Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Chemotherapy after nivolumab for advanced gastric cancer (REVIVE): a prospective observational study.

BACKGROUND: Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC. PATIENTS AND METHODS: We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival. RESULTS: A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%). CONCLUSIONS: The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings.

Novel Functional Peptide for Next-Generation Vital Pulp Therapy.

Although vital pulp therapy should be performed by promoting the wound-healing capacity of dental pulp, existing pulp-capping materials were not developed with a focus on the pulpal repair process. In previous investigations of wound healing in dental pulp, we found that organic dentin matrix components (DMCs) were degraded by matrix metalloproteinase-20, and DMC degradation products containing protein S100A7 (S100A7) and protein S100A8 (S100A8) promoted the pulpal wound-healing process. However, the direct use of recombinant proteins as pulp-capping materials may cause clinical problems or lead to high medical costs. Thus, we hypothesized that functional peptides derived from recombinant proteins could solve the problems associated with direct use of such proteins. In this study, we identified functional peptides derived from the protein S100 family and investigated their effects on dental pulp tissue. We first performed amino acid sequence alignments of protein S100 family members from several mammalian sources, then identified candidate peptides. Next, we used a peptide array method that involved human dental pulp stem cells (hDPSCs) to evaluate the mineralization-inducing ability of each peptide. Our results supported the selection of 4 candidate functional peptides derived from proteins S100A8 and S100A9. Direct pulp-capping experiments in a rat model demonstrated that 1 S100A8-derived peptide induced greater tertiary dentin formation compared with the other peptides. To investigate the mechanism underlying this induction effect, we performed liquid chromatography-tandem mass spectrometry analysis using hDPSCs and the S100A8-derived peptide; the results suggested that this peptide promotes tertiary dentin formation by inhibiting inflammatory responses. In addition, this peptide was located in a hairpin region on the surface of S100A8 and could function by direct interaction with other molecules. In summary, this study demonstrated that a S100A8-derived functional peptide promoted wound healing in dental pulp; our findings provide insights for the development of next-generation biological vital pulp therapies.

Impact of tumor growth rate during preceding treatment on tumor response to nivolumab or irinotecan in advanced gastric cancer.

BACKGROUND: Nivolumab (NIVO) and irinotecan (IRI) are standard treatments for refractory advanced gastric cancer (AGC); however, it is unclear which drug should be administered first or in which cases. The tumor growth rate (TGR) during preceding treatment is reported to be associated with tumor response in metastatic colorectal cancer patients treated with regorafenib or trifluridine/tipiracil, suggesting that TGR may be useful for drug selection. Therefore, we evaluated the association between TGR during preceding treatment and the tumor response to NIVO or IRI. PATIENTS AND METHODS: We retrospectively evaluated consecutive AGC patients treated with NIVO or IRI and divided them into slow-growing (Slow) and rapid-growing (Rapid) groups according to TGR and the presence or absence of new lesions (NL+/NL-, respectively) during preceding treatment (Slow group: NL- with low TGR <0.30%/day; Rapid group: NL+ or high TGR ≥0.30%/day). RESULTS: A total of 117 patients (Rapid/Slow groups, 72/45; NIVO/IRI groups, 32/85) were eligible. All baseline characteristics except peritoneal metastases were similar between patients treated with NIVO and IRI in the Rapid and Slow groups. The response rate was significantly higher in patients treated with NIVO compared with IRI [31%/3%; odds ratio (OR), 13.8; P = 0.01; adjusted OR, 52; P = 0.002] in the Slow group, but there was no difference between patients treated with NIVO and IRI (5%/8%; OR, 0.68; P = 0.73; adjusted OR, 0.94; P = 0.96) in the Rapid group. Disease control rate, progression-free survival, and overall survival were consistent with these results. CONCLUSIONS: Our findings suggest that NIVO treatment is a more favorable option for patients with slow-growing tumors, and NIVO and IRI are similarly recommended for patients with rapid-growing tumors in refractory AGC. TGR and NL emergence during preceding treatment may be helpful for drug selection and warrant further investigation.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Single-center Experience of Living-donor Liver Transplantation in Patients Receiving Maintenance Renal Replacement Therapy.

