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The spread of abnormal opacity on chest computed tomography (CT) has been reported as a predictor of coronavirus disease 2019 (COVID-19) severity; however, the relationship between CT findings and prognosis in patients with severe COVID-19 remains unclear. The objective of this study was to evaluate the extent of abnormal opacity on chest CT and its association with prognosis in patients with COVID-19 in a critical care medical center, using a simple semi-quantitative method. This single-center case-control study included patients diagnosed with severe COVID-19 pneumonia who were admitted to a critical care center. The diagnosis of COVID-19 was based on positive results of a reverse transcription polymerase chain reaction test. All patients underwent non-contrast whole-body CT upon admission. Six representative axial chest CT images were selected for each patient to evaluate the extent of lung lesions. The percentage of the area involved in the representative CT images was visually assessed by 2 radiologists and scored on 4-point scale to obtain the bedside CT score, which was compared between patients who survived and those who died using the Mann-Whitney U test. A total of 63 patients were included in this study: 51 survived and 12 died after intensive treatment. The inter-rater reliability of bedside scores between the 2 radiologists was acceptable. The median bedside CT score of the survival group was 12.5 and that of the mortality group was 16.5; the difference between the 2 groups was statistically significant. The degree of opacity can be easily scored using representative CT images in patients with severe COVID-19 pneumonia, without sophisticated software. A greater extent of abnormal opacity is associated with poorer prognosis. Predicting the prognosis of patients with severe COVID-19 could facilitate prompt and appropriate treatment.

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27–0.74; p p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32–0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28–0.68, p p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.

The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy. Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1–14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively. The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing.

297 Background: An association between improved responses to chemotherapy after exposure to vaccine-based immunotherapy has been previously reported in other cancers. However, it is unclear whether the chemotherapy response improves after exposure to immunotherapy, such as immune checkpoint inhibitors (ICIs). The objective of this retrospective study was to evaluate whether chemotherapy (4th-line) would yield improved efficacy when given after exposure to anti-PD-1 antibody in metastatic gastric cancer (mGC). Methods: We investigated retrospectively clinical characteristics at baseline of mGC patients who received chemotherapy after progression of anti-PD-1 antibody (Nivolumab) between February 2018 and July 2019. Anti-PD-1 antibody was adapted as third-line therapy. Inclusion criteria for the analysis reported herein: histologically proven adenocarcinoma; ECOG PS 0-2; adequate organ functions; and received chemotherapy including 5-fluoropyrimidines (5-FU), platinum, and taxane or irinotecan. We evaluated efficacy outcomes, including ORR, DCR by RECIST version 1.1, PFS, and OS. Results: Out of 27 treated with anti-PD-1 antibody, 10 patients were evaluable for responses and eligible to be included in this analysis. Patient characteristics were as follows: median age (range), 72 (50-88) years; male/female, 8/2; ECOG PS (0/1/2), 4/5/1; HER2 (+/-), 5/5; histology (differentiated/undifferentiated), 5/5; metastatic lesions (LN/peritoneum/liver/lung), 5/3/1/3; number of metastatic sites (1/≥2), 5/5; number of prior CTx regimens (3/4/5), 10/0/0; median period (range) from first line CTx, 18.8 (7.9-47.1) months; and CTx regimens (CPT-11/PTX/S-1+Oxaliplatin), 7/2/1; Among the 10 patients, 1 achieved a partial response, giving an ORR of 10.0%. Six patients had stable disease and three had progressive disease. The DCR was 70%. Median PFS and OS were 5.5M and 8.5M, respectively. These were no new irAEs appeared during CTx. Conclusions: In mGC patients, our study demonstrated that increased efficacy to cytotoxic agents chemotherapy given after exposure to ICI was higher as compared to our historical data from the pre-anti-PD1 era. Updated results will be presented.

