18F-FDG Dedicated Breast PET Complementary to Breast MRI for Evaluating Early Response to Neoadjuvant Chemotherapy.

Purpose To compare quantitative measures of tumor metabolism and perfusion using fluorine 18 (18F) fluorodeoxyglucose (FDG) dedicated breast PET (dbPET) and breast dynamic contrast-enhanced (DCE) MRI during early treatment with neoadjuvant chemotherapy (NAC). Materials and Methods Prospectively collected DCE MRI and 18F-FDG dbPET examinations were analyzed at baseline (T0) and after 3 weeks (T1) of NAC in 20 participants with 22 invasive breast cancers. FDG dbPET-derived standardized uptake value (SUV), metabolic tumor volume, and total lesion glycolysis (TLG) and MRI-derived percent enhancement (PE), signal enhancement ratio (SER), and functional tumor volume (FTV) were calculated at both time points. Differences between FDG dbPET and MRI parameters were evaluated after stratifying by receptor status, Ki-67 index, and residual cancer burden. Parameters were compared using Wilcoxon signed rank and Mann-Whitney U tests. Results High Ki-67 tumors had higher baseline SUVmean (difference, 5.1; P = .01) and SUVpeak (difference, 5.5; P = .04). At T1, decreases were observed in FDG dbPET measures (pseudo-median difference T0 minus T1 value [95% CI]) of SUVmax (-6.2 [-10.2, -2.6]; P < .001), SUVmean (-2.6 [-4.9, -1.3]; P < .001), SUVpeak (-4.2 [-6.9, -2.3]; P < .001), and TLG (-29.1 mL3 [-71.4, -6.8]; P = .005) and MRI measures of SERpeak (-1.0 [-1.3, -0.2]; P = .02) and FTV (-11.6 mL3 [-22.2, -1.7]; P = .009). Relative to nonresponsive tumors, responsive tumors showed a difference (95% CI) in percent change in SUVmax of -34.3% (-55.9%, 1.5%; P = .06) and in PEpeak of -42.4% (95% CI: -110.5%, 8.5%; P = .08). Conclusion 18F-FDG dbPET was sensitive to early changes during NAC and provided complementary information to DCE MRI that may be useful for treatment response evaluation. Keywords: Breast, PET, Dynamic Contrast-enhanced MRI Clinical trial registration no. NCT01042379 Supplemental material is available for this article. © RSNA, 2024.

Laron Syndrome: A Tale of Two Siblings.

Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH receptor or in the post-receptor signaling pathway. This disorder is characterized by postnatal growth failure resembling GH deficiency. Differentiating the two conditions is necessary. We present the cases of two siblings, a 16-year-old female and a 9-year-old male, born from a consanguineous union. Both had normal birth weights with subsequent severe short stature and delayed teeth eruption, with no features suggestive of any systemic illness. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) were both low. Suspecting GH deficiency, provocative testing with clonidine was done revealing peak growth hormone >40 ng/mL in both patients. In view of low IGF1 and IGFBP3 and high GH on stimulation, IGF1 generation test was done for both siblings, with values supporting the diagnosis of GH insensitivity or Laron syndrome.

Traumatic Encephalocele in a 16-Year-Old Male: A Rare Phenomenon.

The term "encephalocele" refers to the herniation of brain tissue caused by a cranial bone defect. It could be congenital, traumatic, neoplastic, or arise spontaneously. The possibility of traumatic fronto-ethmoidal encephalocele should be considered in patients who have experienced trauma. We report a case of a 16-year-old male with a recent history of a bike accident presented with sudden unilateral rhinorrhea. Non-contrast computed tomography (NCCT) brain was done, which showed findings of left fronto-ethmoidal encephalocele. The patient was managed with single-staged surgery without any complications.

Swyer Syndrome Presenting as Dysgerminoma: A Case Report.

Complete gonadal dysgenesis with 46,XY karyotype is a clinical condition characterized by the absence of testicular tissue but with the presence of typical Müllerian structures in a phenotypically female individual. The condition presents as primary amenorrhoea or delayed puberty. Eventually, malignant neoplasms may arise. We report a case of a 16-year-old Indian male with Swyer syndrome presenting with primary amenorrhoea and with an earlier diagnosis of a malignant dysgerminoma in the right ovary.

A Case of Elephantiasic Pretibial Myxedema Successfully Treated With Intralesional Triamcinolone Acetate.

Graves' dermopathy is one of the extra-thyroidal manifestations of Graves' disease (GD) and is characterized by the accumulation of glycosaminoglycans in the reticular dermis. In the majority of cases, pretibial myxedema is self-limiting but, in some cases, it can lead to structural and functional damage. Topical steroids with occlusive dressing remain the conventional treatment, but intralesional steroids have shown promising results. We hereby present a case of pretibial myxedema treated successfully with intralesional triamcinolone acetate.

