Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Evaluating the added value of concurrent contrast-enhanced diagnostic CT for PSMA-PET/CT Interpretation.

RATIONALE AND OBJECTIVES: To determine whether concurrent contrast-enhanced diagnostic CT (DxCT) confers added diagnostic certainty compared to PSMA-PET/CT alone. MATERIALS AND METHODS: This retrospective multi-reader study analyzed imaging comprising combined F-18-piflufolastat PSMA-PET/CT with diagnostic chest/abdominopelvic CT from prostate cancer patients within the first 6 months of FDA-approval of the PET agent. Six nuclear radiology readers were randomly presented with PSMA-PET/CT studies with or without DxCT and asked to report their diagnostic certainty for PSMA-avid lesions found on PET. Subsequently, readers re-reviewed the same study after an interlude (with the CT if not previously presented and vice-versa) to determine if DxCT altered their diagnostic assessment. Inter-rater concordance was assessed on a subset of images read by all readers. Diagnostic certainties for PSMA-PET/CT with and without DxCT were compared, and the variables for which DxCT may add value were examined. RESULTS: Good inter-rater concordance across readers was noted for both PET/CT (Finn's coefficient of reliability for overall scan certainty: 0.85,p < 0.01) and combined DxCT-PET/CT (0.59,p < 0.01). Overall certainty and concordance between PET/CT and combined DxCT-PET/CT datasets were similar (overall scan certainty: 92% ± 16 vs. 92% ± 17,p = 0.43), with no significant advantage for adding DxCT across different anatomic locations or clinical parameters. A slight predilection for combined DxCT-PET/CT was noted when interpreting images acquired for the initial staging of prostate cancer (89% ± 16 vs. 93% ± 17,p = 0.08). CONCLUSION: Good inter-reader concordance can be achieved across different training levels with PSMA-PET/CT. Furthermore, using DxCT concurrent with PSMA-PET/CT does not significantly improve diagnostic certainty for most indications but may be useful for initial staging.

Extended Pharmacokinetics Improve Site-Specific Prodrug Activation Using Radiation.

Radiotherapy is commonly used to treat cancer, and localized energy deposited by radiotherapy has the potential to chemically uncage prodrugs; however, it has been challenging to demonstrate prodrug activation that is both sustained in vivo and truly localized to tumors without affecting off-target tissues. To address this, we developed a series of novel phenyl-azide-caged, radiation-activated chemotherapy drug-conjugates alongside a computational framework for understanding corresponding pharmacokinetic and pharmacodynamic (PK/PD) behaviors. We especially focused on an albumin-bound prodrug of monomethyl auristatin E (MMAE) and found it blocked tumor growth in mice, delivered a 130-fold greater amount of activated drug to irradiated tumor versus unirradiated tissue, was 7.5-fold more efficient than a non albumin-bound prodrug, and showed no appreciable toxicity compared to free or cathepsin-activatable drugs. These data guided computational modeling of drug action, which indicated that extended pharmacokinetics can improve localized and cumulative drug activation, especially for payloads with low vascular permeability and diffusivity and particularly in patients receiving daily treatments of conventional radiotherapy for weeks. This work thus offers a quantitative PK/PD framework and proof-of-principle experimental demonstration of how extending prodrug circulation can improve its localized activity in vivo.

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

NCCN Guidelines® Insights: Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Creating the freedom to thrive: Honoring the legacy of RSNA gold medalist, Deborah Levine, MD.

Awarded the Radiological Society of North America (RSNA) Gold Medal in 2018, Dr. Deborah Levine's research, journalism, and mentorship have left an indelible mark on the radiology field. Her work in ultrasound led to its use as the standard for monitoring benign adnexal cysts. She helped popularize obstetric magnetic resonance imaging (MRI) through her research on its use in placental accreta and fetal abnormalities, which led to the development of the 'Compendium of Fetal MRI' website. This work in research led naturally to a career in journalism, where she eventually became Senior Deputy Editor of Radiology and founded Radiology Select. Concurrently with her personal achievements, Dr. Levine has dedicated herself to the mentorship of her female trainees. She sought various leadership positions to learn more about and advocate for the promotion and support of female leadership in radiology departments. In many ways, Dr. Levine's career and work have transformed radiology as we know it today for both patients and physicians.