298 Background: Stage IV Gastric cancer (GC) is a heterogeneous biological condition with a mixture of distant metastases, including hematologic, lymph nodal and/or peritoneal. In the recent classification introduced by Yoshida et al with the proposal to identify objective principles for conversion surgery, stage IV GC patients were subdivided into 4 new categories. In this study, we retrospectively investigated the efficacy of conversion gastrectomy for stage IV GC patients, with particular focus on the Yoshida’s classification. Methods: A retrospective, single center cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2018. Data were extracted from Hokkaido Cancer Center database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results: Forty-two resected stage IV GC patients were included in this analysis. Median overall survival (OS) was 40.0 months and 1-, 3- and 5-year survivals were 92.9, 70.7 and 57.7%, respectively. Univariate analysis among the patients with conversion gastrectomy identified macroscopic type, clinical response to 1st line therapy, pathological tumor depth, pathological nodal stage, R0 resection as significant prognostic factors. The MSTs of the patients with conversion gastrectomy for each category were 50.1 months for category 1, 46.6 months for category 2, 22.7 months for category 3 and 17.2 months for category 4. Conclusions: Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. Adequate selection of stage IV GC patients for conversion therapy may be an important role.

This study aimed to retrospectively evaluate the efficacy and safety of capecitabine plus oxaliplatin(CapeOX)for heavily pretreated advanced gastric cancer(AGC)refractory to S-1, cisplatin, irinotecan, and taxanes.Twelve patients with AGC refractory to S-1, cisplatin, irinotecan, and taxanes were enrolled in this study.Treatment comprised capecitabine(1,000mg/m / 2 twice a day on days 1-14)and oxaliplatin(130mg/m2 on day 1).Cycles were repeated at 3- week intervals.The overall response rate was 16.7%, and the disease control rate at 6 weeks was 75.0%. The progression free survival was 3.1 months, and the overall survival was 8.3 months after initiation of CapeOX therapy. The most common hematological toxicity was grade 3 neutropenia(50%).Peripheral neuropathy of Grade 1 or 2 was found in 50%of cases, but no Grade 3 or 4 neuropathy was found.CapeOX showed some activities as salvage therapy for heavily pretreated AGC patients.We suggest that CapeOX therapy should be considered a treatment option for pretreated AGC with good performance status.

769 Background: The data from randomized trials suggested that primary tumor location (PTL) could represent a prognostic and predictive factor in mCRC patients, particularly during treatment with anti- EGFR therapy. However, it remains unclear whether anti-EGFR is effective for right- sided primary tumors (RT). Methods: Single-institution, retrospective, case-control study was reviewed. A total of 110 patients with mCRC were enrolled between January 2011 and December 2016. We evaluated the association between PTL and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy (FOLFOX/CapeOX or FOLFIRI/IRIS) plus cetuximab(Cmab) or bevacizumab(Bmab). The impact of PTL for Cmab and Bmab groups was analyzed, respectively. Results: 76 patients presented Left-sided primary tumors (LT) and 34 patients RT. Median PFS, median OS, and ORR were numerically superior in our study patients with LT compared with patients with RT (PFS, L vs R, 13.0 vs 6.8 M, p = 0.0040; OS, 36.2 vs 19.0 M, p = 0.002; ORR, 67.1 vs 44.1 %, p = 0.022951). In the Cmab group, LT were significantly superior to RT in terms of OS (L vs R, 56.3 vs11.3 M, p = 0.0057). Likewise, in the Bmab group, OS showed differences between the LT and RT (L vs R, 27.8 vs 19.7 M, p = 0.0116). In LT, Cmab group were significantly superior to Bmab group in terms of the OS (C vs B, 56.3 vs 27.8 M p = 0.0428). Conversely, in RT, the survival times showed no differences between Cmab and Bmab group (C vs B, 11.3 vs 19.7 M, p = 0.6555). Furthermore, while early tumor shrinkage(ETS) was associated with favorable outcome in patients with RT who treated Cmab, non-ETS represented a less favorable survival (ETS vs non-ETS, NR vs 11.3 M, p = 0.0335). ETS was a predictor for survival benefit acquired from Cmab treatment for patients with RT with wild-type KRAS/RAS tumors. Conclusions: Our study suggests the conclusion that patients with LT with KRAS/RAS wild-type should be preferentially treated with Cmab. By contrast, in RT, chemotherapy plus Bmab may be effective, but optimal treatment has yet to be defined and ETS may be able to predictive of benefit acquired from Cmab.

