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Purpose To develop a convolutional neural network (CNN)-based program to analyse 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 two radiologists (R1 and R2) twice: first without and second with CNN assistance. Diagnostic performance metrics, including accuracy, 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. The accuracy of the radiologists increased from 0.718 to 0.740 for R1, and from 0.679 to 0.733 for R2 with CNN assistance. The mean prediction time was significantly reduced with CNN assistance, decreasing from 11.1 to 6.9 s (p Conclusion The CNN-based program could potentially assist radiologists in predicting lymph node metastasis, increase diagnostic performance, and reduce the time for diagnosis.

Supplemental Materials and Methods, Supplemental Figures.

Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (89Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model.Experimental Design: The effect of 89Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro. 89Zr-labeled bone marrow cells (2 × 107 cells, 16.6 kBq/106 cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 μg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n = 3).Results: 89Zr-oxine–labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4–CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. 89Zr-labeled donor cells engrafted as well as nonlabeled cells.Conclusions: 89Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759–68. ©2016 AACR.

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 ATF6β, by constructing ATF6α-knockout (KO), ATF6β-KO, and ATF6α/β-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, ATF6β-KO, and ATF6α/β-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 ATF6β. 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.

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. 18F-FDG PET/CT showed FDG uptake (SUVmax, 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.

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.

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.

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.

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.

Epstein-Barr virus-positive mucocutaneous ulcer is a newly recognized clinicopathological entity among mature B-cell neoplasms according to the 2016 revision of the World Health Organization diagnostic criteria. Here, we present FDG PET/CT images of 2 Epstein-Barr virus-positive mucocutaneous ulcer cases. Both cases shown in the images mimicked head and neck cancers, which are similar to carcinomas of the tonsil and gingiva, respectively, and both lesions showed intense FDG uptake on PET scan.

This study aimed to investigate the association between the volume-dependent parameters in 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) and a recurrence of thymic carcinoma. A retrospective chart review was performed based on our multi-institutional database to identify patients undergoing PET prior to resection of thymic carcinoma or neuroendocrine carcinoma between 1991 and 2018. The PET parameters (metabolic tumor volume and total lesion glycolysis) were evaluated retrospectively. The relevant factors were extracted and a survival analysis was performed using the Kaplan–Meier method. Sixteen patients were thus deemed to be eligible for analysis. The median follow-up period following resection was 2.65 years (range: 0.96–0.68 years). The recurrence-free survival was significantly longer in patients with a metabolic tumor volume

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.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.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.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.

Epoprostenol is a prostacyclin (prostaglandin I2) analog that causes vasodilation and inhibits platelet aggregation and is used in the management of severe pulmonary arterial hypertension (PAH). We herein report a patient with PAH who developed pancreatic enlargement after the initiation of therapy including epoprostenol. Although it is well known that thyroid enlargement occurs in patients with PAH receiving epoprostenol therapy, the pancreatic findings associated with epoprostenol therapy have not been well described. Although the size of the pancreas was clearly increased, there was no blood data or symptoms suggestive of abnormal pancreatic function and pancreatitis, and the patient's abdominal complaints improved quickly, despite the continuation of epoprostenol therapy. Eleven months after the start of continuous intravenous epoprostenol infusion therapy, the pancreatic enlargement was still evident on imaging, but there were no abdominal symptoms or elevated pancreatic enzymes. This case highlights the fact that epoprostenol therapy may cause pancreatic changes that mimic acute or autoimmune pancreatitis.

