How Effective is the Use of Molecular Testing in Preoperative Decision Making for Management of Indeterminate Thyroid Nodules?

INTRODUCTION: We performed Thyroseq v2 molecular testing on indeterminate thyroid nodules and evaluated whether they underwent a management change from the standard of thyroid lobectomy. METHODS: We conducted a retrospective analysis of all indeterminate thyroid nodules that underwent Thyroseq v2 molecular testing from 2014 to 2019 at a large academic center. Pathology was reviewed by thyroid cytopathologists. Thyroseq results were reported benign (malignancy probability less than 10%) or suspicious (malignancy probability greater than 30%). The primary endpoint was a management change from a diagnostic lobectomy. RESULTS: A total of 142 nodules were included: 113 (80%) Bethesda III and 29 (20%) Bethesda IV. Seventy-three nodules underwent surgical management and 69 did not. We noted a change in management in 64% (91/142) of nodules. Patients who underwent a change in management to no surgery had a significantly higher rate of benign Thyroseq result than those without a change (75.8% vs. 49.0%, p = 0.001). On logistic regression analysis, a benign Thyroseq result was a positive independent predictor of a change to no surgery (OR 3.87, 95% CI 1.69-8.89). Nodule size, multiple nodules, compressive symptoms, and history of hypothyroidism were not significant. Of the 91 patients who underwent a management change, 71% (65/91) did not undergo surgery. On follow-up (average 985 ± 615 days), 12% (8/65) of those nodules were growing or developed suspicious features requiring surgery. CONCLUSIONS: Molecular testing helped avoid surgery in almost half our population with indeterminate thyroid nodules, and benign results may help avoid surgery in asymptomatic patients with indeterminate thyroid nodules.

A program for volunteers accompanying older patients with cognitive dysfunction to improve the quality of emergency department care: A pilot study.

Admission to an emergency department (ED) is challenging for older patients with cognitive dysfunction (PWCD). Targeted patient-oriented approaches to improve the care for PWCD are needed. The aim of this pilot study was to design and evaluate a program for volunteers to support PWCD in the ED. Volunteers (N = 9) first received a training and during the following six months (N = 90 shifts), they accompanied PWCD (N = 112) during their stay. Results showed that the training increased volunteers' knowledge and expertise, but not shift-related self-efficacy. The most frequent strategies applied were conversations, holding hands and touching, and providing food and drinks. After six months, volunteers reported a great sense of meaningfulness and felt that they were highly appreciated by the patients. ED nurses' sceptical attitudes towards the program decreased. The program is beneficial for PWCD, appears to be meaningful for volunteers and is appreciated by ED nurses.

Generating a multimodal artificial intelligence model to differentiate benign and malignant follicular neoplasms of the thyroid: A proof-of-concept study.

BACKGROUND: Machine learning has been increasingly used to develop algorithms that can improve medical diagnostics and prognostication and has shown promise in improving the classification of thyroid ultrasound images. This proof-of-concept study aims to develop a multimodal machine-learning model to classify follicular carcinoma from adenoma. METHODS: This is a retrospective study of patients with follicular adenoma or carcinoma at a single institution between 2010 and 2022. Demographics, imaging, and perioperative variables were collected. The region of interest was annotated on ultrasound and used to perform radiomics analysis. Imaging features and clinical variables were then used to create a random forest classifier to predict malignancy. Leave-one-out cross-validation was conducted to evaluate classifier performance using the area under the receiver operating characteristic curve. RESULTS: Patients with follicular adenomas (n = 7) and carcinomas (n = 11) with complete imaging and perioperative data were included. A total of 910 features were extracted from each image. The t-distributed stochastic neighbor embedding method reduced the dimension to 2 primary represented components. The random forest classifier achieved an area under the receiver operating characteristic curve of 0.76 (clinical only), 0.29 (image only), and 0.79 (multimodal data). CONCLUSION: Our multimodal machine learning model demonstrates promising results in classifying follicular carcinoma from adenoma. This approach can potentially be applied in future studies to generate models for preoperative differentiation of follicular thyroid neoplasms.