174 Background: Although the triplet regimen of docetaxel/cisplatin/S-1 (DCS) has shown promising activity and conversion rate in patients with unresectable metastatic gastric cancer (UMGC) in Japan, it was accompanied by severe adverse events. Recent studies suggested that oxaliplatin was almost as active, and relatively less toxic, than cisplatin in combination regimens for UMGC and can therefore replace cisplatin. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended dose (RD), and preliminary efficacy of docetaxel/oxaliplatin/S-1 (DOS) instead of DCS in patients with UMGC. Methods: Previously untreated 16 patients with histologically proven UMGC were enrolled. Docetaxel and oxaliplatin were administered intravenously on day 8. S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first cycle of treatment. Three dose-escalations of DOS were used in this study namely, level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). Results: Among the six patients, one patient each experienced DLTs (febrile neutropenia and diarrhea) at level 1 and 2 doses, respectively. While two more patients experienced DLTs (febrile neutropenia and diarrhea) after administration of level 3 doses. Therefore, two additional patients were enrolled into the study at level 2. However, both these patients subsequently exhibited DLTs (febrile neutropenia and diarrhea). Therefore, we concluded that the MTD and RD with this regimen were level 2 and level 1, respectively, and that the DLT were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) of the patients with measurable lesions, consisting of two complete response and five partial responses. Five patients underwent conversion surgery. Conclusions: The RD of the 3-weekly DOS regimen in patients with UMGC was docetaxel at 50 mg/m2 and oxaliplatin at 100 mg/m2 on day 8 and S-1 at 80 mg/m2 on days 1-14. The efficacy and ease of administration make the regimen a promising alternative to DCS. A phase II study using this RD regimen is currently underway. Clinical trial information: 000015849.

Besides its effect on calcium metabolism, vitamin D may play a part in preventing the onset and progression of cardiovascular disease (CVD) events. Only a few reports on the studies relating to whether vitamin D may reduce CVD events in patients with predialysis chronic kidney disease (CKD) are available, and many ambiguities remain.We conducted a retrospective cohort study of 665 patients with predialysis CKD. With log-rank test using the Kaplan-Meyer survival curve, comparison of incidences of CVD events, CVD-related mortality, and all-cause mortality were made between patients in the alfacalcidol treatment group (107 patients) in the predialysis stage to whom alfacalcidol 0.25-0.5 microg/day was orally administered for at least 24 weeks, and patients in the nontreatment group (558 patients) who received no administration of alfacalcidol or other type of activated vitamin D and its analogues. Patients to whom alfacalcidol administration was discontinued within 24 weeks as well as initiation of dialysis of24 weeks were excluded for this study. Factors relating to CVD events were examined using Cox's proportional hazards analysis.The mean follow-up period was 55.1 +/- 38.9 months in the alfacalcidol treatment group and 41.9 +/- 38.4 months in the nontreatment group. CVD events occurred in 172 patients during the follow-up period, and 74 of those occurred during the predialysis period. In the alfacalcidol treatment group, the incidence of cumulative CVD events was significantly lower. In relation to all-cause deaths and CVD-related deaths, the cumulative mortality rate was significantly lower in the alfacalcidol treatment group during the follow-up period. Throughout the follow-up period, the association between CVD events and alfacalcidol use was detected when adjusted for age, sex, diabetes, hypertension, use of renin-angiotensin system inhibitors, estimated glomerular filtration rate, and albumin and parathyroid hormone.These data showed that oral administration of alfacalcidol for predialysis CKD patients was associated with reduced risk for CVD.