The aim of this study was to investigate the clinical characteristics of patients with diffuse renal uptake (DRU) of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG), with particular focus on renal function.We retrospectively analyzed 40 patients who showed DRU on FDG PET/CT and the same number of matched controls. The clinical features, imaging parameters (the mean SUVmax of the kidneys and the kidney size), and laboratory data including renal function parameters (Cr, the serum creatinine level; estimated glomerular filtration ratio (eGFR); Cr-ratio, Cr divided by the baseline; max-Cr-ratio, the maximum serum creatinine level within 30 days divided by the baseline) and C-reactive protein (CRP) were compared between the two groups. In the DRU group, follow-up FDG PET/CT scans were additionally evaluated to determine the presence of DRU.No significant differences were observed in the clinical features except for antibiotic administration, Cr, and eGFR. Significantly more patients underwent antibiotic administration within 30 days in the DRU group (p = 0.002). The mean SUVmax of the kidneys was significantly higher (p 0.001) and the kidney size was significantly larger in the DRU group (p = 0.003). Cr-ratio and max-Cr-ratio were significantly higher in the DRU group (p = 0.005 and p 0.001, respectively). CRP was significantly higher in the DRU group (p 0.001). Eighteen of the 40 patients in the DRU group underwent a second FDG PET/CT scan, and 16 of them did not show DRU. Six of the 18 patients showed acute kidney injury (AKI, i.e., Cr-ratio ≥ 1.5) at the time of the initial scan and recovered before the second scan. None of the six patients showed DRU on the second scan.DRU indicates the presence of AKI, could be a reversible finding, and may disappear as renal function improves.

Angiomatous polyp is a benign, nonneoplastic nasal polyp that accounts for 4-5% of all inflammatory nasal polyps but is rarely reported in the literature. It can grow rapidly and exhibit an aggressive clinical behavior that can simulate malignant sinonasal tumor. We herein report a case of a 13-year-old boy with a rapidly growing angiomatous polyp in the nasal cavity. We had followed up the patient without significant changes for two years, but the tumor had rapidly grown in the last six months. At first, the rapid growth of the tumor and the bone erosion of the maxilla were suggestive of a malignant tumor. However, with preoperative magnetic resonance imaging (MRI) and [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography imaging findings, we established the corrective diagnosis of an angiomatous polyp. After the diagnostic imaging, we performed an endoscopic endonasal surgery and totally resected the tumor without unnecessary excessive surgery. Recognition of this disease that can mimic malignancy is important to avoid excessive surgery such as en bloc resection by craniofacial approach, and we believe that MRI findings can be helpful for the imaging diagnosis.

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 ([[We have successfully developed a novel SPECT imaging tracer targeting CCR4, [

We describe case studies of two patients who underwent resection of paratracheal middle mediastinal thymic carcinomas. In both patients, complete resection of these masses via right thoracotomy was performed using three-dimensional computed tomography. Final pathologic diagnoses were thymic squamous cell carcinoma and thymic atypical carcinoid tumor. Challenges and debates in preoperative, intraoperative, and postoperative management are discussed in this article.

A 78-year-old woman was referred to the gynecologic outpatient department because she was suspected of having ovarian cancer based on an imaging study performed during a general medical examination. Further examination using F-FDG PET/CT revealed a bulky mass lesion with low FDG avidity, as well as surprisingly strong bilateral breast radiotracer uptake despite the patient's age. Thus, an estrogen-producing tumor was suspected. Bilateral salpingo-oophorectomy was performed, and surgical pathology diagnosed the tumor as clear cell carcinoma of the ovary.

Recently, the potential value of isocitrate dehydrogenase (IDH) mutation as a prognostic marker in glioblastomas has been established. Glioblastomas are classified by their IDH mutation status under the 2016 WHO classification system. However, noninvasive diagnostic methods for the mutation status in glioblastoma patients have not been established so far. The purpose of this study was to evaluate the difference of acetate metabolism between in glioblastomas with wild-type IDH and in those with IDH mutation by comparing the uptake of 14C-acetate using genetically engineered glioblastoma cell lines in vitro and in vivo. We established glioblastoma cells (U251) expressing IDH1 R132H and examined the cell uptake of [1-14C]acetate. Biodistribution studies and an autoradiographic study for U251 cell tumor-bearing mice (BALB/c-nu/nu) with or without the IDH1 mutation were performed 1 h after [1-14C]acetate administration. Significantly higher uptake of [1-14C]acetate was observed in U251/IDH1 R132H cells than in U251/IDH1 wild-type cells both in vitro (10.11 ± 0.94 vs. 4.26 ± 0.95%dose/mg, p = 0.0047) and in vivo (0.97 ± 0.14 vs. 0.66 ± 0.05%ID/g; p = 0.0037). Tumor-to-muscle ratios were also significantly higher in U251/IDH1 R132H tumors (3.36 ± 0.41 vs. 1.88 ± 0.59, p = 0.0030). The autoradiographic study shows the entirely higher radioactivity of the U251/IDH1 R132H tumor tissue section than that of the U251/IDH1 Wild-type tumor. In vitro and in vivo studies demonstrated that the uptake of radiolabeled acetate was significantly higher in IDH-mutated cells than in IDH-wild-type cells.