From Bench-to-Bedside: How Artificial Intelligence is Changing Thyroid Nodule Diagnostics, a Systematic Review.

CONTEXT: Use of artificial intelligence (AI) to predict clinical outcomes in thyroid nodule diagnostics has grown exponentially over the past decade. The greatest challenge is in understanding the best model to apply to one's own patient population, and how to operationalize such a model in practice. EVIDENCE ACQUISITION: A literature search of PubMed and IEEE Xplore was conducted for English-language publications between January 1, 2015 and January 1, 2023, studying diagnostic tests on suspected thyroid nodules that used AI. We excluded articles without prospective or external validation, nonprimary literature, duplicates, focused on nonnodular thyroid conditions, not using AI, and those incidentally using AI in support of an experimental diagnostic outside standard clinical practice. Quality was graded by Oxford level of evidence. EVIDENCE SYNTHESIS: A total of 61 studies were identified; all performed external validation, 16 studies were prospective, and 33 compared a model to physician prediction of ground truth. Statistical validation was reported in 50 papers. A diagnostic pipeline was abstracted, yielding 5 high-level outcomes: (1) nodule localization, (2) ultrasound (US) risk score, (3) molecular status, (4) malignancy, and (5) long-term prognosis. Seven prospective studies validated a single commercial AI; strengths included automating nodule feature assessment from US and assisting the physician in predicting malignancy risk, while weaknesses included automated margin prediction and interobserver variability. CONCLUSION: Models predominantly used US images to predict malignancy. Of 4 Food and Drug Administration-approved products, only S-Detect was extensively validated. Implementing an AI model locally requires data sanitization and revalidation to ensure appropriate clinical performance.

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci.

Importance: Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. Objective: To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. Design, Setting, and Participants: This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. Main Outcomes and Measures: The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. Results: The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). Conclusions and Relevance: The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

Poor outcomes for trial-ineligible patients receiving polatuzumab for relapsed/refractory diffuse large B-cell lymphoma in routine care: An Australian Lymphoma and Related Diseases Registry project.

Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR-DLBCL have not been replicated in routine care cohorts, as RR-DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR-DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study. Of 58 eligible patients, 74% met the criteria deeming them ineligible for the G029365 original study at the time of pola's commencement. Median progression-free survival and overall survival in our cohort were 2.3 and 3.5 months, respectively. In contrast to the landmark trial cohort, more of our patients ceased therapy prior to completion, the majority due to progressive disease and only 8/58 received any subsequent treatment. Dismal outcomes in this Australian real-world population demonstrate trial eligibility is challenging to meet, and newer treatments can be difficult to deliver in routine care. Clinically applicable results from therapeutic studies require trial cohorts to reflect representative clinical populations wherever possible, and more research is required to address the benefit of novel agents in the increasing majority who are ineligible for modern studies.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains.

Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so-called novel anti-MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0.02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted.

Australian experience with ibrutinib in patients with relapsed/refractory mantle cell lymphoma: a study from the Lymphoma and Related Diseases Registry.

Bruton's tyrosine kinase inhibitors (BTKi) have an established role in the management of patients with relapsed/refractory mantle cell lymphoma (MCL). However, scant data exist on outcomes of patients ineligible for clinical trials testing these therapies. We describe a contemporary cohort of relapsed/refractory MCL patients from the Australasian Lymphoma and Related Diseases Registry treated with ibrutinib December 2014 until July 2018, to determine the proportion potentially eligible for original trials, reasons for ineligibility and survival outcomes. Of 44 patients, 41% met one or more exclusion criteria from previous phase II/III MCL BTKi studies. Median progression-free and overall survival were 13.7 months (95% CI 6.2-28.1) and 15.6 months (95% CI 10.8-29.6) respectively and were shorter in patients excluded from clinical trials based on ECOG ≥2. Ibrutinib has demonstrable clinical effectiveness in a population enriched for unfit and trial-ineligible patients, and a need for more inclusive enrollment criteria in future BTKi studies is highlighted.

