Gingival Hyperplasia Masquerading as Tumor Lesion, Possibly Linked to Amlodipine Use.

ABSTRACT: A 70-year-old woman under amlodipine treatment for hypertension presented with a hemorrhagic mass in the mandibular gingiva. Imaging studies revealed high signal intensity in T2-weighted MRI and moderate 18F-FDG accumulation at the lesion's periphery. Although no malignancy was detected, the lesion continuously grew, prompting excision. Histopathological examination confirmed gingival hyperplasia attributed to amlodipine use. Drug-induced gingival hyperplasia typically presents as diffuse swelling; however, this lesion manifested as a polyp, posing diagnostic challenges. Reports on imaging findings for drug-induced gingival hyperplasia are limited. Understanding imaging patterns alongside clinical history aids in accurate diagnosis.

SMARCA4-Deficient Poorly Differentiated Adenocarcinoma of the Gallbladder.

ABSTRACT: A 64-year-old woman presented with chest pain while eating and was referred to our hospital. Physical examination revealed abdominal distension, tenderness, and lower-extremity edema. Imaging revealed a large gallbladder tumor infiltrating the liver, with ascites and pleural effusion. A biopsy confirmed a poorly differentiated adenocarcinoma with SMARCA4 deficiency (cT3N2M1, cStage IV). Chemotherapy was ineffective and led to tumor progression. The patient died 9 months later. Recently, attention has been paid to SMARCA4 deficiency, which is a genetic mutation found in tumors. Here, we report on poorly differentiated adenocarcinomas of the gallbladder based on imaging findings, including FDG PET.

Association Between Pancreatic Cysts and Diabetes Mellitus in Von Hippel-Lindau Disease.

INTRODUCTION: Pancreatic cysts are frequently observed in patients with von Hippel-Lindau disease (VHL), and they are considered clinically not important. This study aimed to evaluate the association between pancreatic cysts and diabetes mellitus (DM) in patients with VHL. METHODS: Among patients who were on a patient list at the VHL Center at Kyoto University Hospital as of December 2022, those who had undergone an upper abdominal magnetic resonance imaging study after 2010 were retrospectively evaluated. The presence or absence of DM and high glycated hemoglobin (HbA1c) levels (>6.0%) were assessed. Patients were divided into two groups: those with DM or high HbA1c levels, and those without DM or high HbA1c levels. The area of the whole pancreas, including the pancreatic cysts and tumors, the area of the pancreatic cysts, and the percentage of pancreatic cysts, calculated by dividing the area of pancreatic cysts by the area of the whole pancreas, were measured on T2-weighted magnetic resonance images and compared between the two groups. RESULTS: Thirty-six patients with VHL, comprising 22 men and 14 women, with a mean age of 36.4 years (range, 11-79 years), were identified. Seven patients had DM, and two additional patients had high HbA1c levels. The area of the pancreatic cysts (p = 0.0013) was significantly larger and the percentage of the pancreatic cysts (p = 0.0016) was significantly higher in patients with DM or high HbA1c levels (n = 9) than in patients without DM or high HbA1c levels (n = 27); however, the difference in the area of the whole pancreas was not significant (p = 0.068). CONCLUSION: Our findings suggest that patients with VHL who have a large area covered by pancreatic cysts are more likely to have DM than those without.

Utility of Diffusion-weighted MR Imaging for Evaluating the Depth of Invasion in Oral Tongue Squamous Cell Carcinoma.