To develop and evaluate a radiomics approach for classifying histological subtypes and epidermal growth factor receptor (EGFR) mutation status in lung cancer on PET/CT images. PET/CT images of lung cancer patients were obtained from public databases and used to establish two datasets, respectively to classify histological subtypes (156 adenocarcinomas and 32 squamous cell carcinomas) and EGFR mutation status (38 mutant and 100 wild-type samples). Seven types of imaging features were obtained from PET/CT images of lung cancer. Two types of machine learning algorithms were used to predict histological subtypes and EGFR mutation status: random forest (RF) and gradient tree boosting (XGB). The classifiers used either a single type or multiple types of imaging features. In the latter case, the optimal combination of the seven types of imaging features was selected by Bayesian optimization. Receiver operating characteristic analysis, area under the curve (AUC), and tenfold cross validation were used to assess the performance of the approach. In the classification of histological subtypes, the AUC values of the various classifiers were as follows: RF, single type: 0.759; XGB, single type: 0.760; RF, multiple types: 0.720; XGB, multiple types: 0.843. In the classification of EGFR mutation status, the AUC values were: RF, single type: 0.625; XGB, single type: 0.617; RF, multiple types: 0.577; XGB, multiple types: 0.659. The radiomics approach to PET/CT images, together with XGB and Bayesian optimization, is useful for classifying histological subtypes and EGFR mutation status in lung cancer.

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. Fat-suppressed T2-weighted images contributed to their identification. Level vi Evidence from a single descriptive or qualitative study.

A 77-year-old man with parkinsonism was referred to the department of neurology for further examination. Cardiac 123I-MIBG scintigraphy unexpectedly showed strong uptake in the left shoulder, suggestive of MIBG-avid tumors including paraganglioma. MRI revealed multiple nodules suggestive of lymphoma. A biopsy was performed, which led to the pathological diagnosis of diffuse large B-cell lymphoma. Cardiac MIBG scintigraphy sometimes shows unexpected findings outside the mediastinum. In addition, lymphoma should also be added to the list of differential diagnoses for MIBG-positive tumors.

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 O

A 72-year-old woman was referred for whole-body 111In-pentetreotide scintigraphy with SPECT/CT. There was increased uptake of lymphadenopathy in the left axilla and left deltoid muscle. The patient's history revealed that the patient received the first dose of the COVID-19 vaccine 3 days before the 111In-pentetreotide scintigraphy with SPECT/CT. This case demonstrates that the COVID-19 vaccine can cause 111In-pentetreotide uptake in the lymph nodes and the deltoid muscle.

PET/CT imaging with 68Ga-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-D-Phe1-Tyr3-octreotide (DOTATOC) is useful in patients with neuroendocrine tumors (NETs). Functioning NETs by definition secrete abnormal levels of hormones, causing clinical symptoms. It is known that physiologic accumulation can be seen in some organs, but it remains unknown whether elevated hormone levels can affect the physiologic accumulation pattern of 68Ga-DOTATOC. We aimed to investigate the influence of higher hormone levels on physiologic accumulation of 68Ga-DOTATOC. A total of 167 patients with known or suspected NET lesions were enrolled in this study. The numbers of patients with elevations of ACTH, gastrin, insulin, and no elevation were 10, 25, 7, and 125, respectively. We compared the maximum standardized uptake value (SUVmax) in various organs of each group. In the group with elevated ACTH levels, SUVmax in the pituitary gland, the uncinate process of the pancreas and adrenal glands was lower than those in the group with no elevation (5.7 ± 1.9 vs. 8.4 ± 3.1, P = 0.015; 4.7 ± 3.5 vs. 6.4 ± 2.8, P = 0.037; 10.8 ± 4.8 vs. 13.9 ± 4.7, P = 0.020, respectively). There were no differences in physiologic uptake of 68Ga-DOTATOC in the thyroid gland, the pancreatic body, the liver, the spleen, the bowel, or the kidney. In NET patients with elevated ACTH levels, physiologic uptake of 68Ga-DOTATOC in the pituitary gland, the uncinate process of the pancreas and adrenal glands was significantly decreased. Other organs were unaffected.

