Springfield Clinic

The National Cancer Institute organized a virtual Clinical Trials Planning Meeting (CTPM) on ‘Defining the next generation of clinical trials with combination therapies in non-muscle invasive bladder cancer (NMIBC)’ led by the Bladder Cancer Task Force of the NCI Genitourinary Cancers Steering Committee. The purpose of this meeting was to accelerate advances in clinical trials for patients with high-risk NMIBC. The meeting delivered a multidisciplinary expert consensus on optimal strategies for next-generation clinical trial designs in NMIBC with prioritization of combination therapies. Two clinical trial concepts were developed for potential implementation within the National Clinical Trials Network.

Patellar fractures are potentially debilitating injuries due to loss of extensor mechanism function, resulting in an inability to extend the leg. Traditionally, these fractures have been surgically managed with open reduction and internal fixation using a tension band construct. This can be performed with K-wires or cannulated screws with suture or cable as the tension band. Plate osteosynthesis is another option that is increasing in popularity. Incorporating the tension band construct converts tensile force into a healing-compatible compressive force. However, these techniques often fail when used for comminuted patellar fractures. There is also a high reoperation rate due to metal implant discomfort. Reoperation rates have been reported as high as 41% for K-wires and 23% for cannulated screws. A more optimal technique would provide adequate reduction and strong fixation without the risk of implant irritation that can apply to all/most fracture types. We report a new technique that implements a multistrand, long-chain, ultra–high-molecular weight, polyethylene core suture material with a braided jacket of polyester (FiberWire) without the need for any associated plates, K-wires, or cannulated screws. The suture is woven to create a tension band tendon-approximating cerclage construct that incorporates the proximal and distal bone fragments as well as the patellar and quadriceps tendons. This technique can be used for both simple and comminuted fractures and provides optimal fixation strength while minimizing the complications associated with metal implants. The efficacy of this technique may lend to future studies including biomechanical and retrospective analyses.

Introduction To report a series of patients who developed ocular surface disease related to tisotumab vedotin-tftv (TV), an antibody-drug conjugate (ADC) approved for the treatment of recurrent or metastatic cervical cancer. Methods This was a multicenter retrospective chart review study of patients who developed ocular surface disease related to TV between April 1st, 2022 to August 31st, 2023. Results Five patients were identified who developed ocular surface disease while on TV. All patients received a standard ocular adverse event prophylaxis regimen with each infusion per the product label, including a cool ocular compress, topical vasoconstrictor, topical steroid, and artificial tears. All five patients developed conjunctival subepithelial fibrosis. Two patients developed bilateral pseudomembranous conjunctivitis, one of whom subsequently developed conjunctival scarring. Two patients developed a bilateral culture positive conjunctivitis, which responded to topical antibiotics. One patient developed bilateral infectious keratitis and was treated with partial thickness corneal transplantation of both eyes. Conclusion TV can be associated with ocular surface disease, including conjunctival scarring and infectious keratitis. Some cases may require surgical intervention. Oncologists and ophthalmologists should be aware of the possibility of these ocular complications, especially as more ADCs are approved. Further studies are required to determine toxicity mechanisms as well as optimal prophylaxis and management strategies.

A 27-year-old male patient with chronic alcohol use disorder was diagnosed with Marchiafava-Bignami disease (MBD) after experiencing an episode of unconsciousness. MRI scans revealed lesions in the corpus callosum and adjacent white matter. Despite prompt initiation of intensive treatment with high-dose thiamine and corticosteroids, the patient only partially recovered, remaining disoriented and exhibiting persistent neurological deficits during follow-up. MBD is a rare condition seen in individuals with chronic alcohol use disorder and malnutrition, often resulting in unfavorable outcomes despite prompt intervention. This case underscores the impact of the patient’s young age at the onset of alcohol dependence, a low Glasgow Coma Scale score, and the presence of extracallosal lesions on his overall prognosis. We discuss the pathophysiology, presentation, and treatment. We also describe the role of each prognostic factor of MBD in an unfavourable outcome highlighting the need for a larger study to define various prognostic indicators at presentation and identify appropriate treatment approaches.

Enzo Traverso's Singular Pasts: The “I” in Historiography argues that contemporary historical writing is undergoing a “subjectivist turn” characterized by the increasing prevalence of first‐person narration, or homodiegesis. Traverso attributes this shift to the influence of neoliberalism and its emphasis on individual experience. This review essay follows Judith Surkis's analysis of the linguistic turn in questioning whether “turn talk” obscures more than it illuminates about contemporary historiography, especially given the extreme diversity of the field in terms of method, object, and approach. This essay proposes Hayden White's notion of the “practical past” as a better context for understanding the increasing prevalence of first‐person narration in historiography, insofar as it brings to the foreground what is lost or ruled out when history bases its authority and epistemological status on third‐person narration and a rigid distinction between historical and literary writing.

