Small Cell Lung Cancer (SCLC)

Briefly, during a one to two hour visit, subjects will provide written informed consent and then undergo: 1. brief medical history and vital signs, 2. full pulmonary function tests, 3. proton MRI, 4. spin-density, diffusion weighted, and/or dissolved phase 129-Xe MRI, 5. Low-dose thoracic CT Full pulmonary function tests including spirometry, plethysmography and diffusing capacity of carbon monoxide (DLCO), Multiple Breath Nitrogen Washout (MBNW) to measure Lung Clearance Index (LCI), and Forced Oscillation Technique (FOT) will be performed according to American Thoracic Society (ATS) guidelines. MedGraphics Elite Series, MedGraphics Corporation. St. Paul, Minnesota USA and/or nDD EasyOne Spirometer, nDD Medical Technologies Inc. Andover, Massachusetts USA will be used. All measurements will be performed in the Pulmonary Function Laboratory at Robarts Research Institute. Subjects will be placed in the 3T Magnetic Resonance (MR) scanner with one of three 129-Xe chest coils fitted over their torso and chest. Hearing protection will be provided to each subject to muffle the noise produced by the gradient radiofrequency (RF) coils. A pulse oximeter lead will be attached to all of the subjects to monitor their heart rate and oxygen saturation. MRI will be performed for up to a period of 30 minutes. All subjects will have supplemental oxygen available via nasal cannula at a flow-rate of 2 liters per minute as a precaution in the event of oxygen desaturation. Thoracic low dose CT will be performed with the same inhalation breath-hold volume and maneuver (nitrogen gas only) used for MRI to obtain participant-specific high resolution images of lung anatomy (tissue structure and airway morphology).

Evaluate the safety of the novel FAP targeted molecular probe 18F-FAPI-YQ104 labeled with radioactive isotopes in clinical applications and verify its effectiveness in tumor diagnosis.

The main technical difficulties in radioactive iodine-125 seed implantation (RISI) lie in the complexity of operation and the control of operation quality. The current data shows that under the combined guidance of 3D-printing template and CT, the accuracy of RISI has been significantly improved, and the actual target dose could meet the design requirements of preoperative plan. At present, 3D printing templates (3DPT) are divided into non-coplanar templates (3DPNCT) and coplanar templates (3DPCT). In clinical practice, due to the complex technical requirements, high production cost and long printing time of 3DPNCT, a considerable number of patients can also complete the treatment with 3DPCT. Moreover, compared with 3DPNCT, 3DPCT has the advantages of accurate needle path control, fast needle path adjustment, convenient for intraoperative real-time optimization, without waiting for printing time, easy for doctors to master, lower cost than 3DPNCT, and easy to carry out at the grass-roots level. Therefore, this study intends to explore 3DPCT technology to further clarify: (1) the accuracy of 3DPCT assisted CT guided RISI in the treatment of thoracic malignant tumors; (2) the short-term efficacy and toxicity of 3DPCT assisted CT guided RISI in the treatment of thoracic malignant tumors.

