Furthermore, the models developed in this study could be used to design interventions to improve compliance with Medicare reimbursement guidelines regarding 30 day HF rehospitalization.

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer.

BACKGROUNDEpidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODSThirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTSMetformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSIONTranslational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATIONClinicalTrials.gov NCT01579812.

Impact of Infant Supraglottoplasty on Quality of Life.

Objectives The objective of the present study is to examine the impact of supraglottoplasty on the quality of life (QOL) of caregivers and infants with severe laryngomalacia and moderate laryngomalacia with feeding difficulties. Study Design Prospective cohort study. Setting Tertiary children's hospital. Subjects and Methods Thirty-nine infants who underwent supraglottoplasty were examined. The primary caregiver answered the 47-item short form of the Infant and Toddler Quality of Life Questionnaire-47 pre- and postoperatively; the subsection scores were compared. A 1-way analysis of variance was performed to analyze the effect of age and sex. A comparison was made between our cohort and a general population of healthy children. Results The average age at surgery was 4.0 months, and 53% of the patients were male. There was significant postoperative improvement in overall health, physical ability, growth and development, bodily pain, temperament, emotional impact on the caregiver, impact on caregiver's time, and family cohesion scores ( P < .05). The same subscale scores remained significantly improved postoperatively after age and sex were controlled. Preoperative QOL scores were significantly worse than those of the general population in nearly all categories. Postoperative physical ability ( P = .009) and temperament ( P = .011) QOL scores were higher than the those of the general population. Scores for growth and development ( P = .132), bodily pain ( P = .481), and family cohesion ( P = .717) were equivalent to those of the general population. Conclusion QOL was significantly improved after supraglottoplasty for infants with severe laryngomalacia and moderate laryngomalacia with feeding difficulties. After supraglottoplasty, QOL was similar to that of the general infant population in most categories.

Long-term impact of intrathoracic impedance findings on survival and heart failure hospitalizations after cardiac resynchronization therapy in ICD Registry patients.

Aims: To determine adjusted associations among OptiVol® threshold crossings, long-term survival, and hospitalizations among heart failure (HF) patients with Medicare coverage in the United States. Methods and results: A cohort with OptiVol®-enabled cardiac resynchronization therapy defibrillators (CRT-D) devices from the Implantable Cardioverter Defibrillator Registry was linked to both Medicare claims/summary data and Medtronic's CareLink® Network data. An extended multivariable Cox model was used to analyse associations among OptiVol® threshold crossings (treated as time-dependent covariates), mortality, and HF-related hospitalizations (HFH). We analysed N = 1565 patients with OptiVol®-enabled CRT-D devices (mean age 72.8, 28% women). The median follow-up was 6.3 years. Patients with >15.1% of days above OptiVol® threshold (highest quartile) had more than a 4-fold increase in mortality [hazard ratio (HR) 4.2, 95% confidence interval (CI): 3.3-5.3] and more than a 3-fold increase in HFH (HR 3.2, 95% CI: 2.4-4.2) compared with patients having <4.1% of days above threshold (lowest quartile) after adjustment for key covariates. In addition, a single OptiVol® crossing was associated with significantly increased rates of both mortality (HR 1.87, 95% CI: 1.27-2.75) and HFH (HR 1.70, 95% CI: 1.28-2.27). Conclusion: In a CRT-D cohort with over 6 years of follow-up, both single OptiVol® crossings and time above OptiVol® threshold were associated with increased rates of mortality and hospitalization, which has important implications for clinical care. This is the first study integrating device data with Medicare outcomes to validate the long-term significance of OptiVol® findings.