Outcomes and predictors of survival for tracheal cancer.

INTRODUCTION: Primary tracheal cancer is uncommon, with poor survival. While surgical resection is the mainstay of therapy, the role of chemotherapy and radiation is poorly defined. We aimed to study the impact of treatment modalities on survival. METHODS: Patients with primary tracheal cancer were identified from the National Cancer Database over 12 years, 2004-2015. Patient characteristics, tumor characteristics, treatment modalities, and survival were recorded. Factors associated with survival were assessed using Cox Regression. RESULTS: Of the 1726 patients identified, 59% were male, 83% White race, 62% had a comorbidity index of zero, median age 64 years, median tumor size 2.7 cm, and median survival was 28.5 months (89 months for patients undergoing surgical resection). Cox Regression for all patients found adenoid cystic carcinoma (ACC) (p < 0.001), radiation (p < 0.001), and surgical resection (p < 0.001) to be associated with improved survival, while increasing age (p < 0.001) decreased survival. For patients receiving resection, ACC (p < 0.001) was associated with improved survival, while increasing age (p < 0.001) and positive margins (p = 0.002) were associated with worse survival. For R0 resections, ACC (p < 0.001) was associated with improved survival, while increasing age (p < 0.001) decreased survival, with chemotherapy and radiation having no impact. For R1/2 resections, ACC (p < 0.001) and radiation (p < 0.001) were associated with improved survival, while increasing age (p < 0.001) decreased survival, with chemotherapy having no impact on survival. CONCLUSIONS: Primary tracheal cancer is highly lethal, with surgical resection leading to the best chance of survival. For patients undergoing resection, radiation provided survival benefits for R1/2 but not R0, while chemotherapy did not impact survival regardless of margin status.

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Deep learning based automated delineation of the intraprostatic gross tumour volume in PSMA-PET for patients with primary prostate cancer.

PURPOSE: With the increased use of focal radiation dose escalation for primary prostate cancer (PCa), accurate delineation of gross tumor volume (GTV) in prostate-specific membrane antigen PET (PSMA-PET) becomes crucial. Manual approaches are time-consuming and observer dependent. The purpose of this study was to create a deep learning model for the accurate delineation of the intraprostatic GTV in PSMA-PET. METHODS: A 3D U-Net was trained on 128 different 18F-PSMA-1007 PET images from three different institutions. Testing was done on 52 patients including one independent internal cohort (Freiburg: n = 19) and three independent external cohorts (Dresden: n = 14 18F-PSMA-1007, Boston: Massachusetts General Hospital (MGH): n = 9 18F-DCFPyL-PSMA and Dana-Farber Cancer Institute (DFCI): n = 10 68Ga-PSMA-11). Expert contours were generated in consensus using a validated technique. CNN predictions were compared to expert contours using Dice similarity coefficient (DSC). Co-registered whole-mount histology was used for the internal testing cohort to assess sensitivity/specificity. RESULTS: Median DSCs were Freiburg: 0.82 (IQR: 0.73-0.88), Dresden: 0.71 (IQR: 0.53-0.75), MGH: 0.80 (IQR: 0.64-0.83) and DFCI: 0.80 (IQR: 0.67-0.84), respectively. Median sensitivity for CNN and expert contours were 0.88 (IQR: 0.68-0.97) and 0.85 (IQR: 0.75-0.88) (p = 0.40), respectively. GTV volumes did not differ significantly (p > 0.1 for all comparisons). Median specificity of 0.83 (IQR: 0.57-0.97) and 0.88 (IQR: 0.69-0.98) were observed for CNN and expert contours (p = 0.014), respectively. CNN prediction took 3.81 seconds on average per patient. CONCLUSION: The CNN was trained and tested on internal and external datasets as well as histopathology reference, achieving a fast GTV segmentation for three PSMA-PET tracers with high diagnostic accuracy comparable to manual experts.

Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin-Drug Conjugate Response.