Radiotherapy for cancer has been a forerunner of personalized medicine, developing individualized treatments based on patient-specific anatomical information. Despite many advances in radiotherapy over the past decade, which have effectively enhanced local or loco-regional tumor control for many patients, there remains substantial room for improvement. The challenges for radiotherapy to further widen the therapeutic window in the era of precision medicine are mainly two-fold: (a) further improve radiation dose conformity to the defined target volume, and (b) adapt novel biological strategies for personalized treatment. Four-dimensional (4D) imaging and deformable image registration (DIR) are key tools in modern radiotherapy, playing critical roles in many recent advances, including 4D radiotherapy, adaptive radiotherapy, and treatment assessment. However, current 4D imaging and DIR technologies are facing significant challenges as the requirement for precision increases. The current standard of 4D imaging in radiotherapy is 4D-CT. However, it has two major limitations preventing it from precision radiotherapy applications: (a) low soft-tissue contrast. 4D-CT is therefore not ideal for abdominal applications; (b) motion artifacts caused by irregular breathing. 4D-CT motion artifacts have been shown to cause errors in various radiotherapy applications, including motion measurement, target volume delineation, dose calculation, DIR, and lung ventilation calculation. 4D-MRI is an emerging 4D imaging technology for radiotherapy. It has superior soft-tissue contrast to 4D-CT and is therefore superb for abdominal imaging. Despite many recent advances in 4D-MRI, current 4D-MRI implementations have inadequate image quality for precision radiotherapy application due to at least one of the following deficiencies: low temporal and/or spatial resolutions, long image acquisition time, and suboptimal contrast in the lungs. Resulting 4D-MRI images lack sufficient anatomical details for clinical applications, which can adversely affect the performance of DIR. Current DIR techniques focus on morphological similarity but not on the physiological plausibility of the deformation. Studies have shown that an increased morphological similarity of the aligned data does not always imply increased registration accuracy. Therefore, more sophisticated approaches are desirable. The investigators will take a systematic approach to address the aforementioned limitations of 4D imaging and deformable image registration (DIR) based on the development and cross-fertilization of two major techniques: ultra-quality 4D-MRI and physiological-based hybrid DIR. There are two parts of this research, comprising three main objectives: Part 1. Technical development in healthy subjects: The investigators will extend their existing pulse sequence strategy for ultra-quality 3D MRI to enable ultra-quality 4D-MRI. Compared to 4D-CT and current 4D-MRI techniques, the proposed ultra-quality 4D-MRI technique offers the following advantages: (a) high spatial resolution (1.5 mm isotropic) with rich image features (e.g. vessel trees) in the whole torso; (b) high temporal pseudo-resolution (\>20 phases/cycle); and (c) (nearly) free of motion artifacts. • Objective 1: Develop an MRI pulse sequence and image reconstruction pipeline that generates images meeting these three design goals. Part 2. Evaluation of 4D-MRI in a patient study: 4D-MRI will be compared with existing DIR and 4D-CT methods. There will be two classes of comparisons, each formulated as a separate objective: * Objective 2: Compare motion modelling based on 4D-MRI with deformable image registration (DIR) in healthy volunteers and cancer patients. An improved motion modeling method will be developed that is tailored for the ultra-quality 4D-MRI applications. The investigators hypothesize that a new motion modeling method based on 4D-MRI will outperform current DIR algorithms for respiratory motion estimation. This hypothesis will be tested by comparing the new method to five DIR algorithms which include a mix of commercial software and publicly available algorithms. * Objective 3: Compare 4D-MRI with 4D-CT in lung and liver cancer patients. The overall hypothesis of this objective is that the ultra-quality 4D-MRI provides better image quality than 4D-CT for motion management of radiotherapy in the lungs and the liver, especially in patients with irregular breathing.

Conventional 18F-FDG PET/CT has important diagnostic value in cell metabolism level, early metastasis, judging malignant potential and prognosis of tumors. It has been routinely used for staging and restaging of most tumors, but there are still some tumors with low uptake of 18F-FDG PET/CT. Moreover, 18F-FDG cannot distinguish between tumors and inflammatory diseases, such as tuberculosis and granuloma. Receptor imaging with a single target also has some limitations in clinical application. For example, not all diseased cells express a large amount of single receptor on the surface, which greatly affects the judgment of the nature of the lesion. The dual-target molecular imaging based on FAP expressed in the lesion site and integrin αvβ3 receptor highly expressed on the surface of the lesion neovascularization will overcome the above limitations and make full use of the advantages of the dual-target molecular imaging, which will greatly assist the diagnosis of malignant tumors such as lung cancer. In this study, a novel dual-target imaging agent 68Ga-FAPI-RGD was used for PET/CT imaging of lung cancer, compared with conventional 18F-FDG, or single target imaging agent 68Ga-RGD or 68Ga-FAPI PET/CT imaging.

Currently, there are limited methods available in clinical practice to distinguish pseudoprogression after immunotherapy. Most patients rely on follow-up observations to monitor the disease, which does not meet clinical needs. 68Ga-grazytracer is a novel imaging agent targeting granzyme B. By detecting the concentration of granzyme B, it reflects the localization of cytotoxic T cells in the tumor region and their potential ability to kill tumor cells. This study aims to leverage the simplicity, non-invasiveness, visualization, and semi-quantitative advantages of 68Ga-grazytracer PET imaging to evaluate its effectiveness and feasibility in diagnosing pseudoprogression.

