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Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody–drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.Cancer cells, like non-malignant cells, are dependent on folate uptake for growth. However, cancer cells are much more reliant on folate receptors (FRs) and particularly FRα for folate uptake than non-malignant cells. In this Review, the authors describe the available data on the role of FRα as a biomarker and as a target of imaging probes, and of targeted therapies in patients with solid tumours.

Abstract Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors [MPNST]). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.

Medical image classification requires labeled, task-specific datasets which are used to train deep learning networks de novo, or to fine-tune foundation models. However, this process is computationally and technically demanding. In language processing, in-context learning provides an alternative, where models learn from within prompts, bypassing the need for parameter updates. Yet, in-context learning remains underexplored in medical image analysis. Here, we systematically evaluate the model Generative Pretrained Transformer 4 with Vision capabilities (GPT-4V) on cancer image processing with in-context learning on three cancer histopathology tasks of high importance: Classification of tissue subtypes in colorectal cancer, colon polyp subtyping and breast tumor detection in lymph node sections. Our results show that in-context learning is sufficient to match or even outperform specialized neural networks trained for particular tasks, while only requiring a minimal number of samples. In summary, this study demonstrates that large vision language models trained on non-domain specific data can be applied out-of-the box to solve medical image-processing tasks in histopathology. This democratizes access of generalist AI models to medical experts without technical background especially for areas where annotated data is scarce. Medical image classification remains a challenging process in deep learning. Here, the authors evaluate a large vision language foundation model (GPT-4V) with in-context learning for cancer image processing and show that such models can learn from examples and reach performance similar to specialized neural networks while reducing the gap to current state-of-the art pathology foundation models.

Histopathological images are a rich but incompletely explored data type for studying cancer. Manual inspection is time consuming, making it challenging to use for image data mining. Here we show that convolutional neural networks (CNNs) can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors. We develop CNN architectures to analyze 27,815 hematoxylin and eosin scanned images from The Cancer Genome Atlas for tumor/normal, cancer subtype, and mutation classification. Our CNNs are able to classify TCGA pathologist-annotated tumor/normal status of whole slide images (WSIs) in 19 cancer types with consistently high AUCs (0.995 ± 0.008), as well as subtypes with lower but significant accuracy (AUC 0.87 ± 0.1). Remarkably, tumor/normal CNNs trained on one tissue are effective in others (AUC 0.88 ± 0.11), with classifier relationships also recapitulating known adenocarcinoma, carcinoma, and developmental biology. Moreover, classifier comparisons reveal intra-slide spatial similarities, with an average tile-level correlation of 0.45 ± 0.16 between classifier pairs. Breast cancers, bladder cancers, and uterine cancers have spatial patterns that are particularly easy to detect, suggesting these cancers can be canonical types for image analysis. Patterns for TP53 mutations can also be detected, with WSI self- and cross-tissue AUCs ranging from 0.65-0.80. Finally, we comparatively evaluate CNNs on 170 breast and colon cancer images with pathologist-annotated nuclei, finding that both cellular and intercellular regions contribute to CNN accuracy. These results demonstrate the power of CNNs not only for histopathological classification, but also for cross-comparisons to reveal conserved spatial behaviors across tumors. Histopathological images are a rich but incompletely explored data type for studying cancer. Here the authors show that convolutional neural networks can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors.

Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.

ObjectiveTo evaluate the impact of PET/CT on clinical management in patients with cancer of unknown primary (CUP).MethodsA cohort of patients with CUP undergoing PET/CT was prospectively enrolled in a local PET/CT registry study between April 2013 and June 2018. Questionnaire data from referring physicians on intended patient management prior and after PET/CT were recorded including items on the intended treatment concept and intended additional diagnostics. Changes in management after PET/CT were recorded. Patient outcome of different cohorts was analyzed for overall survival drawn from patient records.ResultsOne hundred fifty-five patients (53 female; 63.4 ± 12.1 years) were included. Intended therapeutic management was revised in 45.8% of patients after PET/CT, including major changes affecting the intended treatment goal in 26.5% of patients and minor changes (therapy adjustments) in 19.3% of patients. Invasive and additional diagnostic procedures were intended in 25.8% and 63.2% prior PET/CT and 13.5% and 6.5% after PET/CT. PET/CT-based curative therapy concepts were associated with significantly longer patient survival (4.7 ± 0.3 years) than palliative therapy concepts (1.8 ± 0.5 years, p = .0001). Patients with cervical CUP showed a significantly longer survival (4.3 ± 0.3 years) than patients with extracervical CUP (3.5 ± 0.5 years, p = .01). The identification of the primary did not significantly affect survival.ConclusionThis registry study confirms previous studies reporting that PET/CT significantly influences clinical management in patients with CUP, helping physicians to select a more individualized treatment and to avoid additional diagnostics. Furthermore, we could confirm that tumor localization and extent as shown by PET/CT have a significant impact on patient prognosis.Key Points• PET/CT significantly influences intended clinical management in patients with CUP, helping physicians to select a more individualized treatment and to avoid additional diagnostics.• Tumor localization and extent as shown by PET/CT have a significant impact on patient prognosis.• The identification of the primary tumor has no significant impact on overall patient survival.