Ultrasensitive Detection of MCF-7 Cells with a Carbon Nanotube-Based Optoelectronic-Pulse Sensor Framework.

Biosensors are of vital significance for healthcare by supporting the management of infectious diseases for preventing pandemics and the diagnosis of life-threatening conditions such as cancer. However, the advancement of the field can be limited by low sensing accuracy. Here, we altered the bioelectrical signatures of the cells using carbon nanotubes (CNTs) via structural loosening effects. Using an alternating current (AC) pulse under light irradiation, we developed a photo-assisted AC pulse sensor based on CNTs to differentiate between healthy breast epithelial cells (MCF-10A) and luminal breast cancer cells (MCF-7) within a heterogeneous cell population. We observed a previously undemonstrated increase in current contrast for MCF-7 cells with CNTs compared to MCF-10A cells with CNTs under light exposure. Moreover, we obtained a detection limit of ∼1.5 × 103 cells below a baseline of ∼1 × 104 cells for existing electrical-based sensors for an adherent, heterogeneous cell population. All-atom molecular dynamics (MD) simulations reveal that interactions between the embedded CNT and cancer cell membranes result in a less rigid lipid bilayer structure, which can facilitate CNT translocation for enhancing current. This as-yet unconsidered cancer cell-specific method based on the unique optoelectrical properties of CNTs represents a strategy for unlocking the detection of a small population of cancer cells and provides a promising route for the early diagnosis, monitoring, and staging of cancer.

Ultralong recovery time in nanosecond electroporation systems enabled by orientational-disordering processes.

The growing importance of applications based on molecular medicine and genetic engineering is driving the need to develop high-performance electroporation technologies. The electroporation phenomenon involves disruption of the cell for increasing membrane permeability. Although there is a multitude of research focused on exploring new electroporation techniques, the engineering of programming schemes suitable for these electroporation methods remains a challenge. Nanosecond stimulations could be promising candidates for these techniques owing to their ability to generate a wide range of biological responses. Here we control the membrane permeabilization of cancer cells using different numbers of electric-field pulses through orientational disordering effects. We then report our exploration of a few-volt nanosecond alternating-current (AC) stimulation method with an increased number of pulses for developing electroporation systems. A recovery time of ∼720 min was achieved, which is above the average of ∼76 min for existing electroporation methods using medium cell populations, as well as a previously unreported increased conductance with an increase in the number of pulses using weak bias amplitudes. All-atom molecular dynamics (MD) simulations reveal the orientation-disordering-facilitated increase in the degree of permeabilization. These findings highlight the potential of few-volt nanosecond AC-stimulation with an increased number of pulse strategies for the development of next-generation low-power electroporation systems.

WS2/Polyethylene Glycol Nanostructures for Ultra-Efficient MCF-7 Cancer Cell Ablation and Electrothermal Therapy.

Developing novel nanostructures and advanced nanotechnologies for cancer treatment has attracted ever-increasing interest. Electrothermal therapy offers many advantages such as high efficiency and minimal invasiveness, but finding a balance between increasing stability of the nanostructure state and, at the same time, enhancing the nanostructure biodegradability presents a key challenge. Here, we modulate the biodegradation process of two-dimensional-material-based nanostructures by using polyethylene glycol (PEG) via nanostructure disrupt-and-release effects. We then demonstrate the development of a previously unreported alternating current (AC) pulse WS2/PEG nanostructure system for enhancing therapeutic performance. A decrease in cell viability of ∼42% for MCF-7 cells with WS2/PEG was achieved, which is above an average of ∼25% for current electrothermal-based therapeutic methods using similar energy densities, as well as degradation time of the WS2 of ∼1 week, below an average of ∼3.5 weeks for state-of-the-art nanostructure-based systems in physiological media. Moreover, the incubation time of MCF-7 cells with WS2/PEG reached ∼24 h, which is above the average of ∼4.5 h for current electrothermal-based therapeutic methods and with the use of the amount of time harnessed to incubate the cells with nanostructures before applying a stimulus as a measure of incubation time. Material characterizations further disclose the degradation of WS2 and the grafting of PEG on WS2 surfaces. These WS2-based systems offer strong therapeutic performance and, simultaneously, maintain excellent biodegradability/biocompatibility, thus providing a promising route for the ablation of cancer.