PURPOSE: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies. EXPERIMENTAL DESIGN: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE). RESULTS: FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri. CONCLUSIONS: These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.

Surgeon Quality and Patient Survival After Resection for Non-Small-Cell Lung Cancer.

PURPOSE: The quality and outcomes of curative-intent lung cancer surgery vary in populations. Surgeons are key drivers of surgical quality. We examined the association between surgeon-level intermediate outcomes differences, patient survival differences, and potential mitigation by processes of care. PATIENTS AND METHODS: Using a baseline population-based surgical resection cohort, we derived surgeon-level cut points for rates of positive margins, nonexamination of lymph nodes, nonexamination of mediastinal lymph nodes, and wedge resections. Applying the baseline cut points to a subsequent cohort from the same population-based data set, we assign surgeons into three performance categories in reference to each metric: 1 (<25th percentile), 2 (25th-75th percentile), and 3 (>75th percentile). The sum of performance scores created three surgeon quality tiers: 1 (4-6, low), 2 (7-9, intermediate), and 3 (10-12, high). We used chi-squared, Wilcoxon-Mann-Whitney, and Kruskal-Wallis tests to compare patient characteristics between the baseline and subsequent cohorts and across surgeon tiers. We applied Cox proportional hazards models to examine the association between patient survival and surgeon performance tier, sequentially adjusting for clinical stage, patient characteristics, and four specific processes. RESULTS: From 2009 to 2021, 39 surgeons performed 4,082 resections across the baseline and subsequent cohorts. Among 31 subsequent cohort surgeons, five were tier 1, five were tier 2, and 21 were tier 3. Tier 1 and 2 surgeons had significantly worse outcomes than tier 3 surgeons (hazard ratio [HR], 1.37; 95% CI, 1.10 to 1.72 and 1.19; 95% CI, 1.00 to 1.43, respectively). Adjustment for specific processes mitigated the surgeon-tiered survival differences, with adjusted HRs of 1.02 (95% CI, 0.8 to 1.3) and 0.93 (95% CI, 0.7 to 1.25), respectively. CONCLUSION: Readily accessible intermediate outcomes metrics can be used to stratify surgeon performance for targeted process improvement, potentially reducing patient survival disparities.

NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 2.2023.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

COVID-19: Findings in nuclear medicine from head to toe.

COVID-19 is a multisystemic disease, and hence its potential manifestations on nuclear medicine imaging can extend beyond the lung. Therefore, it is important for the nuclear medicine physician to recognize these manifestations in the clinic. While FDG-PET/CT is not indicated routinely in COVID-19 evaluation, its unique capability to provide a functional and anatomical assessment of the entire body means that it can be a powerful tool to monitor acute, subacute, and long-term effects of COVID-19. Single-photon scintigraphy is routinely used to assess conditions such as pulmonary embolism, cardiac ischemia, and thyroiditis, and COVID-19 may present in these studies. The most common nuclear imaging finding of COVID-19 vaccination to date is hypermetabolic axillary lymphadenopathy. This may pose important diagnostic and management dilemmas in oncologic patients, particularly those with malignancies where the axilla constitutes a lymphatic drainage area. This article aims to summarize the relevant literature published since the beginning of the pandemic on the intersection between COVID-19 and nuclear medicine.

Neurolymphomatosis in Recrudescent Diffuse Large B-cell Lymphoma.

Neurolymphomatosis is an uncommon manifestation of lymphoma, often presenting with painful polyneuropathy or polyradiculopathy and concomitant distal extremity weakness. Differentiation from other etiologies resulting in similar neuropathic symptoms such as compressive or inflammatory pathologies can be difficult and often results in delayed diagnosis. Here we describe a case of neurolymphomatosis affecting a 64-year-old man with a history of diffuse large B-cell lymphoma (DLBCL) in remission presenting with a right-sided foot drop following a gunshot wound. MRI at that time demonstrated thickening and enhancement of the cauda equina nerve roots. Over the course of the subsequent eight months, he developed left lower extremity sensory symptoms, left-sided foot drop and signs of upper motor neuron involvement, including left facial weakness, dysphonia, and dysphagia. 18F-FDG PET/CT revealed intensely avid left lumbosacral nerve roots, bilateral lower extremity and left upper extremity neurovascular bundles. Left sural nerve biopsies showed infiltration of DLBCL and confirmed neurolymphomatosis. We highlight the role of 18F-FDG PET/CT, with histological verification, for the diagnosis of an extended course of neurolymphomatosis occurring in the absence of typical painful neuropathy but with cranial and peripheral neuropathies.