Radiation therapy is one of the first-line treatments for many cancers, with no less than half of cancer patients receiving it in the US. Despite the development of innovative and high-precision radiation therapy strategies, many patients still experience local tumor recurrence after the treatment, at least in part, due to the existence of radioresistant cells in malignant tumor tissues. Among the various biological processes known to induce radioresistance, a post-translational protein modification, ubiquitination, has received marked attention in recent years. Ubiquitination, in which highly conserved ubiquitin polypeptides are covalently attached to their target proteins, has long been recognized as a system to tag unnecessary proteins for 26S proteasome-dependent proteolysis. However, accumulating lines of evidence recently revealed that it acts as a signal molecule in diverse biological processes as well, and its functional disorder was found to cause not only tumor development and various diseases but also tumor radioresistance. The present review summarizes the latest knowledge about how the cancer-related disorder of the ubiquitination systems induces the radioresistance of cancer cells by influencing intrinsic pathways, each of which potentially affects the radioresistance/radiosensitivity of cells, such as DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties. In addition, this review aims to provide insights into how we can exploit the disorders in order to develop novel radiosensitizing strategies.

Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1α) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization.

Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (89Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model. Experimental Design: The effect of 89Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro. 89Zr-labeled bone marrow cells (2 × 107 cells, 16.6 kBq/106 cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 μg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n = 3). Results: 89Zr-oxine–labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4–CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. 89Zr-labeled donor cells engrafted as well as nonlabeled cells. Conclusions: 89Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759–68. ©2016 AACR.

Objective. This study investigated whether the metformin (Met)-induced enhanced intestinal uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is reduced by loperamide, a long-acting anti-diarrheal agent. Methods. Mean 18F-FDG uptake in the mouse small intestine and colon with Met exposure was compared with that in control mice. In the Met group, high-dose (1.0 mg/kg body weight) and low-dose (0.1 mg/kg body weight) loperamide were introduced, and 18F-FDG uptake in the small intestine and colon was compared with that of control mice administered high-dose loperamide. The percent injected dose of 18F-FDG per gram of tissue (%ID/g) in the extracted tissues was then determined. Results. 18F-FDG uptake increased significantly in the small intestine (0.64±0.06 vs. 1.01±0.15, p=0.040) and, especially, the colon (0.46±0.13 vs. 2.16±0.51, p18F-FDG uptake in the small intestine (0.82±0.31 vs. 0.84±0.22, p=0.93 and 0.78±0.25 vs. 0.70±0.15, p=0.13, respectively) or colon (2.13±0.41 vs. 1.67±0.55, p=0.063 and 1.77±0.39 vs. 1.80±0.25, p=0.56, respectively). The colonic %ID/g was significantly higher in Met groups irrespective of loperamide introduction than in control group, whereas the significant difference in the small intestine was observed only between Met and control groups. Conclusion. Metformin increased 18F-FDG uptake in intestines especially in colon. Loperamide administration partially, but not sufficiently, suppresses the Met-induced increased colonic uptake of 18F-FDG.

Recently, the potential value of isocitrate dehydrogenase (IDH) mutation as a prognostic marker in glioblastomas has been established. Glioblastomas are classified by their IDH mutation status under the 2016 WHO classification system. However, noninvasive diagnostic methods for the mutation status in glioblastoma patients have not been established so far. The purpose of this study was to evaluate the difference of acetate metabolism between in glioblastomas with wild-type IDH and in those with IDH mutation by comparing the uptake ofWe established glioblastoma cells (U251) expressing IDH1 R132H and examined the cell uptake of [1-Significantly higher uptake of [1-In vitro and in vivo studies demonstrated that the uptake of radiolabeled acetate was significantly higher in IDH-mutated cells than in IDH-wild-type cells.