BACKGROUND AND OBJECTIVES The utility of oral 5-aminolevulinic acid (5-ALA)/protoporphyrin fluorescence for the resection of high-grade gliomas is well documented, but the problem of false-negative observations remains. This study compares high-grade glioma visualization with low/standard dose 5-ALA (<30 mg/kg) to high-dose 5-ALA (>40 mg/kg) to see if by using this higher dose, it is possible to reduce the rate of false-negative observations without increasing the rate of false-positive (FP) observations and therefore increase the sensitivity. METHODS This is a prospective study of consecutive patients with radiological evidence of presumed high-grade glioma. We reviewed the data from patients who received preoperative low/standard doses and patients who received a preoperative high dose of 5-ALA. Adverse events, dose to observation time, intensity of tumor fluorescence, and results of biopsies in areas of tumor and tumor bed under deep blue light were recorded. RESULTS A total of 22 patients with high-grade glioma received a dose >40 mg/kg (high-dose) and 9 patients received <30 mg/kg (low/standard dose). There were no serious adverse events related to 5-ALA in any subject. There was a very high sensitivity and specificity of 5-ALA for the presence of tumor in both groups. There were no FP observations (fluorescence with no tumor) in either group. The specificity and the positive predictive value were 100% in both groups. The sensitivity and the negative predictive value were 53.3% and 30.0% in the low/standard dose group and 59.5% and 31.8% in the high-dose group, respectively. CONCLUSION High-dose oral 5-aminolevulinic/protoporphyrin fluorescence is a safe and effective aid to the intraoperative detection of high-grade gliomas with high sensitivity and specificity. False-negative observations with a high dose do not seem to be less than that with a low/standard dose. The rate of FP observations with both groups remains very low.

The strong coupling between carrier and phonon transport in thermoelectric (TE) materials severely limits improvements to the figure of merit (ZT). In this work, an approach is proposed to weaken electron‐phonon coupling, effectively enhancing the TE performance of GeTe. Alloying with Zn4Sb3 reduces excessive carrier concentration (nH), widens the bandgap, and promotes band convergence, synergistically improving charge carrier transport and ensuring a high power factor. Additional Pb doping further optimizes nH, boosting the power factor even more. Moreover, phonon transport is suppressed through Pb doping, as reflected in enhanced acoustic‐optical interactions due to the crossing of optical and acoustic modes, and a reduction in sound group velocity. This reinforced strong phonon scattering, combined with multi‐scale hierarchical nano/microstructures in the matrix, significantly reduces lattice thermal conductivity. As a result, a high ZT of 2.1 is achieved at 753 K in Ge0.9Pb0.1Te+0.9%Zn4Sb3. Alongside optimized mechanical performance, a high power density of 1.46 W cm⁻² is realized at a temperature difference of 350 K in the fabricated 7‐pair TE module. The findings demonstrate the effectiveness of a stepwise optimization strategy for developing high‐performance TE materials.

BACKGROUND Trimodality therapy (TMT) is a viable option for muscle-invasive localized bladder cancer, providing an alternative to radical cystectomy in properly selected patients. The approval of novel therapeutics in different stages of bladder cancer treatment has sparked interest in exploring concurrent systemic therapies with radiation in clinical trials to enhance long-term outcomes. Achieving uniformity in trial eligibility criteria and endpoint definitions is imperative in describing clinical significance, comparing trials, and changing standard of care guidelines. OBJECTIVE To delineate eligibility criteria and appropriate endpoints for TMT clinical trials in an attempt to achieve uniformity in trial eligibility criteria and endpoint definitions which will then help move the field of bladder preservation forward and improve the current standard of care. METHODS An expert panel, comprising individuals with extensive experience in bladder cancer clinical trials, clinical practice focused on bladder cancer treatment, and patient advocacy, was assembled. The panel systematically reviewed phase II/III clinical trials previously published and assessing the role of radiation in definitive therapy with the specific goal of preserving native bladder function during bladder cancer treatment. Recommendations were summarized based on review of these trials and past experiences of the investigators. To ensure a holistic perspective, the summary was further subjected to rigorous reevaluation by a patient advocate, who added valuable insights from a patient’s standpoint. The resulting consensus statements were summarized in this publication to contribute to the evolving landscape of bladder cancer research and treatment. RESULTS The eligibility criteria for TMT should be pragmatic to encompass patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, bladder cancer stage T2-T4a N0±N1M0, unilateral tumor-associated hydronephrosis, attempted maximal transurethral resection of bladder tumor (TURBT), both pure urothelial carcinoma and/or mixed histologic subtypes (excluding rare and aggressive small cell variants) and patients who are non- cystectomy candidates. Bladder intact event-free survival (BIEFS) is proposed as a suitable endpoint for registration trials designed to compare two different treatment interventions, defined as the time from randomization to muscle-invasive or locoregional recurrence, systemic recurrence, radical cystectomy from any cause, or death from any cause. Overall survival is deemed an appropriate secondary endpoint or a co-primary end point as recent improvements in systemic therapy can produce significant improvement in long-term outcomes. Primary and secondary endpoints should be supported with patient-reported quality of life assessments, when available. CONCLUSIONS The standardization of clinical trial design, eligibility criteria, and endpoints is essential for expediting progress in the field. Inclusivity, patient-centricity, and clinically meaningful endpoints will facilitate the analysis, comparison, and meta-analysis of different trials, fostering advancements in bladder cancer treatment.