BACKGROUND: For most patients with liver failure receiving maintenance renal replacement therapy (RRT), treatment with living-donor liver transplantation (LDLT) alone is indicated in Japan. MATERIAL AND METHODS: We retrospectively reviewed patients who underwent LDLT while receiving RRT in our hospital. RESULTS: Three of the 5 patients who underwent LDLT while on RRT died during the first year after transplantation. CONCLUSIONS: The indications for liver transplantation in patients on RRT require careful examination.

Portal Vein Stent Placement in Living-donor Liver Transplantation: A Single-center Experience.

INTRODUCTION: Portal vein thrombosis (PVT) and portal vein stenosis (PVS) are rare complications after liver transplantation that can lead to graft failure and patient death. MATERIAL AND METHODS: The aim of this study was to evaluate the effect of interventional treatment for PVT and PVS occlusion after liver transplantation. Follow-up data of 7 patients who underwent stent replacement for PVT and/or PVS were analyzed. The clinical success, complications, and portal vein patency were analyzed. RESULTS: Clinical success was obtained in 6 of the 7 patients. No portal hypertension-related symptoms reoccurred in the 6 patients during the follow-up. CONCLUSIONS: Interventional radiologic treatment produced a high success rate and a favorable long-term outcome.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer (GC) was published in 2016, and covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic GC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic GC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Site-specific Chemotherapy Based on Predicted Primary Site by Pathological Profile for Carcinoma of Unknown Primary Site.

AIMS: Although platinum-based combination chemotherapies are commonly used for unfavourable subsets of cancer of unknown primary (CUP), the prognosis remains poor. Several studies have suggested that gene expression profiling or immunohistochemistry was useful for the prediction of primary sites in CUP, and site-specific therapy based on predicted primary sites might improve overall outcomes. In Japan, to identify primary sites, immunohistochemical tests were commonly used for CUP in clinical practice. However, it is unclear whether site-specific therapy based on predicted primary sites by pathological examination contributes survival benefit for unfavourable CUP subsets. PATIENTS AND METHODS: In this study, 122 patients with unfavourable subsets of CUP were retrospectively reviewed. Ninety patients assigned to cohort A after July 2012 had received chemotherapy according to predicted primary sites; 32 patients assigned to cohort B before June 2012 had received platinum-based empiric chemotherapy. RESULTS: In cohort A, 56 patients (62.2%) with predicted primary sites by pathological examination received site-specific therapy; 34 patients (37.8%) with unpredictable primary sites received platinum-based empiric chemotherapy, the same as cohort B. The median overall survival was 20.3 months in patients with predictable primary sites in cohort A and 10.7 months in those of cohort B, with a significant difference between these cohorts (P = 0.03, adjusted hazard ratio = 0.57, 95% confidence interval 0.34-0.94). CONCLUSION: Site-specific therapy based on predicted primary sites by pathological examination could improve prognosis in patients with an unfavourable subset of CUP.

Duodenal Ulcer as a Postoperative Complication in the Donor in Living-Donor Liver Transplantation.

INTRODUCTION: Donor safety is one of the most important factors in living-donor liver transplantation. Duodenal ulcer (DU) is a common postoperative complication. Here we aimed to reveal the risk factors associated with postoperative DU in the donors. METHODS: Between April 2007 and March 2017, 318 cases underwent donor hepatectomy for liver transplantation at Kumamoto University Hospital. We classified the donors into two groups: a DU group and a non-DU group. DU was defined as mucosal break with unequivocal depth requiring an endoscopic procedure. The characteristics and clinical factors of the donors were retrospectively analyzed. RESULTS: Postoperative DU occurred in 17 donors during the study period. The mean interval after donor hepatectomy to occurrence of DU was 124.8 ± 185.4 days. The two groups were comparable in terms of age at time of the donor hepatectomy (P = .45). The male-to-female ratio (P = .03) was significantly different between the two groups and left-side hepatectomy was performed more often in the DU group (P = .003). Multivariable logistic regression revealed that left-side hepatectomy was independently associated with postoperative DU in the donors. CONCLUSIONS: These findings indicated that left-side hepatectomy is a risk factor for postoperative DU in the donors.