PURPOSE: The 8th edition of the American Joint Committee on Cancer staging system included the depth of invasion (DOI) for the T classification of oral cancer. However, no standardized method has been established to clinically measure the DOI. This study aimed to investigate the accuracy of MRI-based DOI for oral tongue squamous cell carcinoma (OTSCC) in each MRI sequence. METHODS: We enrolled 49 patients with histologically proven OTSCC, treated surgically between April 2017 and February 2021. We divided the DOI into three groups using 5 and 10 mm, the thresholds for determining the T stage, and retrospectively evaluated the agreement between MRI-based DOI and pathological DOI (pDOI) for each MRI sequence, axial T1-weighted imaging (T1WI), T2-weighted imaging with fat suppression (FS-T2WI), contrast-enhanced T1WI with fat suppression (CE-T1WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. We also divided the DOI into two groups using 3 mm, the threshold for considering elective neck dissection, and evaluated the overestimation rate of MRI-based DOI in lesions with pDOI ≤ 3 mm. RESULTS: With 5-mm and 10-mm divisions, the accuracy of the DOI assessment was highest on DWI (0.82, weighted kappa = 0.85). With a 3-mm division, the accuracy was also highest on DWI (0.87, kappa = 0.73). The overestimation rate of the MRI-based DOI in lesions with pDOI ≤ 3 mm was lowest on DWI (27.8%). CONCLUSION: DOI on DWI exhibits a comparatively higher rate of concordance with pDOI. DWI may be more useful than other MRI sequences in evaluating the DOI of OTSCC.

Hyalinizing Clear Cell Carcinoma in the Sphenoid Sinus.

ABSTRACT: A 39-year-old man presented with a 1-month history of headaches. Imaging revealed a mass with extensive destruction. T2-weighted imaging displayed mixture of low and sponge-like high intensities and also dark area, with FDG PET/CT showing uneven but intense accumulation. Biopsy confirmed EWSR1 rearrangement, and hyalinizing clear cell carcinoma (HCCC) was diagnosed. HCCC, recently renamed from clear cell carcinoma in the fifth edition of the World Health Organization Classification of Head and Neck Tumors, is a rare tumor. This case describes the features of T2-weighted imaging and FDG PET patterns in HCCC, possibly contributing to their consideration in the differential diagnosis.

DDX5 enhances HIF-1 activity by promoting the interaction of HIF-1α with HIF-1ß and recruiting the resulting heterodimer to its target gene loci.

BACKGROUND INFORMATION: Cancer cells acquire malignant characteristics and therapy resistance by employing the hypoxia-inducible factor 1 (HIF-1)-dependent adaptive response to hypoxic microenvironment in solid tumors. Since the underlying molecular mechanisms remain unclear, difficulties are associated with establishing effective therapeutic strategies. RESULTS: We herein identified DEAD-box helicase 5 (DDX5) as a novel activator of HIF-1 and found that it enhanced the heterodimer formation of HIF-1α and HIF-1ß and facilitated the recruitment of the resulting HIF-1 to its recognition sequence, hypoxia-response element (HRE), leading to the expression of a subset of cancer-related genes under hypoxia. CONCLUSIONS: This study reveals that the regulation of HIF-1 recruitment to HRE is an important regulatory step in the control of HIF-1 activity. SIGNIFICANCE: The present study provides novel insights for the development of strategies to inhibit the HIF-1-dependent expression of cancer-related genes.

Convolutional neural network-based program to predict lymph node metastasis of non-small cell lung cancer using 18F-FDG PET.

PURPOSE: To develop a convolutional neural network (CNN)-based program to analyze maximum intensity projection (MIP) images of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) positron emission tomography (PET) scans, aimed at predicting lymph node metastasis of non-small cell lung cancer (NSCLC), and to evaluate its effectiveness in providing diagnostic assistance to radiologists. METHODS: We obtained PET images of NSCLC from public datasets, including those of 435 patients with available N-stage information, which were divided into a training set (n = 304) and a test set (n = 131). We generated 36 maximum intensity projection (MIP) images for each patient. A residual network (ResNet-50)-based CNN was trained using the MIP images of the training set to predict lymph node metastasis. Lymph node metastasis in the test set was predicted by the trained CNN as well as by seven radiologists twice: first without and second with CNN assistance. Diagnostic performance metrics, including accuracy and prediction error (the difference between the truth and the predictions), were calculated, and reading times were recorded. RESULTS: In the test set, 67 (51%) patients exhibited lymph node metastases and the CNN yielded 0.748 predictive accuracy. With the assistance of the CNN, the prediction error was significantly reduced for six of the seven radiologists although the accuracy did not change significantly. The prediction time was significantly reduced for five of the seven radiologists with the median reduction ratio 38.0%. CONCLUSION: The CNN-based program could potentially assist radiologists in predicting lymph node metastasis by increasing diagnostic confidence and reducing reading time without affecting diagnostic accuracy, at least in the limited situations using MIP images.

Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.

Novel Manifestation of Retinal Hemangioblastomas Detected by OCT Angiography in von Hippel-Lindau Disease.

PURPOSE: To elucidate the clinical characteristics of atypical retinal vascular proliferation in patients with von Hippel-Lindau (VHL) disease using OCT angiography (OCTA). DESIGN: Prospective, observational study. PARTICIPANTS: Fifty-seven consecutive patients with a diagnosis of VHL disease who visited Kyoto University Hospital between January 2019 and March 2022. METHODS: Retinal hemangioblastomas (RHs) were assessed using multimodal imaging including OCTA. Retinal hemangioblastomas were classified into 2 phenotypes: nodular and flat. Nodular RHs were defined as typical RHs that were globular, well-circumscribed tumors, often accompanied with dilated feeder arterioles and draining venules. Flat RHs lacked a protruded red or colored mass, had variable and indistinct borders, and were not accompanied with feeder and draining vessels. MAIN OUTCOME MEASURES: The prevalence, distribution, and description of atypical flat RHs. RESULTS: Among 57 consecutive patients with VHL disease, 37 patients (64.9%) showed RHs in at least 1 eye. Bilateral RHs were seen in 23 patients (62.2%). Among 58 eyes of 37 patients with RHs, typical nodular RHs were detected in 54 eyes. Nodular RHs were seen mainly in the peripheral retina and occasionally in the peripapillary region, and they showed exudative changes in some cases. Flat RHs were detected in 7 eyes (12.1%). Four eyes showed only flat RHs, and 3 eyes showed both types in the same eye. Most flat RHs appeared as retinal hemorrhages or faint flat abnormal retinal vessels in the inner retina on the fundus examination, often within the macula area or peripapillary. In all eyes with flat RHs, OCTA showed abundant blood flow in the lesions. OCT revealed that flat RHs were seen mainly between the retinal nerve fiber layer and the ganglion cell layer, and occasionally within the inner nuclear layer. During a mean follow-up period of 20.4 ± 15.0 months, no flat RHs accompanied exudative change, tractional retinal detachment, or progression in size. CONCLUSIONS: Patients with VHL disease can demonstrate 2 distinct types of RHs: the classic nodular type and an atypical flat type. OCT angiography can be useful in improving the detection of atypical flat RHs, which can be difficult to detect clinically. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Inverted FDG Uptake Pattern in Subcutaneous Panniculitis-Like T-Cell Lymphoma.

ABSTRACT: A 47-year-old woman presented with a 2-month history of subcutaneous nodules, erythema, and fever. 18F-FDG PET images demonstrated inverted FDG uptake pattern corresponding to the subcutaneous lesion against lymph nodes. The specimen of the inguinal lesion showed massive infiltration of small lymphocytes in the adipose tissue with rimming adipocytes, whereas very few tumor cells infiltrated the lymph nodes. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) was diagnosed. SPTCL normally shows quite interesting distribution of tumor cells, that is, lymph node involvement is usually absent. Therefore, this case highlighted the importance of the inverted accumulation pattern on FDG PET to suspect SPTCL.

Loss of ATF6α in a human carcinoma cell line is compensated not by its paralogue ATF6ß but by sustained activation of the IRE1 and PERK arms for tumor growth in nude mice.

