Early evaluation of CAR-T cell therapy response in R/R DLBCL patients using 18F-FDG PET/CT.

OBJECTIVE: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. SUBJECTS AND METHODS: Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. RESULTS: Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. CONCLUSION: Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.

Hepatic Artery Embolization Enhances Expression of Programmed Cell Death 1 Ligand 1 in an Orthotopic Rat Hepatocellular Carcinoma Model: In Vivo and in Vitro Experimentation.

PURPOSE: To evaluate the effects of hepatic artery embolization (HAE) on the expression of programmed cell death 1 ligand 1 (PD-L1) in an orthotopic rat hepatocellular carcinoma (HCC) model. MATERIALS AND METHODS: A rat HCC model was established in Sprague-Dawley rats with the RH7777 cell line. Six animals each were assigned to receive HAE or sham treatment. Liver tissues were harvested 24 h after the procedure. Immunohistochemistry (IHC) was used to compare expression of PD-L1 and hypoxia-inducible factor (HIF)-1α in the intratumoral and peritumoral regions and normal liver tissue. In vitro cell culture study was performed for 24 h under normoxic and hypoxic conditions, and protein expression of PD-L1 and HIF-1α and the effects of HIF-1α inhibitors were assessed. RESULTS: IHC showed that PD-L1- and HIF-1α-positive areas were significantly larger in the HAE group vs the sham group in intratumoral (P = .006 and P < .001, respectively) and peritumoral regions (both P < .001). The expression of PD-L1 positively correlated with HIF-1α expression in the intratumoral region (r2 = 0.551; P < .001). In vitro cell culture study revealed that protein expression of PD-L1 and HIF-1α were significantly higher when cells were incubated under hypoxic vs normoxic conditions (P = .028 and P = .010, respectively). PD-L1 expression was suppressed significantly when the HIF-1α inhibitor rapamycin was added to the culture medium (P = .024). CONCLUSIONS: HAE enhances intratumoral and peritumoral PD-L1 expression in a rat HCC model. The HIF-1α pathway is a possible mechanism underlying increased intratumoral PD-L1 expression after HAE.

Disseminated Carcinomatosis of the Bone Marrow from Castration-Resistant Prostate Cancer Revealed by Choline Positron Emission Tomography-Computed Tomography.

Introduction: Disseminated carcinomatosis of the bone marrow is caused by cancer metastasis to the bone marrow and is the diagnosis is very difficult by imaging. Case Presentation: We report a 75-year-old male with disseminated carcinomatosis of the bone marrow from castration-resistant prostate cancer revealed by 11C-choline positron emission tomography-computed tomography (PET/CT). Although he already received radiotherapy to the prostate, combined androgen blockade, enzalutamide and apalutamide, and external beam radiotherapy for the pelvic bone metastases, serum prostate-specific antigen (PSA) value rapidly increased from 32 ng/mL to 104 ng/mL in recent 1 month. Bone scintigraphy showed almost no abnormal uptake in the whole body, whereas 11C-choline PET/CT showed diffuse bone marrow 11C-choline uptake. The disseminated carcinomatosis of the bone marrow was diagnosed from the discordant findings between bone scintigraphy and 11C-choline PET/CT examinations and confirmed pathologically by iliac marrow biopsy pathologically. Although docetaxel therapy was started, PSA value continued rising and he died after 4 months of the diagnosis. Conclusion: The discordant findings of choline PET/CT and bone scintigraphy can diagnose disseminated carcinomatosis of the bone marrow from prostate cancer.

Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1.

Mechanistic target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase that is activated by extracellular signals, such as nutrients and growth factors. It plays a key role in the control of various biological processes, such as protein synthesis and energy metabolism by mediating or regulating the phosphorylation of multiple target molecules, some of which remain to be identified. We have here reanalysed a large-scale phosphoproteomics data set for mTORC1 target molecules and identified pre-B cell leukemia transcription factor 2 (PBX2) as such a novel target that is dephosphorylated downstream of mTORC1. We confirmed that PBX2, but not other members of the PBX family, is dephosphorylated in an mTORC1 activity-dependent manner. Furthermore, pharmacological and gene knockdown experiments revealed that glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1) are responsible for the phosphorylation and dephosphorylation of PBX2, respectively. Our results thus suggest that the balance between the antagonistic actions of GSK3 and PP1 determines the phosphorylation status of PBX2 and its regulation by mTORC1.

Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.

Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

Radiofrequency Ablation by a 21-Gauge Internally Cooled Electrode: Ex Vivo and In Vivo Evaluation by Rat Liver.

PURPOSE: To evaluate the coagulative performance of a 21-gauge (G) internally cooled radiofrequency (RF) electrode using ex vivo and in vivo rat liver. MATERIALS AND METHODS: We developed a prototype of 21-G internally cooled monopolar RF electrode with 5.0 mm active tip length. The ablative zone size created by this electrode was evaluated in ex vivo and in vivo rat liver. Five RF powers (3 W, 5 W, 7 W, 9 W, and 11 W) were applied with and without circulation of chilled water within the electrode. The ablation zone sizes were compared. Histopathological evaluation of the ablation zone was also performed at 24 h and at 7 days after RF ablation. RESULTS: From ex vivo experiments, the ablation volume was found to increase significantly when RF energy was applied with the chilled water circulation. Results of in vivo experiments demonstrate that the ablation volume reached its maximum value when RF power of 7 W was applied (532.3 ± 110.3 mm3). Histopathological examination showed delineated coagulation necrosis at 24 h after RF ablation, which clarified the ablation zone border. Fibrotic change was also observed at 7 days after RF ablation. CONCLUSION: RF ablation using a 21-gauge electrode produced coagulation necrosis in the rat liver. The ablation volume became maximum when RF power of 7 W was applied with chilled water circulation.

Time-saving method for directly amplifying and capturing a minimal amount of pancreatic tumor-derived mutations from fine-needle aspirates using digital PCR.

It is challenging to secure a cytopathologic diagnosis using minute amounts of tumor fluids and tissue fragments. Hence, we developed a rapid, accurate, low-cost method for detecting tumor cell-derived DNA from limited amounts of specimens and samples with a low tumor cellularity, to detect KRAS mutations in pancreatic ductal carcinomas (PDA) using digital PCR (dPCR). The core invention is based on the suspension of tumor samples in pure water, which causes an osmotic burst; the crude suspension could be directly subjected to emulsion PCR in the platform. We examined the feasibility of this process using needle aspirates from surgically resected pancreatic tumor specimens (n = 12). We successfully amplified and detected mutant KRAS in 11 of 12 tumor samples harboring the mutation; the positive mutation frequency was as low as 0.8%. We used residual specimens from fine-needle aspiration/biopsy and needle flush processes (n = 10) for method validation. In 9 of 10 oncogenic KRAS pancreatic tumor samples, the "water-burst" method resulted in a positive mutation call. We describe a dPCR-based, super-sensitive screening protocol for determining KRAS mutation availability using tiny needle aspirates from PDAs processed using simple steps. This method might enable pathologists to secure a more accurate, minimally invasive diagnosis using minute tissue fragments.

Clinical course of conservative management for isolated superior mesenteric arterial dissection.

OBJECTIVES: Isolated superior mesenteric arterial dissection (ISMAD) is an uncommon type of arterial dissection and treated with surgery, stenting, or conservative management. This study aimed to evaluate the criteria for conservative therapy for ISMAD patients based on imaging findings. METHODS: Eighteen consecutive ISMAD patients without peritoneal irritation at onset were retrospectively studied. The decision to perform stenting was based on the emergence of peritoneal irritation, aneurysm, or mesenteric ischemia. Clinical manifestations, follow-up contrast-enhanced computed tomography (CECT) findings, and patient outcome were evaluated. RESULTS: Most patients (16, 89%) were successfully treated conservatively; two patients (11%) required endovascular stenting because of an aneurysm or ulcer-like projection (ULP) sign. The median duration of fasting and hospital stays was 3 (range, 1-8) and 9 (range, 4-34) days, respectively. On CECT, the median distance from the superior mesenteric artery (SMA) origin to the entry site was 12 mm (range, 5-35 mm), and the median length of dissection was 87.5 mm (range, 20-150 mm). Among 16 patients treated conservatively, serial imaging was obtained in 11 patients (69%), and disappearance of the dissection within 4 months occurred in five patients. Two patients treated with endovascular stent underwent follow-up CECT 1 year after onset, and there were no complications. CONCLUSIONS: ISMAD patients without peritoneal irritation can be treated conservatively if there are no signs of an aneurysm, ULP, or mesenteric ischemia. When an aneurysm or ULP sign exists, endovascular stenting was able to preserve SMA blood flow with the improvement of the dissection.