The Outcome of Complex Hepato-Pancreato-Biliary Surgery for Elderly Patients: A Propensity Score Matching Analysis

Background/Aims: Postoperative mortality and morbidity rates after hepato-pancreato-biliary (HPB) surgery remain high, and the number of elderly patients requiring such surgery has been increasing. This study aimed to investigate postoperative outcomes of complex HPB surgery for elderly patients. Methods: We retrospectively reviewed perioperative data of 721 patients who underwent complex HPB surgery between 2010 and 2015. The patients were divided into 2 groups: elderly (≥75 years) and non-elderly (< 75 years). Surgical outcomes of both groups were compared after propensity score-matching analysis. Subsequently, risk factors for serious postoperative morbidity were identified by multivariate analysis. Results: Before matching, the elderly group (n = 170) had more comorbidities, such as cardiovascular and renal disease, than the non-elderly group (n = 551). Matching yielded elderly (n = 170) and non-elderly groups (n = 170) with similar preoperative backgrounds. The mortality and morbidity rates did not differ significantly between the groups. In multivariate analyses, operative time (OR 1.79; p = 0.005) and blood loss (OR 1.66; p = 0.03) were identified as independent risk factors for serious postoperative morbidity, whereas older age did not have a predictive impact (OR 1.16; p = 0.52). Conclusions: Although elderly ­patients had more comorbidities and higher incidences of postoperative mortality and several complications before matching, their postoperative outcomes were equivalent to those of non-elderly patients after matching

Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP -301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Evaluation of spatial dependence of point spread function-based PET reconstruction using a traceable point-like 22Na source

Abstract Background The point spread function (PSF) of positron emission tomography (PET) depends on the position across the field of view (FOV). Reconstruction based on PSF improves spatial resolution and quantitative accuracy. The present study aimed to quantify the effects of PSF correction as a function of the position of a traceable point-like 22Na source over the FOV on two PET scanners with a different detector design. Methods We used Discovery 600 and Discovery 710 (GE Healthcare) PET scanners and traceable point-like 22Na sources (<1 MBq) with a spherical absorber design that assures uniform angular distribution of the emitted annihilation photons. The source was moved in three directions at intervals of 1 cm from the center towards the peripheral FOV using a three-dimensional (3D)-positioning robot, and data were acquired over a period of 2 min per point. The PET data were reconstructed by filtered back projection (FBP), the ordered subset expectation maximization (OSEM), OSEM + PSF, and OSEM + PSF + time-of-flight (TOF). Full width at half maximum (FWHM) was determined according to the NEMA method, and total counts in regions of interest (ROI) for each reconstruction were quantified. Results The radial FWHM of FBP and OSEM increased towards the peripheral FOV, whereas PSF-based reconstruction recovered the FWHM at all points in the FOV of both scanners. The radial FWHM for PSF was 30–50 % lower than that of OSEM at the center of the FOV. The accuracy of PSF correction was independent of detector design. Quantitative values were stable across the FOV in all reconstruction methods. The effect of TOF on spatial resolution and quantitation accuracy was less noticeable. Conclusions The traceable 22Na point-like source allowed the evaluation of spatial resolution and quantitative accuracy across the FOV using different reconstruction methods and scanners. PSF-based reconstruction reduces dependence of the spatial resolution on the position. The quantitative accuracy over the entire FOV of the PET system is good, regardless of the reconstruction methods, although it depends slightly on the position

Multicentre analysis of PET SUV using vendor-neutral software: the Japanese Harmonization Technology (J-Hart) study