A comparative study of dipolarization fronts at MMS and Cluster.

We present a statistical study of dipolarization fronts (DFs), using magnetic field data from MMS and Cluster, at radial distances below 12 RE and 20 RE , respectively. Assuming that the DFs have a semicircular cross section and are propelled by the magnetic tension force, we used multispacecraft observations to determine the DF velocities. About three quarters of the DFs propagate earthward and about one quarter tailward. Generally, MMS is in a more dipolar magnetic field region and observes larger-amplitude DFs than Cluster. The major findings obtained in this study are as follows: (1) At MMS ∼57 % of the DFs move faster than 150 km/s, while at Cluster only ∼35 %, indicating a variable flux transport rate inside the flow-braking region. (2) Larger DF velocities correspond to higher Bz  values directly ahead of the DFs. We interpret this as a snow plow-like phenomenon, resulting from a higher magnetic flux pileup ahead of DFs with higher velocities.

Observational Test for a Random Sweeping Model in Solar Wind Turbulence.

Evidence of frequency broadening at ion kinetic scales due to large-scale eddies and waves is found in solar wind turbulence by a test for a random sweeping model using the magnetic energy spectrum in the frequency vs wave number domain in the comoving frame of the flow obtained from multispacecraft observations. The statistical analysis of the frequency vs wave number spectra without using Taylor's hypothesis shows Gaussian frequency broadening around nearly zero frequencies that increases for larger wave numbers and non-Gaussian tails at higher frequencies. Comparison of the observed frequency broadening with a random sweeping model derived from hydrodynamic turbulence reveals similarities with respect to the Gaussian shape. The standard deviation of the broadening scales with ∼k^{1.6±0.2} and differs from the hydrodynamic turbulence model that predicts ∼k^{2/3}. We interpret this stronger increasing broadening as a consequence of the more diverse large scale structures (eddies and waves) in plasma turbulence and the accompanied more complex sweeping. Consequently, an identification and association of waves with normal modes based on their dispersion relation only, in particular at ion kinetic scales and below, is not possible in solar wind turbulence.

Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas.

AIMS: Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor-κB (NF-κB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL. METHODS: We conducted the systematic sequencing of 21 genes relevant to the NF-κB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation. RESULTS: The results showed that 68 out of 71 PCNSLs had mutations in the NF-κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265. CONCLUSIONS: The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.

Effect of GDF-5 and BMP-2 on the expression of tendo/ligamentogenesis-related markers in human PDL-derived cells.

OBJECTIVES: The effect of growth differentiation factor 5 and bone morphogenetic protein 2 on human periodontal ligament-derived cells was investigated with special reference to tendo/ligamentogenesis-related markers. MATERIALS AND METHODS: Effects of each factor were analyzed by quantitative PCR for scleraxis and tenomodulin and by western blotting for scleraxis. After exposure to those factors, STRO-1-positive and STRO-1-negative fractions of human periodontal ligament tissues were isolated with an immunomagnetic cell sorting system, and the expression of scleraxis in each fraction was analyzed by western blotting. Non-separated crude cells were used as a control. RESULTS: Growth differentiation factor 5 and bone morphogenetic protein 2 did not increase alkaline phosphatase activity in crude periodontal ligament-derived cells. Growth differentiation factor 5, but not bone morphogenetic protein 2, increased the expression of scleraxis in crude, STRO-1-positive and STRO-1-negative periodontal ligament-derived cells. The expression of scleraxis in STRO-1-positive periodontal ligament-derived cells was significantly less compared to that in crude P2 and STRO-1-negative periodontal ligament-derived cells. CONCLUSION: Growth differentiation factor 5 induced the expression of scleraxis and may enhance tendo/ligamentogenesis in human periodontal ligament-derived cells. The expression of scleraxis was higher in STRO-1-negative fraction, suggesting more differentiated state of the cells.

SU-E-J-135: 3-D Fourier-Based Volumetric Registration for Estimating Intra-Fractional Lung Tumor Motion.