SignificanceCancers, fibroses, and inflammatory disorders are characterized by increased deposition of the extracellular matrix (ECM). ECM biomarkers that are selectively expressed at these disease sites are attractive targets for imaging and therapeutic approaches. Nanobodies against these biomarkers would be pertinent vehicles for the accumulation of imaging and therapeutic cargo at disease sites, potentially increasing specificity and reducing background. We demonstrate the specificity of one such anti-ECM nanobody by using immuno-PET/CT and show that it detects multiple models of cancer, including early lesions and metastases, and also fibroses, with excellent specificity and clarity. Thus, novel strategies for delivering imaging and therapeutic probes specifically to the ECM in disease sites may prove particularly valuable for detection and treatment of cancer in patients. Extracellular matrix (ECM) deposition is a hallmark of many diseases, including cancer and fibroses. To exploit the ECM as an imaging and therapeutic target, we developed alpaca-derived libraries of “nanobodies” against disease-associated ECM proteins. We describe here one such nanobody, NJB2, specific for an alternatively spliced domain of fibronectin expressed in disease ECM and neovasculature. We showed by noninvasive in vivo immuno-PET/CT imaging that NJB2 detects primary tumors and metastatic sites with excellent specificity in multiple models of breast cancer, including human and mouse triple-negative breast cancer, and in melanoma. We also imaged mice with pancreatic ductal adenocarcinoma (PDAC) in which NJB2 was able to detect not only PDAC tumors but also early pancreatic lesions called pancreatic intraepithelial neoplasias, which are challenging to detect by any current imaging modalities, with excellent clarity and signal-to-noise ratios that outperformed conventional 2-fluorodeoxyglucose PET/CT imaging. NJB2 also detected pulmonary fibrosis in a bleomycin-induced fibrosis model. We propose NJB2 and similar anti-ECM nanobodies as powerful tools for noninvasive detection of tumors, metastatic lesions, and fibroses. Furthermore, the selective recognition of disease tissues makes NJB2 a promising candidate for nanobody-based therapeutic applications.

Ectopic adrenocorticotropic hormone (ACTH) secretion is a less common cause of Cushing syndrome and is seen in 5 to 10% of cases with endogenous hypercortisolemia. We hereby describe our experience of patients with ectopic ACTH syndrome, who have been managed over the past 10 years at a tertiary care center in Southern India. The inpatient and outpatient records of patients from 2006 to 2015 were retrospectively reviewed. The clinical features, clinical history, biochemical values, imaging features, including radiologic findings and positron emission tomography scans, management, details of follow-up, and outcomes, were documented. We compared the biochemical findings in these patients with 20 consecutive patients with Cushing disease (Cushing syndrome of pituitary origin). A total of 21 patients were studied. The median age at presentation was 34 years (range, 19 to 55 years). Seven patients had thymic carcinoid, 7 had bronchial carcinoid, 3 had lung malignancies, 2 had medullary carcinoma thyroid, 1 patient had a pancreatic neuroendocrine tumor, and 1 patient had an occult source of ACTH. The most common clinical features at presentation were muscle weakness (95%), hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%), and striae (52%). Extensive acne was seen in a large number of patients (43%). Only 3 patients (14%) had central obesity. The median 8 am cortisol was 55.5 μg/dL (range, 3.8 to 131 μg/dL), median 8 am ACTH was 207 pg/mL (range, 31.1 to 703 pg/mL), and the median 24-hour urinary free cortisol was 2,484 μg (range, 248 to 25,438 μg). Basal cortisol and ACTH, as well as midnight cortisol and ACTH level, were markedly higher in patients with ectopic Cushing syndrome as compared to patients with Cushing disease. Twelve of 21 patients had developed life-threatening infections by follow-up. Nine patients had undergone surgical intervention to address the primary tumor. However, only 1 patient exhibited a complete cure on follow-up. In our series, ectopic Cushing syndrome was most commonly seen in association with intrathoracic tumors such as bronchial or thymic carcinoid. Hyperpigmentation and proximal myopathy were frequent, while central obesity was uncommon. Early and rapid control of hypercortisolemia was important in order to prevent life-threatening infections and metabolic complications. ACTH = adrenocorticotropic hormone CT = computed tomography DOTATATE = Ga-DOTA-Tyr -octreotate ECS = ectopic Cushing syndrome FDG = fluorodeoxyglucose MTC = medullary thyroid cancer NET = neuroendocrine tumor PET = positron emission tomography.

This study aimed to determine the sonographic features suggestive of extrathyroidal extension (ETE) of thyroid cancers. We retrospectively reviewed the sonographic images of 1656 consecutive patients who had undergone thyroidectomy in 2017. The diagnostic performance of sonographic features suggestive of ETE was evaluated using operation and histopathologic reports. Sonographic features for gross ETE to the strap muscle and minor ETE were assessed for thyroid cancer abutting the anterolateral thyroid capsule. Sonographic features for tracheal invasion were assessed according to whether the angle between the tumor and the trachea was an acute, right, or obtuse angle. Sonographic features for recurrent laryngeal nerve (RLN) invasion were assessed based on the association between the tumor and tracheoesophageal groove (TEG) as preserved normal tissue, abutting or protruding into the TEG. ETE was observed in 783 patients (47.3%), including 123 patients with gross ETE (7.4% [strap muscle, n = 97; RLN, n = 24; and trachea, n = 14]) and 660 patients with minor ETE (39.9%). Regarding the diagnosis of gross and minor ETE to the strap muscle, sonographic features of replacement of the strap muscle and capsular disruption showed the highest positive predictive value (75.9% and 58.5%, respectively). Thyroid cancer forming an obtuse angle with the trachea had the highest sensitivity for the diagnosis of tracheal invasion (85.7%), and thyroid cancer protrusion into the TEG showed the highest sensitivity for the diagnosis of RLN (83.3%). Sonography is considered beneficial in the diagnosis of ETE to the strap muscle, trachea, and RLN. Assessment of ETE is important for the accurate staging of thyroid cancer, which in turn determines the extent of surgery or whether active surveillance is appropriate or not.