Venturing beyond typical arrhythmias, a case of ventricular tachycardia (VT) in a 28-year-old woman who was initially presenting as benign tachycardia took an unexpected turn as her palpitations evolved to include severe sweating and significant weight loss. Initially, her symptoms like palpitations were treated with metoprolol, and given her age and lack of significant risk factors, the tachycardia was considered benign. However, as time passed, she developed severe sweating and noticeable weight loss, prompting a deeper investigation. This thorough exploration uncovered a 4 cm adrenal mass, which turned out to be pheochromocytoma, a rare tumor that can present with atypical symptoms. Initial diagnoses considered a range of conditions, from idiopathic VT and structural heart disease to electrolyte imbalances and thyroid disorders. Each possibility was carefully evaluated and ruled out, leading to the discovery of elevated plasma free metanephrines and imaging findings that confirmed pheochromocytoma. The successful diagnosis of this case demonstrates the importance of keeping rare conditions like pheochromocytoma in mind, even when initial symptoms suggest a different diagnosis. It serves as a reminder of the value of a comprehensive diagnostic approach and the need to stay vigilant for less common causes behind seemingly straightforward symptoms.

Aortic dissection is a critical and life-threatening condition that can present with atypical symptoms, often leading to misdiagnosis and delayed treatment. The report presents a case of a 65-year-old male who initially exhibited fever, right-sided chest pain, and a productive cough, resulting in an initial diagnosis of pneumonia. Despite empirical antibiotic therapy, his symptoms persisted, prompting further investigation. A computed tomography (CT) scan ultimately revealed a Type B aortic dissection. The patient was then transferred to a specialized tertiary care facility for successful endovascular intervention. This case underscores the importance of considering aortic dissection in patients presenting with persistent, atypical symptoms that do not respond to standard treatments, such as unexplained fever and chest pain. It highlights the crucial role of advanced imaging techniques, such as CT scans, in achieving an accurate and timely diagnosis. Clinicians must maintain a high index of suspicion and ensure prompt referral to specialized centers to improve patient outcomes in this potentially fatal condition.

Muir-Torre syndrome (MTS) is a rare autosomal dominant genetic disorder that manifests through the co-occurrence of sebaceous skin tumors and internal malignancies, primarily due to mutations in mismatch repair (MMR) genes such as MSH2, MLH1, and MSH6. This paper presents a detailed case report of a 57-year-old female diagnosed with MTS, highlighting her extensive medical history and the critical role of genetic testing and multidisciplinary management. The patient’s dermatological and oncological assessments revealed multiple sebaceous carcinomas and recurrent urothelial carcinoma, confirmed by a pathogenic MSH2 mutation. Through comprehensive preventive surgeries and rigorous follow-up, this case underscores the necessity of proactive cancer surveillance. The discussion integrates findings from key genetic studies and emphasizes the importance of immunohistochemistry in diagnosis. Recommendations for clinical practice include routine genetic testing, stringent surveillance, and multidisciplinary management, underscoring the need for ongoing research to understand better and manage this complex syndrome.

Prostate cancer is a leading cause of cancer-related morbidity and mortality in men, frequently exhibiting resistance to conventional anti-androgen therapies. This review investigates the emerging significance of the aryl hydrocarbon receptor (AhR) in prostate cancer, focusing on its role in modulating androgen receptor (AR) signaling and its potential as a therapeutic target. AhR, traditionally known for detoxifying harmful compounds, has been increasingly recognized for its dual capacity to either enhance or inhibit AR activity based on cellular context and specific coactivators. Furthermore, AhR influences tumor progression independently of AR by regulating genes involved in cell cycle control and apoptosis. This narrative review synthesizes current research on AhR’s multifaceted roles in prostate cancer, evaluates its potential as a biomarker, and discusses the therapeutic implications of targeting AhR, particularly for hormone-refractory prostate cancer. Our findings underscore the necessity for personalized AhR-targeted therapies and advocate for continued clinical research to fully leverage AhR's therapeutic potential.