Abstract Background Recent developments in hardware and software for PET technologies have resulted in wide variations in basic performance. Multicentre studies require a standard imaging protocol and SUV harmonization to reduce inter- and intra-scanner variability in the SUV. The Japanese standardised uptake value (SUV) Harmonization Technology (J-Hart) study aimed to determine the applicability of vendor-neutral software on the SUV derived from positron emission tomography (PET) images. The effects of SUV harmonization were evaluated based on the reproducibility of several scanners and the repeatability of an individual scanner. Images were acquired from 12 PET scanners at nine institutions. PET images were acquired over a period of 30 min from a National Electrical Manufacturers Association (NEMA) International Electrotechnical Commission (IEC) body phantom containing six spheres of different diameters and an 18F solution with a background activity of 2.65 kBq/mL and a sphere-to-background ratio of 4. The images were reconstructed to determine parameters for harmonization and to evaluate reproducibility. PET images with 2-min acquisition × 15 contiguous frames were reconstructed to evaluate repeatability. Various Gaussian filters (GFs) with full-width at half maximum (FWHM) values ranging from 1 to 15 mm in 1-mm increments were also applied using vendor-neutral software. The SUVmax of spheres was compared with the reference range proposed by the Japanese Society of Nuclear Medicine (JSNM) and the digital reference object (DRO) of the NEMA phantom. The coefficient of variation (CV) of the SUVmax determined using 12 PET scanners (CVrepro) was measured to evaluate reproducibility. The CV of the SUVmax determined from 15 frames (CVrepeat) per PET scanner was measured to determine repeatability. Results Three PET scanners did not require an additional GF for harmonization, whereas the other nine required additional FWHM values of GF ranging from 5 to 9 mm. The pre- and post-harmonization CVrepro of six spheres were (means ± SD) 9.45% ± 4.69% (range, 3.83–15.3%) and 6.05% ± 3.61% (range, 2.30–10.7%), respectively. Harmonization significantly improved reproducibility of PET SUVmax (P = 0.0055). The pre- and post-harmonization CVrepeat of nine scanners were (means ± SD) 6.59% ± 1.29% (range, 5.00–8.98%) and 4.88% ± 1.64% (range, 2.65–6.72%), respectively. Harmonization also significantly improved the repeatability of PET SUVmax (P < 0.0001). Conclusions Harmonizing SUV using vendor-neutral software produced SUVmax for 12 scanners that fell within the JSNM reference range of a NEMA body phantom and improved SUVmax reproducibility and repeatability

Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation

Multicentre analysis of PET SUV using vendor-neutral software: the Japanese Harmonization Technology (J-Hart) study

Background: Recent developments in hardware and software for PET technologies have resulted in wide variations in basic performance. Multicentre studies require a standard imaging protocol and SUV harmonization to reduce inter- and intra-scanner variability in the SUV. The Japanese standardised uptake value (SUV) Harmonization Technology (J-Hart) study aimed to determine the applicability of vendor-neutral software on the SUV derived from positron emission tomography (PET) images. The effects of SUV harmonization were evaluated based on the reproducibility of several scanners and the repeatability of an individual scanner. Images were acquired from 12 PET scanners at nine institutions. PET images were acquired over a period of 30 min from a National Electrical Manufacturers Association (NEMA) International Electrotechnical Commission (IEC) body phantom containing six spheres of different diameters and an 18F solution with a background activity of 2.65 kBq/mL and a sphere-to-background ratio of 4. The images were reconstructed to determine parameters for harmonization and to evaluate reproducibility. PET images with 2-min acquisition × 15 contiguous frames were reconstructed to evaluate repeatability. Various Gaussian filters (GFs) with full-width at half maximum (FWHM) values ranging from 1 to 15 mm in 1-mm increments were also applied using vendor-neutral software. The SUVmax of spheres was compared with the reference range proposed by the Japanese Society of Nuclear Medicine (JSNM) and the digital reference object (DRO) of the NEMA phantom. The coefficient of variation (CV) of the SUVmax determined using 12 PET scanners (CVrepro) was measured to evaluate reproducibility. The CV of the SUVmax determined from 15 frames (CVrepeat) per PET scanner was measured to determine repeatability. Results: Three PET scanners did not require an additional GF for harmonization, whereas the other nine required additional FWHM values of GF ranging from 5 to 9 mm. The pre- and post-harmonization CVrepro of six spheres were (means ± SD) 9.45% ± 4.69% (range, 3.83–15.3%) and 6.05% ± 3.61% (range, 2.30–10.7%), respectively. Harmonization significantly improved reproducibility of PET SUVmax (P = 0.0055). The pre- and post-harmonization CVrepeat of nine scanners were (means ± SD) 6.59% ± 1.29% (range, 5.00–8.98%) and 4.88% ± 1.64% (range, 2.65–6.72%), respectively. Harmonization also significantly improved the repeatability of PET SUVmax (P < 0.0001). Conclusions: Harmonizing SUV using vendor-neutral software produced SUVmax for 12 scanners that fell within the JSNM reference range of a NEMA body phantom and improved SUVmax reproducibility and repeatability