To develop and evaluate a radiomics approach for classifying histological subtypes and epidermal growth factor receptor (EGFR) mutation status in lung cancer on PET/CT images.PET/CT images of lung cancer patients were obtained from public databases and used to establish two datasets, respectively to classify histological subtypes (156 adenocarcinomas and 32 squamous cell carcinomas) and EGFR mutation status (38 mutant and 100 wild-type samples). Seven types of imaging features were obtained from PET/CT images of lung cancer. Two types of machine learning algorithms were used to predict histological subtypes and EGFR mutation status: random forest (RF) and gradient tree boosting (XGB). The classifiers used either a single type or multiple types of imaging features. In the latter case, the optimal combination of the seven types of imaging features was selected by Bayesian optimization. Receiver operating characteristic analysis, area under the curve (AUC), and tenfold cross validation were used to assess the performance of the approach.In the classification of histological subtypes, the AUC values of the various classifiers were as follows: RF, single type: 0.759; XGB, single type: 0.760; RF, multiple types: 0.720; XGB, multiple types: 0.843. In the classification of EGFR mutation status, the AUC values were: RF, single type: 0.625; XGB, single type: 0.617; RF, multiple types: 0.577; XGB, multiple types: 0.659.The radiomics approach to PET/CT images, together with XGB and Bayesian optimization, is useful for classifying histological subtypes and EGFR mutation status in lung cancer.

This study evaluated the clinical significance of 18F-FDG PET/CT in patients with interstitial lung disease (ILD), by investigating the relationships between 18F-FDG PET/CT parameters and clinical indicators and by evaluating the prognostic implications of 18F-FDG PET/CT results. Methods: Ninety patients (51 men, 39 women; mean age, 55.4 y; age range, 26–78 y) with ILD who underwent 18F-FDG PET/CT were retrospectively analyzed. SUVmean was defined as the mean SUV of the less-affected lung field, SUVTF as adjusted SUVmean using tissue fraction (TF), and CTmean as the mean attenuation of the corresponding region of interest on high-resolution CT. SUVmean, SUVTF, and CTmean were compared in the 90 ILD patients and in 15 age- and sex-matched controls. Correlations of SUVmax, SUVmean, SUVTF, and CTmean with clinical indicators, including estimated percentage of forced vital capacity (%FVC), estimated percentage of diffusion capacity of the lungs for carbon monoxide (%DLco), sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), C-reactive protein (CRP), lactate dehydrogenase (LDH), and ILD-sex-age-physiology (GAP) index, were evaluated using the Spearman rank correlation test and the Tukey–Kramer test. A Cox proportional hazards model was used for univariate and multivariate analyses of factors associated with lung transplantation-free survival. Results: SUVmean, SUVTF, and CTmean were significantly higher in ILD patients than in healthy controls, except for CTmean in patients with a nonusual interstitial pneumonia pattern. SUVmean and CTmean were significantly correlated with %FVC, %DLco, KL-6, and SP-D; SUVTF was significantly correlated with %DLco, KL-6, SP-D, and LDH; and SUVmax was weakly correlated with KL-6 and CRP. Univariate analysis showed that SUVmean, SUVTF, sex, %FVC, %DLco, KL-6, and ILD-GAP index were significantly prognostic of lung transplantation-free survival; and multivariate analysis showed that SUVmean and ILD-GAP index were independently prognostic of lung transplantation-free survival. A higher SUVmean indicated a poorer prognosis, especially in patients with moderate risk based on ILD-GAP index. Conclusion: SUVmean was significantly but moderately correlated with clinical indicators, providing independent prognostic information in patients with ILD. 18F-FDG PET/CT may be helpful for monitoring and risk stratification of ILD patients.