To survive poor nutritional conditions, tumor cells activate the unfolded protein response, which is composed of the IRE1, PERK, and ATF6 arms, to maintain the homeostasis of the endoplasmic reticulum, where secretory and transmembrane proteins destined for the secretory pathway gain their correct three-dimensional structure. The requirement of the IRE1 and PERK arms for tumor growth in nude mice is established. Here we investigated the requirement for the ATF6 arm, which consists of ubiquitously expressed ATF6α and ATF6ß, by constructing ATF6α-knockout (KO), ATF6ß-KO, and ATF6α/ß-double KO (DKO) in HCT116 cells derived from human colorectal carcinoma. Results showed that these KO cells grew similarly to wild-type (WT) cells in nude mice, contrary to expectations from our analysis of ATF6α-KO, ATF6ß-KO, and ATF6α/ß-DKO mice. We then found that the loss of ATF6α in HCT116 cells resulted in sustained activation of the IRE1 and PERK arms in marked contrast to mouse embryonic fibroblasts, in which the loss of ATF6α is compensated for by ATF6ß. Although IRE1-KO in HCT116 cells unexpectedly did not affect tumor growth in nude mice, IRE1-KO HCT116 cells with ATF6α knockdown grew significantly more slowly than WT or IRE1-KO HCT116 cells. These results have unraveled the situation-dependent differential compensation strategies of ATF6α.

Preoperative Localization of Parathyroid Adenomas with Diffusion MR Imaging: Readout-segmented versus Single-shot Echo-planar Imaging.

PURPOSE: To evaluate whether readout-segmented echo-planar imaging (RS-EPI) diffusion-weighted imaging (DWI) can reduce image distortion and improve the lesion identification in parathyroid adenomas (PTAs) compared to single-shot EPI (SS-EPI) DWI, and to determine whether PTAs can be differentiated from other soft tissue structures of the head and neck region by using the apparent diffusion coefficient (ADC) value. METHODS: We retrospectively analyzed the preoperative MR images including DWI of 24 patients with surgically confirmed PTA. RS-EPI and SS-EPI DWI were evaluated by two independent readers for the identification of the lesions and distortion. The ADC values of the PTAs were compared with those of thyroid glands and cervical lymph nodes. RESULTS: RS-EPI provided significantly less distortion compared to SS-EPI. RS-EPI tended to have better lesion identification compared with SS-EPI without a statistically significant difference. On SS-EPI, the PTAs had significantly higher ADC values compared with the cervical lymph nodes. On RS-EPI, the PTAs had significantly higher ADC values compared with the thyroid glands and cervical lymph nodes. CONCLUSION: RS-EPI reduces the DWI distortion in PTAs. The ADC value obtained using RS-EPI enables the differentiation of PTAs from nearby structures, such as thyroid glands and cervical lymph nodes.

A Von Hippel-Lindau Disease-Associated Microcystic Adenoma of the Ethmoid Sinus Mimicking Metastatic Clear Cell Renal Cell Carcinoma.

ABSTRACT: A 38-year-old man with von Hippel-Lindau (VHL) disease and a history of renal cell carcinoma presented with a 2-month history of recurrent epistaxis. MRI revealed a microcystic tumor in the left ethmoid sinus with strong contrast enhancement. 18 F-FDG PET/CT showed FDG uptake (SUV max , 4.2) in the lesion. Under the suspicion of renal cell carcinoma metastasis, the patient underwent 2 surgical resections. However, based on the morphological and immunohistochemical findings, the patient was finally diagnosed with a VHL-associated microcystic adenoma of the ethmoid sinus, which is an extremely rare tumor that occurs in VHL disease.

Unilateral Reduction of 18F-FDG Accumulation in Brown Adipose Tissue by Sympathectomy for Hyperhidrosis.

ABSTRACT: A 30-year-old woman with left breast cancer underwent 18F-FDG PET/CT for staging. Intense FDG uptake was observed in the primary lesion, as well as on the left side of the neck to the supraclavicular fossa and left paravertebral region. History taking revealed that she had undergone a right thoracic sympathectomy for hyperhidrosis, which resulted in attenuated FDG uptake in the right-sided brown adipose tissue (BAT). With another examination keeping adequate warming, the accumulation of BAT was reduced and a diagnosis of cT1N1M0 was made. Unilateral sympathetic blockade can cause asymmetric FDG accumulation in BAT, which interferes with interpretation in tumors.