Small cell lung cancer (SCLC) constitutes approximately 15% of all lung cancers and is characterized by its aggressive biology, rapid growth, and early, widespread metastasis. It is highly lethal, with a 5-year survival rate of less than 7% for patients with extensive-stage disease. The current standard of care relies on the clinical staging of patients as either limited-stage (LS-SCLC) or extensive-stage (ES-SCLC), which fundamentally dictates therapeutic strategies. LS-SCLC, where disease is confined to a single radiation port, is potentially curable with concurrent chemoradiotherapy. Conversely, ES-SCLC, with metastases beyond a single radiation field, is treated primarily with systemic chemotherapy. Accurate staging is therefore critical for optimal patient management. \[18F\]-FDG PET/CT is a cornerstone for staging SCLC due to its high sensitivity in detecting metabolically active tumor sites, including occult metastases. This capability has significantly improved the accuracy of distinguishing LS-SCLC from ES-SCLC, thereby guiding appropriate use of definitive radiotherapy. However, the clinical utility of \[18F\]-FDG-PET/CT is hampered by its suboptimal specificity. FDG avidity is common in inflammatory processes and other malignancies, leading to false-positive interpretations, particularly in lymph nodes. This limitation can result in overstaging, causing a subset of patients with truly limited-stage disease to be incorrectly classified as extensive-stage. Consequently, these patients may be denied potentially curative radiotherapy and receive only palliative chemotherapy, representing a significant missed therapeutic opportunity. There is a clear unmet need for a more specific imaging agent for SCLC. Delta-like ligand 3 (DLL3) is a cell-surface protein that is rarely expressed in healthy adult tissues but is overexpressed in over 80% of SCLC cases, as well as in other high-grade neuroendocrine tumors (e.g., neuroendocrine prostate cancer, neuroendocrine tumors of the gastrointestinal tract). Its highly restricted expression profile makes DLL3 an exceptionally promising target for both diagnosis and therapy. Several DLL3-targeted therapeutic agents, such as antibody-drug conjugates (e.g., rovalpituzumab tesirine) and bispecific T-cell engagers, are in development or clinical trials. Therefore, an imaging probe for detecting DLL3 expression could not only aid in diagnosis and staging but also serve as a biomarker to select patients most likely to benefit from these targeted therapies-a concept known as patient stratification for theranostics. To translate this target into imaging, the probe must have favorable pharmacokinetics. Nanobodies, derived from camelid single-domain antibodies, are approximately 15 kDa in size, significantly smaller than conventional monoclonal antibodies (\~150 kDa). This small size confers several advantages for imaging: superior tissue penetration, rapid clearance from the bloodstream, and reduced immunogenicity. PFD3 is a novel probe constructed by conjugating a DLL3-specific nanobody with a chelator for 68Ga radiolabeling. This design offers dual advantages: first, the high affinity and specificity of the nanobody for DLL3 ensure targeted accumulation in tumors, minimizing off-target binding. Second, the nanobody's pharmacokinetics result in a shorter in vivo residence time compared to monoclonal antibody-based probes, enabling same-day imaging protocols with enhanced patient convenience and potentially improved safety profiles due to more predictable radiopharmaceutical retention. Furthermore, the growing pipeline of DLL3-directed therapeutics makes the development of an accompanying diagnostic tool like PFD3 clinically relevant for both patient selection and treatment monitoring. Given this background, this study aims to evaluate the safety and imaging performance of \[68Ga\]Ga-PFD3 PET/CT in human subjects with SCLC. Furthermore, a head-to-head comparison between \[68Ga\]Ga-PFD3 PET/CT and the widely used \[18F\]-FDG PET/CT will be conducted to determine the relative diagnostic performance of this novel, target-specific tracer.

This study is looking at patients diagnosed with small-cell lung cancer \& have declined prophylactic cranial irradiation. Patients must have had a 1.5t/3t MRI performed within 4 weeks of consenting to the trial that was negative for brain metastases. Patients will then undergo a 7t MRI \& be followed for their standard of care scans for 12 months or until confirmed metastases are detected. Once a patient has confirmed brain mets, their standard of care scans will be used for an analysis compared to the 7t scan to determine if earlier detection of brain micro metastases are feasible.