Background and objective Currently, it is challenging to detect acute ischemic stroke (AIS)-related changes on computed tomography (CT) images. Therefore, we aimed to develop and evaluate an automatic AIS detection system involving a two-stage deep learning model. Methods We included 238 cases from two different institutions. AIS-related findings were annotated on each of the 238 sets of head CT images by referring to head magnetic resonance imaging (MRI) images in which an MRI examination was performed within 24 h following the CT scan. These 238 annotated cases were divided into a training set including 189 cases and test set including 49 cases. Subsequently, a two-stage deep learning detection model was constructed from the training set using the You Only Look Once v3 model and Visual Geometry Group 16 classification model. Then, the two-stage model performed the AIS detection process in the test set. To assess the detection model's results, a board-certified radiologist also evaluated the test set head CT images with and without the aid of the detection model. The sensitivity of AIS detection and number of false positives were calculated for the evaluation of the test set detection results. The sensitivity of the radiologist with and without the software detection results was compared using the McNemar test. A p-value of less than 0.05 was considered statistically significant. Results For the two-stage model and radiologist without and with the use of the software results, the sensitivity was 37.3%, 33.3%, and 41.3%, respectively, and the number of false positives per one case was 1.265, 0.327, and 0.388, respectively. On using the two-stage detection model's results, the board-certified radiologist's detection sensitivity significantly improved (p-value = 0.0313). Conclusions Our detection system involving the two-stage deep learning model significantly improved the radiologist's sensitivity in AIS detection.

Background No studies have addressed the relationship between obstructive sleep apnea (OSA) and abdominal aortic calcification (AAC), a marker for subclinical atherosclerosis and future cardiovascular events. Objectives To investigate 1) the association between OSA severity and AAC, and 2) whether OSA can impact the extent of AAC independent of comorbid atherogenic risk factors. Methods 390 participants aged 40–70 years underwent polysomnography and abdominal computed tomography. AAC was separately quantified in the upper and lower abdominal aorta using the modified Agatston scoring method, and the total AAC score was calculated as a sum of the two scores. OSA was defined as none/mild (apnea-hypopnea index [AHI] Results Log-transformed total AAC score adjusted for age and body mass index (BMI) was greater in participants with an elevated AHI (3.4 for none/mild OSA, 3.7 for moderate OSA, and 4.2 for severe OSA, p = 0.04). Multivariate linear regression analysis including age and BMI as covariates showed that severe OSA was associated with higher scores for the lower and total AAC (β = 0.15 and 0.14, p = 0.01 and 0.01, respectively). The association did not persist after additionally adjusting for traditional atherogenic risk factors including visceral fat, smoking, hypertension, dyslipidemia, and diabetes. Conclusions Severe OSA was associated with a greater extent of AAC, which was dependent on coexisting atherogenic risk factors. Comorbid cardiometabolic disorders may largely mediate the association of OSA with subclinical atherosclerosis.

PET/CT imaging withA total of 167 patients with known or suspected NET lesions were enrolled in this study. The numbers of patients with elevations of ACTH, gastrin, insulin, and no elevation were 10, 25, 7, and 125, respectively. We compared the maximum standardized uptake value (SUVmax) in various organs of each group.In the group with elevated ACTH levels, SUVmax in the pituitary gland, the uncinate process of the pancreas and adrenal glands was lower than those in the group with no elevation (5.7 ± 1.9 vs. 8.4 ± 3.1, P = 0.015; 4.7 ± 3.5 vs. 6.4 ± 2.8, P = 0.037; 10.8 ± 4.8 vs. 13.9 ± 4.7, P = 0.020, respectively). There were no differences in physiologic uptake ofIn NET patients with elevated ACTH levels, physiologic uptake of