ZBTB2 links p53 deficiency to HIF-1-mediated hypoxia signaling to promote cancer aggressiveness.

Aberrant activation of the hypoxia-inducible transcription factor HIF-1 and dysfunction of the tumor suppressor p53 have been reported to induce malignant phenotypes and therapy resistance of cancers. However, their mechanistic and functional relationship remains largely unknown. Here, we reveal a mechanism by which p53 deficiency triggers the activation of HIF-1-dependent hypoxia signaling and identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as an important mediator. ZBTB2 forms homodimers via its N-terminus region and increases the transactivation activity of HIF-1 only when functional p53 is absent. The ZBTB2 homodimer facilitates invasion, distant metastasis, and growth of p53-deficient, but not p53-proficient, cancers. The intratumoral expression levels of ZBTB2 are associated with poor prognosis in lung cancer patients. ZBTB2 N-terminus-mimetic polypeptides competitively inhibit ZBTB2 homodimerization and significantly suppress the ZBTB2-HIF-1 axis, leading to antitumor effects. Our data reveal an important link between aberrant activation of hypoxia signaling and loss of a tumor suppressor and provide a rationale for targeting a key mediator, ZBTB2, to suppress cancer aggressiveness.

The added value of non-contrast 3-Tesla MRI for the pre-operative localization of hyperparathyroidism

Abstract Objective: We investigated the efficacy of non-contrast 3-Tesla MR imaging added to the combination of sestamibi with99mTc (MIBI) scintigraphy and Ultrasonography (US) for the pre-operative localization of Primary Hyperparathyroidism (PHPT) lesions. Methods: A total of 34 parathyroid glands, including nine normal glands, were examined with MIBI, US, and non-contrast 3-Tesla MRI. MRI was performed with the acquisition of T1- and T2-weighted images and fat-suppressed T2-weighted images. We calculated the sensitivities of MIBI, US, and the ‛additional' MRI, with knowledge of the former two modalities' results. Results: For the diagnosis of PHPT lesions, the sensitivity values of MIBI, US, and additional MRI were 88.0% (22/25), 84.0% (21/25), and 92.0% (23/25), respectively. Normal glands were not visualized with any modality (0/9). One lesion was detected neither with US nor MRI, but only with MIBI, with the limitation that MIBI represented no more than laterality. The two glands not identified in MRI were 4 mm and 6 mm in their size, which are within the range of normal gland's size. Two lesions were not detected with US or MIBI but were visualized with the additional MRI, which indicated that the MRI contributed an 8.0% (2/25) improvement of sensitivity, compared from that of US. Fat-suppressed T2-weighted images were useful in the identification of parathyroid lesions, as these images helped to differentiate between the lesion and the adjacent tissue. Conclusion: Additional non-contrast 3-Tesla MRI was a useful adjunctive tool for localization of PHPT, which improved the sensitivity of the pre-operative localization of PHPT lesions. Fatsuppressed T2-weighted images contributed to their identification. Level VI: Evidence from a single descriptive or qualitative study.

[68Ga-DOTATOC PET/CT for Diagnosing Neuroendocrine Tumors].

Lutathera is a peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors and was approved as the first PRRT drug in Japan in 2021. Although neuroendocrine tumors are often less aggressive than other highly malignant and invasive tumors, there have been few effective therapy options, so "Lutathera"is a long-awaited treatment. Lutathera is indicated for the treatment of "somatostatin receptor-positive neuroendocrine tumors". Currently, in Japan, the only imaging method to evaluate the expression of somatostatin receptors in lesions is scintigraphy using In-111 pentetreotide(OctreoScan). In this section, we would like to introduce the current status of the 68Ga-DOTA-SSA PET/CT using somatostatin analogue(SSA)in our institution.