PURPOSE: To develop a three-dimensional (3-D) volumetric registration algorithm to estimate the intra-fractional lung tumor motion between respiratory phases for improving the accuracy of radiotherapy treatment. METHODS: The 3-D thoracic CT volumes (512×512×160 voxels, with dimensions 0.97×0.97×2.5 mm3 ) in different respiratory phases were acquired on a General Electric Optima T580 scanner in cine mode. As a preprocess, a bicubic interpolation was used to interpolate the original 3-D volumes along the cephalo-caudal axis to volumes of size 512×512×400 voxels, with dimensions 0.97×0.97×1 mm3 . In each respiratory phase, a sub-volume covering the tumor was roughly specified manually. A 3-D phase correlation of two sub-volumes was computed by using the 3-D inverse Fourier transformation of the normalized cross power spectrum of two sub-volumes. The 3-D displacements along three axes were estimated by finding the location of the highest peak in the 3-D phase correlation. RESULTS: Experiments were conducted on an artificial 4-D CT data set and three clinical 4-D CT data sets. Experimental results shown that the proposed algorithm was capable of estimating the tumor motion between respiratory phases with a high-accuracy (mean square error <1 mm). CONCLUSIONS: This work extended the conventional image registration techniques from 2-D to 3-D for tumor motion estimation. This work indicates a potential for significant accuracy improvement in radiotherapy treatment planning. The high-accurate 3-D tumor motion information provides a reliable basis for expanding a clinical target volume (CTV) to a planning target volume (PTV) to incorporate the intra-fractional tumor motion.

SU-D-BRA-02: An Extended Time-Variant Seasonal Autoregressive Model-Based Prediction for Irregular Breathing Motion Tracking.

PURPOSE: Real-time tumor position/shape measurement and dynamic beam tracking techniques allow accurate and continuous irradiation to moving tumor, but there can be a delay of several hundred milliseconds between observation and irradiation. A time-variant seasonal autoregressive (TVSAR) model has been proposed for compensating the delay by predicting respiratory tumor motion with sub-millimeter accuracy for a second latency. This is the-state-of-the-art model for almost regular breathing prediction so far. In this study, we propose an extended prediction method based on TVSAR to be usable for various breathing patterns, by predicting the residual component obtained from conventional TVSAR. METHODS: An essential core of the method is to take into account the residual component that is not predictable by only TVSAR. The residual component involves baseline shift, amplitude variation, and so on. In this study, the time series of the residual obtained for every new sample are predicted by using autoregressive (AR) model. The order and parameters of the AR model is adaptively determined for each residual component by using an information criterion. Eleven data sets of 3-D lung tumor motion, observed at Georgetown University Hospital by using Cyberknife Synchrony system, were used for evaluation of the prediction performance. RESULTS: Experimental results indicated that the proposed method is superior to those of conventional and the state-of-the-art methods for 0 to 1 s ahead prediction. The average prediction error of the proposed method was 0.920 plus/minus 0.348 mm for 0.5 s forward prediction. CONCLUSION: We have developed the new prediction method based on TVSAR model with adaptive residual prediction. The new method can predict various respiratory motions including not only regular but also a variety of irregular breathing patterns and thus can compensate the bad effect of the delay in dynamic irradiation system for moving tumor tracking. A part of this work has been financially supported by Varian Medical Systems Inc., Palo Alto, CA and Japan Society for the Promotion of Science (JSPS), Japan.

Wave-number-frequency spectrum for turbulence from a random sweeping hypothesis with mean flow.

We derive the energy spectrum in wave-number-frequency space for turbulent flows based on Kraichnan's idealized random sweeping hypothesis with additional mean flow, which yields the instantaneous energy spectrum multiplied by a Gaussian frequency distribution. The model spectrum has two adjustable parameters, the mean flow velocity and the sweeping velocity, and has the property that the power-law index of the wave-number spectrum translates to the frequency spectrum, invariant for arbitrary choices of the mean velocity and sweeping velocity. The model spectrum incorporates both Taylor's frozen-in flow approximation and the random sweeping approximation in a natural way and can be used to distinguish between these two effects when applied to real time-resolved multipoint turbulence data. Evaluated in real space, its properties with respect to space-time velocity correlations are discussed, and a comparison to the recently introduced elliptic model is drawn.