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF-1α may become stable and active even under normoxic conditions; for example, when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor functioning in cellular adaptive responses to hypoxia. Recent studies have suggested that HIF-1 activity is upregulated by one of the important circadian clock genes, period circadian clock 2 (PER2); however, its underlying mechanism remains unclear. Here, we show that PER2 functions as an effector protein for the recruitment of HIF-1α to its cognate enhancer sequence, the hypoxia-response element (HRE). We found that the forced expression of PER2 enhanced HIF-1 activity without influencing expression levels of the regulatory subunit of HIF-1, HIF-1α, at either mRNA or protein levels. A series of coimmunoprecipitation-based experiments revealed that PER2 interacted with HIF-1α and facilitated the recruitment of HIF-1α to HRE derived from vascular endothelial growth factor (VEGF) promoter. The PER2-mediated activation of HIF-1 was observed only when the asparagine residue at position 803 of HIF-1α (HIF-1α N803) was kept unhydroxylated by hypoxic stimulation, by introducing an N803A point mutation, or by an inhibitor of N803-dioxygenase, deferoxamine. However, the extent of PER-2-HIF-1α interaction was equivalent regardless of the N803 hydroxylation status. Taken together, these results suggest that, with the help of an unknown sensor molecule for the N803 hydroxylation status, PER2 functions as an effector molecule for the recruitment of HIF-1 to promoter regions of its downstream genes. Our findings reveal a novel regulatory step in the activation of HIF-1, which can be targeted to develop therapeutic strategies against HIF-1-related diseases, such as cancers.

OBJECTIVES: The optimal material for anterior chest wall reconstruction following chest wall resection remains controversial. The aim of this experimental study was to evaluate short-term, morphological and histological outcomes of anterior chest wall reconstruction with a rigid and bioabsorbable material in a canine model. METHODS: Twenty adult beagle dogs underwent anterior chest wall resection. In the experimental group (n= 10), the anterior chest wall was reconstructed with a rigid and bioabsorbable material composed of poly-L-lactide acid matrix (60 wt%) and uncalcined and unsintered hydroxyapatite particles (40 wt%), whereas in the control group it was (n= 10) reconstructed with dual polypropylene mesh sheets. Short-term complication rates were compared with a χ 2 test. Postoperative sternal deviations were evaluated with sternal alignment angles using computed tomography and multiplanar reconstruction and were compared with Mann–Whitney U-test immediately after reconstruction, and at 1, 3, 6, 9 and 12 months postoperatively. Histological findings of the regenerated chest wall tissue were obtained after staining with haematoxylin and eosin and Elastica van Gieson (EVG) and compared at 3, 6, 9 and 12 months. RESULTS: There was not a significant difference in the short-term postoperative complication rate (P= 0.53) and the complication rate was 20% (wound infection, n= 1 and lethal mediastinitis, n= 1) in the control group and 10% (wound infection, n= 1) in the experimental group. The postoperative sternal deviation was significantly less remarkable at 1 month (123.3 ± 32.2° vs 159.4 ± 19.7°, P= 0.027), 3 months (109.8 ± 34.7° vs 150.9 ± 34.2°, P= 0.039) and 12 months (61 ± 15.6° vs 170.3 ± 6.6°, P= 0.046) in the experimental group than in the control group, whereas no significant difference was noted immediately after reconstruction (165.7 ± 6.4° vs 168.4 ± 9.1°, P= 0.50). Histological findings showed dense connective tissue in the regenerated chest wall in both groups and showed chondroblasts in the regenerated chest wall tissue at 3 and 6 months only in the experimental group. CONCLUSIONS: Our results suggest that anterior chest wall reconstruction with a rigid and bioabsorbable material is feasible and may be a valuable alternative to reconstruction with a non-rigid and non-absorbable material.

To evaluate whether readout-segmented echo-planar imaging (RS-EPI) diffusion weighted image (DWI) can diminish image distortion in the head and neck area, compared with single-shot (SS)-EPI DWI. We conducted phantom and patient studies using 3 T magnetic resonance imaging (MRI) with a 16-channel coil. For the phantom study, we evaluated distortion and signal homogeneity in gel phantoms. For the patient study, 29 consecutive patients with clinically suspicious parotid lesions were prospectively enrolled. RS-EPI and SS-EPI DWI were evaluated by two independent readers for identification of organ/lesion and distortion, using semiquantitative scales and quantitative scores. Apparent diffusion coefficient (ADC) values and contrast-noise ratios of parotid tumours (if present; n = 15) were also compared. The phantom experiments showed that RS-EPI provided less distorted and more homogeneous ADC maps than SS-EPI. In the patient study, RS-EPI was found to provide significantly less distortion in almost all organs/lesions (p