Development of a novel Indium-111 radiolabeled mogamulizumab targeting CCR4 for imaging adult T-cell leukemia/lymphoma in vivo.

OBJECTIVE: Adult T-cell leukemia/lymphoma (ATL), caused by human T-cell lymphotropic virus type I (HTLV-1) infection, is among the most aggressive categories and has the worst prognosis among T-cell lymphomas. Mogamulizumab, an anti-CC chemokine receptor 4 (CCR 4), has been shown to be effective in the treatment of ATL; however, some ATL cases are often resistant, particularly the lymphoma-type ATL. To evaluate drug delivery in vivo and identify the distribution of CCR4-positive cells in the body, we developed a novel mogamulizumab tracer labeled with Indium-111 (111In) via diethylenetriaminepentaacetic acid (DTPA) for single-photon emission computerized tomography (SPECT), named [111In]In-DTPA-mogamulizumab, and evaluated its potential for visualizing CCR4 expression in vivo. METHODS: [111In]In-DTPA-mogamulizumab was added to HCT116/CCR4 or HCT116/empty vector (EV) cells, and their radioactivity was measured 1 h after administration. A blocking study was additionally performed by treating HCT116/CCR4 cells with excess mogamulizumab in addition to [111In]In-DTPA-mogamulizumab. The biodistribution and SPECT imaging of [111In]In-DTPA-mogamulizumab in HCT116/CCR4 and HCT116/EV dual-xenografted BALB/c-nu mice were evaluated for 72 h after intravenous injection. RESULTS: [111In]In-DTPA-mogamulizumab was acquired with a radiochemical purity > 95%. The cellular uptake level of [111In]In-DTPA-mogamulizumab by HCT116/CCR4 cells was significantly higher than that by HCT116/EV cells (HCT116/CCR4: 0.951 ± 0.069, HCT116/EV: 0.006 ± 0.001%dose/mg protein, p < 0.01), and the uptake was significantly suppressed by co-incubation with excess mogamulizumab (0.013 ± 0.003%dose/mg protein, p < 0.01). In the in vivo study, the radioactivity of the HCT116/CCR4 tumor tissue was significantly higher than that of the HCT116/EV tumor tissue at 72 h after the administration of [111In]In-DTPA-mogamulizumab (HCT116/CCR4: 20.5 ± 5.4, HCT116/EV: 5.7 ± 1.0%ID/g), and HCT116/CCR4 tumors were clearly and specifically visualized on SPECT imaging. CONCLUSIONS: We have successfully developed a novel SPECT imaging tracer targeting CCR4, [111In]In-DTPA-mogamulizumab, which showed good specificity and pharmacokinetics, indicating potential in visualizing CCR4 expression in vivo.

Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase.

Cancer cells acquire chemoresistance in hypoxic regions of solid tumors, which is suggested to be at least partly due to reduction of their proliferative activity. However, molecular mechanisms behind it have not been fully elucidated. Here, we revealed the importance of active proteolysis of a histone acetylation reader, ATPase family AAA domain containing 2 (ATAD2), under hypoxia. We found that inactivation of an O2/Fe2+/α-ketoglutarate-dependent dioxygenase triggered ATAD2 proteolysis by the proteasome system upon severe hypoxia in a hypoxia-inducible factors (HIFs)-independent manner. Consistently, ATAD2 expression levels were markedly lower in perinecrotic hypoxic regions in both xenografted and clinical tumor tissues. The ATAD2 proteolysis was accompanied by a decrease in the amount of acetylated histone H3 lysine 27 and inhibited cell cycle progression from the early to late S phase under severe hypoxia. The retardation of S phase progression induced chemoresistance, which was blocked by overexpression of ATAD2. Together, these results indicate that ATAD2 proteolysis upon severe hypoxia induces chemoresistance of cancer cells through heterochromatinization and the subsequent retardation of S phase progression; therefore, inhibition of ATAD2 proteolysis is expected to be a strategy to overcome chemoresistance of hypoxic tumor cells.