Schnitzler syndrome (SS) is a rare autoinflammatory disorder characterized by a constellation of symptoms that include chronic urticarial rash, recurrent fever, arthralgias/arthritis, and monoclonal gammopathy, typically involving immunoglobulin M (IgM). However, cases with overlapping clinical features but lacking specific criteria fall under the umbrella of Schnitzler-like syndromes. This case report describes a 40-year-old male with Schnitzer-like syndrome and underscores the diagnostic complexities and therapeutic challenges of Schnitzer-like syndrome with IgG kappa monoclonal gammopathy, highlighting the need for a comprehensive diagnostic approach and targeted therapy.

Objective To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases. Design Experimental study. Subjects Brown Norway rats and New Zealand White Cross rabbits. Methods Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents. Main Outcome Measures Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101. Results RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo. Conclusions RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans. Financial Disclosure(s) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BACKGROUND Poor differentiation predicts adverse outcomes in cutaneous squamous cell carcinoma (CSCC), but there is no standardized, reliable grading system. OBJECTIVE To explore which histologic features have the greatest impact on CSCC differentiation interrater agreement. MATERIALS AND METHODS In a prior study, 40 raters graded differentiation for 45 squamous cell carcinomas, and percent interrater agreements were calculated. Cases graded as well/moderately differentiated with 100% agreement (10), those graded as poorly differentiated with ≥80% agreement (5), and those that received a variety of grades with ≤60% agreement (7) were pulled for the current study. Three raters graded individual histologic features for each case, and percent interrater agreements were calculated using both the well/moderately/poorly differentiated grading system and a dichotomized system. RESULTS The percent interrater agreements were 34.8% for mitoses, 53% for pleomorphism, 59.1% for keratinization, 66.7% for cellular cohesion/intercellular bridges, and 78.8% for tumor edges. Percent agreements improved with dichotomous grading; the largest improvement was seen within the group of cases that had been graded as well/moderately differentiated with 100% agreement in the prior study. CONCLUSION Future squamous cell carcinoma differentiation grading systems would benefit from eliminating mitotic rate, clearly defining how to grade other features, and dichotomous grading.

With disparate rates of morbidity and mortality among minoritized communities, COVID-19 illuminated the need for equity-informed practices in public health. Pacia et al posit FQHCs as entities that addressed inequity when others failed. This commentary further situates how FQHCs address the public health crisis of institutional racism and related health inequities every day and presents a FQHC-led Ethics and Equity Framework and Workflow Checklist to guide ethical and equitable engagement with FQHCs.

PURPOSE The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m ² once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 ( P = .24). CONCLUSION Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

The characteristic structural anomaly of the heart in the left ventricular non-compaction (LVNC) is identified with a prominent layer of the trabecular meshwork, thin compacted myocardium, and intertrabecular recesses within the depths of the left ventricle. Despite growing clinical recognition, the prevalence of LVNC in adults and the full clinical spectrum remain poorly explored. The disease shows heterogeneous phenotypes from an asymptomatic presentation to severe cardiac complications like cardiac failure, arrhythmias, and thromboembolic events. Current diagnostic practices for LVNC lack standardized guidelines, making patient management difficult. We here report a case of an adult patient who presented with features of congestive cardiac failure and on detailed imaging with echocardiogram and magnetic resonance imaging (MRI) was diagnosed to have LVNC. We here also emphasize that there is a great need for refined diagnostic criteria that include genetic, clinical, and imaging data. Cases of LVNC with full-blown phenotypic expression should be used for diagnostic criteria.

Exploration of metastable phases holds profound implications for functional materials. Herein, we engineer the metastable phase to enhance the thermoelectric performance of germanium selenide (GeSe) through tailoring the chemical bonding mechanism. Initially, AgInTe2 alloying fosters a transition from stable orthorhombic to metastable rhombohedral phase in GeSe by substantially promoting p‐state electron bonding to form metavalent bonding (MVB). Besides, extra Pb is employed to prevent a transition into a stable hexagonal phase at elevated temperatures by moderately enhancing the degree of MVB. The stabilization of the metastable rhombohedral phase generates an optimized bandgap, sharpened valence band edge, and stimulative band convergence compared to stable phases. This leads to decent carrier concentration, improved carrier mobility, and enhanced density‐of‐state effective mass, culminating in a superior power factor. Moreover, lattice thermal conductivity is suppressed by pronounced lattice anharmonicity, low sound velocity, and strong phonon scattering induced by multiple defects. Consequently, a maximum zT of 1.0 at 773 K is achieved in (Ge0.98Pb0.02Se)0.875(AgInTe2)0.125, resulting in a maximum energy conversion efficiency of 4.90% under the temperature difference of 500 K. This work underscores the significance of regulating MVB to stabilize metastable phases in chalcogenides.