Myriad Manifestations of 3-Beta-Hydroxysteroid Dehydrogenase 2 Deficiency-A Tale of Two Infants.

3-Beta-hydroxysteroid dehydrogenase type 2 (3ß-HSD2) deficiency is a rare variety of congenital adrenal hyperplasia. Based on the severity of the enzymatic defect, it can present with a salt-wasting crisis in both sexes to undervirilization in males and virilization in females. We report two cases of infants with extremes of presentation of this congenital adrenal hyperplasia. First was a 28-day-old child presenting with a salt-wasting crisis while the other was a one-month-old child presenting with ambiguous genitalia. Clinical exome sequencing of the first child confirmed the diagnosis and we report a novel mutation of this gene, while the second child was diagnosed biochemically by raised synacthen-stimulated 17-OH-pregnenolone. The first case was managed with glucocorticoid and mineralocorticoid supplementation, while the second child was managed conservatively. Due to variable presentations, 3ß-HSD2 deficiency should be kept as a differential diagnosis while evaluating a child with congenital adrenal hyperplasia.

A Novel Homozygous CYP19A1 Gene Mutation Causing Aromatase Deficiency.

Aromatase deficiency is a rare autosomal recessive disorder and its exact prevalence is not known. Aromatase enzyme catalyzes the conversion of androgens to estrogens in gonadal and extra-gonadal tissues. Deficiency of aromatase enzyme can lead to ambiguous genitalia in a female child and maternal virilization during pregnancy due to raised androgen levels in the mother. A 10-month-old child was referred to our outpatient department for the evaluation of ambiguous genitalia. There was a history of maternal virilization during pregnancy. Karyotype of the child was 46XX. Congenital adrenal hyperplasia was ruled out as serum cortisol, plasma adrenocorticotropic hormone, and 17-hydroxyprogesterone were within normal limits. Hormonal assays showed elevated follicle-stimulating hormone and luteinizing hormone, with raised testosterone and low estradiol levels. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation c.1376delA located on exon 10 was identified on the CYP19A1 gene. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy.

Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival.

Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which is increasingly treatable but still incurable. In 90% of MM patients, severe osteolysis results from pathological interactions between MM cells and the bone microenvironment. Delineating specific molecules and pathways for their role in cancer supportive interactions in the BM is vital for developing new therapies. Very Late Antigen 4 (VLA4, integrin α4ß1) is a key player in cell-cell adhesion and signaling between MM and BM cells. We evaluated a VLA4 selective near infrared fluorescent probe, LLP2A-Cy5, for in vitro and in vivo optical imaging of VLA4. Furthermore, two VLA4-null murine 5TGM1 MM cell (KO) clones were generated by CRISPR/Cas9 knockout of the Itga4 (α4) subunit, which induced significant alterations in the transcriptome. In contrast to the VLA4+ 5TGM1 parental cells, C57Bl/KaLwRij immunocompetent syngeneic mice inoculated with the VLA4-null clones showed prolonged survival, reduced medullary disease, and increased extramedullary disease burden. The KO tumor foci showed significantly reduced uptake of LLP2A-Cy5, confirming in vivo specificity of this imaging agent. This work provides new insights into the pathogenic role of VLA4 in MM, and evaluates an optical tool to measure its expression in preclinical models.

Evaluation of primary breast cancers using dedicated breast PET and whole-body PET.

Metabolic imaging of the primary breast tumor with 18F-fluorodeoxyglucose ([18F]FDG) PET may assist in predicting treatment response in the neoadjuvant chemotherapy (NAC) setting. Dedicated breast PET (dbPET) is a high-resolution imaging modality with demonstrated ability in highlighting intratumoral heterogeneity and identifying small lesions in the breast volume. In this study, we characterized similarities and differences in the uptake of [18F]FDG in dbPET compared to whole-body PET (wbPET) in a cohort of ten patients with biopsy-confirmed, locally advanced breast cancer at the pre-treatment timepoint. Patients received bilateral dbPET and wbPET following administration of 186 MBq and 307 MBq [18F]FDG on separate days, respectively. [18F]FDG uptake measurements and 20 radiomic features based on morphology, tumor intensity, and texture were calculated and compared. There was a fivefold increase in SULpeak for dbPET (median difference (95% CI): 4.0 mL-1 (1.8-6.4 mL-1), p = 0.006). Additionally, spatial heterogeneity features showed statistically significant differences between dbPET and wbPET. The higher [18F]FDG uptake in dbPET highlighted the dynamic range of this breast-specific imaging modality. Combining with the higher spatial resolution, dbPET may be able to detect treatment response in the primary tumor during NAC, and future studies with larger cohorts are warranted.

Current Landscape of Breast Cancer Imaging and Potential Quantitative Imaging Markers of Response in ER-Positive Breast Cancers Treated with Neoadjuvant Therapy.