Key Factors to Attract More U.S. Diagnostic Radiology Residents into the Field of Nuclear Medicine and Molecular Imaging: A National Survey.

RATIONALE AND OBJECTIVES: To understand the current state of radiology residents' exposure to nuclear medicine and molecular imaging (NM/MI), determine key factors that may attract more trainees into the field, and identify differentiating aspects between those specializing in NM/MI and those who are not. MATERIALS AND METHODS: An anonymous web-based survey was sent to contacts at all diagnostic radiology residency programs in the United States for dissemination to their residents, collecting information about trainees' NM/MI exposure during residency and factors that may attract them to NM/MI. RESULTS: A total of 198 trainees responded to the survey, 34 of whom plan on pursuing a career in NM/MI. Most trainees reported early exposure to NM/MI during residency; most (97.4%) reported ample exposure to general NM/MI and oncologic studies. Less than 3% of trainees reported adequate exposure to therapies, neurological applications, molecular imaging/research advances, and physics. Respondents reported a need for better quality education (38.9%) and exposure to mentors (28.8%) as ways to attract trainees to NM/MI. Routinely encountered clinical pathology was the most interesting for those specializing in NM/MI (29.4%), whereas lifestyle was the most attractive aspect of NM/MI for those not pursuing a career in the field (27.4%). NM/MI-associated research was the least attractive for those specializing in NM/MI (35.3%), while job market concerns was the least attractive aspect for those not specializing in NM/MI (37.2%). Trainees planning to specialize in NM/MI reported higher satisfaction with their orientation to NM/MI during their first clinical rotation compared to those who do not plan to specialize in the field (3.03/5.00 and 2.67/5.00, respectively, p = 0.04). CONCLUSION: This survey highlights several factors that training programs and national societies can target to improve interest in NM/MI among radiology residents. We found that optimized education initiatives, including improved orientation to the field, increased mentoring, and career opportunities are essential levers for recruiting radiology trainees into the NM/MI workforce.

Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

Probing immune infiltration dynamics in cancer by in vivo imaging.

Cancer immunotherapies typically aim to stimulate the accumulation and activity of cytotoxic T-cells or pro-inflammatory antigen-presenting cells, reduce immunosuppressive myeloid cells or regulatory T-cells, or elicit some combination of effects thereof. Notwithstanding the encouraging results, immunotherapies such as PD-1/PD-L1-targeted immune checkpoint blockade act heterogeneously across individual patients. It remains challenging to predict and monitor individual responses, especially across multiple sites of metastasis or sites of potential toxicity. To address this need, in vivo imaging of both adaptive and innate immune cell populations has emerged as a tool to quantify spatial leukocyte accumulation in tumors non-invasively. Here we review recent progress in the translational development of probes for in vivo leukocyte imaging, focusing on complementary perspectives provided by imaging of T-cells, phagocytic macrophages, and their responses to therapy.

Confocal Imaging of Single-Cell Signaling in Orthotopic Models of Ovarian Cancer.

Ovarian cancer (OVCA) is frequently detected at late stages of disease, often with dissemination throughout the peritoneal cavity surface, abdomen, and ascites fluid. Tumor signaling via mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways can promote OVCA progression and depend on local microenvironmental cues. To better study OVCA in situ within native tissue contexts, here we describe confocal microscopy techniques to image mouse models of intraperitoneal disease at a single-cell resolution. As a proof of principle demonstration, examples are highlighted for simultaneously imaging tumor vascularization, infiltrating and often immunosuppressive immune cells (tumor-associated macrophages), and OVCA kinase activity.