At present, radiopharmaceuticals targeting FAP have been developed for the diagnosis and treatment of various tumors. Considering the problems of fast tumor tissue clearance and short retention time in small molecule FAP inhibitors based on quinoline rings, this project optimized their ligands and developed a new FAP targeted technetium labeled molecular imaging probe for SPECT/CT imaging research to evaluate its safety in clinical application and its effectiveness in tumor diagnosis.

Background: * Somatostatin receptors (SSTR) have been shown to be over-expressed in a number of human tumors, including gastrointestinal (GI) neuroendocrine tumors (NET), pheochromocytoma/paragangliomas (PPGL), small cell lung cancers (SCLC), kidney cancers (KC), and some head and neck (H\&N) cancers. * Targeted radioligand therapy (TRT) is a class of cancer therapeutic agents formed by attaching a radioactive isotope to a ligand that can target specific surface receptors such as SSTR on a tumor cell membrane. Efficacy is typically determined by the radiation dose deposited onto a tumor, which is determined by the radioactive isotope being used as well as the binding characteristics of the ligand-receptor/transporter pair. * Alpha emitters such as 212Pb emit alpha particles that are more damaging to tumor cells than beta emitters such as 177Lu. Therefore, TRT agents using alpha emitters are considered to be more potent than beta-emitting TRTs. * VMT-Alpha-NET is a peptide that binds to SSTR, which when attached to 212Pb becomes an alpha particle-emitting TRT that can be used to treat tumors that have SSTR surface expression. * \[203Pb\]VMT-Alpha-NET is the chemically identical imaging surrogate for \[212Pb\]VMT-Alpha-NET and has the same mechanism of action via binding to SSTR2. The nuclide 203Pb contained in \[203Pb\]VMT-Alpha-NET emits gamma radiation suitable for single-photon emission computerized tomography (SPECT) imaging. These images can be used to assess drug product biodistribution throughout the body. Objective: -To determine the maximum tolerated dose (MTD) of \[212Pb\]VMT-Alpha-NET (dose escalation cohort) and assess the safety of \[212Pb\]VMT-Alpha-NET at the MTD (dose expansions cohorts). Eligibility: * Age \>= 18 years. * Histopathologically confirmed GI NET, PPGL, SCLC, KC, or H\&N (nasopharyngeal carcinoma \[NPC\], olfactory neuroblastoma \[ONB\], sinonasal neuroendocrine carcinoma \[SNEC\]) cancers that are metastatic or inoperable. * No prior systemic radioligand therapy. * Eastern Cooperative Oncology Group (ECOG) Performance Status \<= 1. Design: * This is an open-label, single-arm, single-center, phase I study evaluating the safety, preliminary efficacy, and pharmacokinetic properties of \[212Pb\]VMT-Alpha-NET in GI NET, PPGL, SCLC, KC, or H\&N cancers. * First, participants will be accrued in Dose Escalation Part with 4 dose levels to estimate MTD of \[212Pb\]VMT-Alpha-NET. Once MTD is estimated, the following participants with GI NET, PPGL, SCLC, KC, or H\&N cancers will be accrued in separate cohorts and treated at MTD of \[212Pb\]VMT-Alpha-NET. * \[212Pb\]VMT-Alpha-NET will be given IV every 8 weeks for a total of 4 administrations. * A subset of participants (Dosimetry Arm 1) will have \[203Pb\]VMT-Alpha-NET administration followed by whole-body gamma scans combined with dosimetry SPECT/ Computed Tomography (CT) scans and collection of blood and urine samples prior to each cycle. * Participants will have timed clinical laboratory evaluations, imaging studies, and research blood, and urine samples while on the study therapy for safety and efficacy evaluations. * Following completion of treatment, participants will be seen at the NIH Clinical Center approximately 30 days later, every 12 weeks for 3 years after that for safety and efficacy assessments. Beyond 3 years, participants will be contacted annually through any NIH-approved platform to assess for overall survival and health status.