In recent years, neoadjuvant treatment trials have shown that breast cancer subtypes identified on the basis of genomic and/or molecular signatures exhibit different response rates and recurrence outcomes, with the implication that subtype-specific treatment approaches are needed. Estrogen receptor-positive (ER+) breast cancers present a unique set of challenges for determining optimal neoadjuvant treatment approaches. There is increased recognition that not all ER+ breast cancers benefit from chemotherapy, and that there may be a subset of ER+ breast cancers that can be treated effectively using endocrine therapies alone. With this uncertainty, there is a need to improve the assessment and to optimize the treatment of ER+ breast cancers. While pathology-based markers offer a snapshot of tumor response to neoadjuvant therapy, non-invasive imaging of the ER disease in response to treatment would provide broader insights into tumor heterogeneity, ER biology, and the timing of surrogate endpoint measurements. In this review, we provide an overview of the current landscape of breast imaging in neoadjuvant studies and highlight the technological advances in each imaging modality. We then further examine some potential imaging markers for neoadjuvant treatment response in ER+ breast cancers.

Longitudinal preclinical magnetic resonance imaging of diffuse tumor burden in intramedullary myeloma following bortezomib therapy.

Multiple myeloma (MM) is a largely incurable, debilitating hematologic malignancy of terminally differentiated plasma cells in the bone marrow (BM). Identification of therapeutic response is critical for improving outcomes and minimizing costs and off-target toxicities. To assess changes in BM environmental factors and therapy efficacy, there is a need for noninvasive, nonionizing, longitudinal, preclinical methods. Here, we demonstrate the feasibility of preclinical magnetic resonance imaging (MRI) for longitudinal imaging of diffuse tumor burden in a syngeneic, immunocompetent model of intramedullary MM. C57Bl/KaLwRij mice were implanted intravenously with 5TGM1-GFP tumors and treated with a proteasome inhibitor, bortezomib, or vehicle control. MRI was performed weekly with a Helmholtz radiofrequency coil placed on the hind leg. Mean normalized T1-weighted signal intensities and T2 relaxation times were quantified for each animal following manual delineation of BM regions in the femur and tibia. Finally, tumor burden was quantified for each tissue using hematoxylin and eosin staining. Changes in T2 relaxation times correlated strongly to cell density and overall tumor burden in the BM. Median T2 relaxation times and regional T1-weighted contrast uptake were shown to be most relevant in identifying posttherapy disease stage in this model of intramedullary MM. In summary, our results highlighted potential preclinical MRI markers for assessing tumor burden and BM heterogeneity following bortezomib therapy, and demonstrated the application of longitudinal imaging with preclinical MRI in an immunocompetent, intramedullary setting.

Chronic intermittent hypoxia enhances disease progression in myeloma-resistant mice.

Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.

Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with 18F-FDOPA and 18F-FDG PET.

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic 18F-FDG and 18F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUVmax, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with an increase in 18F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. Conclusion:18F-FDOPA PET/CT complemented 18F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.

Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma.

PURPOSE: We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of 11C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo EXPERIMENTAL DESIGN: Acetate fate tracking using 13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using 11C-acetate-PET/CT imaging and tissue biodistribution. RESULTS: In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, 11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise, 11C-acetate uptake was significantly reduced in MM tumors after treatment. CONCLUSIONS: Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. 11C-Acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. 11C-Acetate-PET also detected response to therapy in vivo Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that 11C-acetate-PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416-29. ©2016 AACR.

Enhancing in vivo tumor boundary delineation with structured illumination fluorescence molecular imaging and spatial gradient mapping.

Fluorescence imaging, in combination with tumor-avid near-infrared (NIR) fluorescent molecular probes, provides high specificity and sensitivity for cancer detection in preclinical animal models, and more recently, assistance during oncologic surgery. However, conventional camera-based fluorescence imaging techniques are heavily surface-weighted such that surface reflection from skin or other nontumor tissue and nonspecific fluorescence signals dominate, obscuring true cancer-specific signals and blurring tumor boundaries. To address this challenge, we applied structured illumination fluorescence molecular imaging (SIFMI) in live animals for automated subtraction of nonspecific surface signals to better delineate accumulation of an NIR fluorescent probe targeting α4ß1 integrin in mice bearing subcutaneous plasma cell xenografts. SIFMI demonstrated a fivefold improvement in tumor-to-background contrast when compared with other full-field fluorescence imaging methods and required significantly reduced scanning time compared with diffuse optical spectroscopy imaging. Furthermore, the spatial gradient mapping enhanced highlighting of tumor boundaries. Through the relatively simple hardware and software modifications described, SIFMI can be integrated with clinical fluorescence imaging systems, enhancing intraoperative tumor boundary delineation from the uninvolved tissue.