An Efficient, Short Stimulus PANC-1 Cancer Cell Ablation and Electrothermal Therapy Driven by Hydrophobic Interactions.

Promising results in clinical studies have been demonstrated by the utilization of electrothermal agents (ETAs) in cancer therapy. However, a difficulty arises from the balance between facilitating the degradation of ETAs, and at the same time, increasing the electrothermal performance/stability required for highly efficient treatment. In this study, we controlled the thermal signature of the MoS2 by harnessing MoS2 nanostructures with M13 phage (MNM) via the structural assembling (hydrophobic interaction) phenomena and developed a combined PANC-1 cancer cell-MNM alternating current (AC)-stimulus framework for cancer cell ablation and electrothermal therapy. A percentage decrease in the cell viability of ~23% was achieved, as well as a degradation time of 2 weeks; a stimulus length of 100 µs was also achieved. Molecular dynamics (MD) simulations revealed the assembling kinetics in integrated M13 phage-cancer cell protein systems and the structural origin of the hydrophobic interaction-enabled increase in thermal conduction. This study not only introduced an 'ideal' agent that avoided the limitations of ETAs but also provided a proof-of-concept application of MoS2-based materials in efficacious cancer therapy.

Ultralong-Time Recovery and Low-Voltage Electroporation for Biological Cell Monitoring Enabled by a Microsized Multipulse Framework.

Long-term nondestructive monitoring of cells is of significant importance for understanding cell proliferation, cell signaling, cell death, and other processes. However, traditional monitoring methods are limited to a certain range of testing conditions and may reduce cell viability. Here, we present a microgap, multishot electroporation (M2E) system for monitoring cell recovery for up to ∼2 h using ∼5 V pulses and with excellent cell viability using a medium cell population. Electric field simulations reveal the bias-voltage- and gap-size-dependent electric field intensities in the M2E system. In addition to excellent transparency with low cell toxicity, the M2E system does not require specialized components, expensive materials, complicated fabrication processes, or cell manipulations; it just consists of a micrometer-sized pattern and a low-voltage square-wave generator. Ultimately, the M2E system can offer a long-term and nontoxic method of cell monitoring.

Ultrasensitive two-dimensional material-based MCF-7 cancer cell sensor driven by perturbation processes.

Changes in lipid composition and structure during cell development can be markers for cell apoptosis or various diseases such as cancer. Although traditional fluorescence techniques utilising molecular probes have been studied, these methods are limited in studying these micro-changes as they require complex probe preparation and cannot be reused, making cell monitoring and detection challenging. Here, we developed a direct current (DC) resistance sensor based on two-dimensional (2D) molybdenum disulfide (MoS2) nanosheets to enable cancer cell-specific detection dependent on micro-changes in the cancer cell membrane. Atomistic molecular dynamics (MD) simulations were used to study the interaction between 2D MoS2 and cancer lipid bilayer systems, and revealed that previously unconsidered perturbations in the lipid bilayer can cause an increase in resistance. Under an applied DC sweep, we observed an increase in resistance when cancer cells were incubated with the nanosheets. Furthermore, a correlation was observed between the resistance and breast cancer epithelial cell (MCF-7) population, illustrating a cell population-dependent sensitivity of our method. Our method has a detection limit of ∼3 × 103 cells, below a baseline of ∼1 × 104 cells for the current state-of-the-art electrical-based biosensors using an adherent monolayer with homogenous cells. This combination of a unique 2D material and electrical resistance framework represents a promising approach for the early detection of cancerous cells and to reduce the risk of post-surgery cancer recurrence.