711 Background: Left- and right-sided colon cancers are significantly different in epidemiologic, clinicopathological and molecular characteristics. However, the impact of primary tumor location in mCRC treated biological targeted agent in combination with chemotherapy is unclear. We therefore investigated the prognostic and predictive impact of primary tumor location in mCRC. Methods: Single-institution, retrospective, case-control study was reviewed. A total of 96 patients with mCRC were enrolled between January 2011 and December 2015. We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy plus cetuximab or bevacizumab. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. Left-sided primary tumors were defined as tumors from rectum to splenic flexure, while right-sided primary tumors were defined as tumors from cecum to the distal part of the transverse colon. Results: 68 patients presented left-sided tumors and 28 patients right-sided primary tumors. In the cetuximab group, left-sided tumors were significantly superior to right-sided tumors in terms of the progression-free survival (PFS) and Overall survival (OS) (PFS, left vs right, 18.3 vs 6.8 M, p = 0.0415; OS, 50.6 vs10.5 M, p = 0.0004). Likewise, in the bevacizumab group, OS showed differences between the left- and right-sided tumors (PFS, left vs right, 11.6 vs 7.3 M, p = 0.1904; OS, 25.7 vs 16.2 M, p = 0.0389). In left-sided tumors, cetuximab group were significantly superior to bevacizumab group in terms of the OS (PFS, cetuximab vs bevacizumab, 18.0 vs 11.6 M, p = 0.1088; OS, 50.6 vs 25.7 m p = 0.0354). Conversely, in right-sided, the survival times showed no differences between cetuximab- and bevacizumab group (PFS, cetuximab vs bevacizumab, 6.8 vs 7.3 M, p = 0.7816; OS, 10.5 vs 16.2 M, p = 0.1088). Conclusions: Our study demonstrates that primary tumor location is an important prognostic factor in previously untreated mCRC. Furthermore, left-sided primary tumor location might be a strong predictor of PFS and OS in cetuximab therapy.

205 Background: Chemotherapy occasionally converts an initially unresectable gastric cancer to a resectable cancer. However, the association between clinical factors and long-term prognosis after conversion surgery for unresectable gastric cancer has not been investigated. Methods: We retrospective reviewed 36 gastric cancer patients who underwent conversion surgery at our institute between 2005 and 2015. Clinicopathologic characteristics and patient outcomes were analyzed, with particular focus on the potential to predict long-term survival. Results: The number of incurable factors was one in 31 patients and two in 5, including metastases to non-regional lymph node in 22, peritoneum in 10, liver in 6, and lung in 3. The regimen of chemotherapy was Docetaxel/CDDP/S-1 in 23 patients, Docetaxel/CDDP/S-1+Trastuzmab in 7, S-1/CDDP in 2, Docetaxel/S-1 in 1, CPT/CDDP in 1, and S-1 monotherapy in 1. Complete resection with no residual tumor (R0) was achieved in 25 of 36 patients, microscopic residual tumor status (R1) in 10, and macroscopic residual tumor (R2) in 1. The 3-year overall survival (OS) rate among the 36 patients who underwent conversion surgery was 60.3 % (median survival time, 1200 days). The 3-year OS rate among patients who underwent R0 resection was 70.8 % (median survival time, 1503 days). Patients who underwent R0 resection had significantly longer OS times than those who underwent R1 and R2 resection ( p=0.0124). We selected 16 variables in addition to residual tumor for Kaplan–Meier analysis. According to the log rank test, the following four variables were significantly associated with a better OS: clinical response to 1st line therapy (CR or PR vs. SD or PD)( p=0.0283), pathological response grade (1b-3 vs. 0-1a) ( p=0.0304), pathological tumor depth (CR or T1~T3 vs. T4) ( p=0.0261), and pathological nodal stage (N0〜2 vs. N3) ( p=0.0086). Conclusions: Our data indicates that clinical response to 1st line therapy in preoperative characteristics, R0 resection, pathological response grade, pathological tumor depth, pathological nodal stage in postoperative characteristics are predictive factors that can be expected to long-term survival.

Colonic angiodysplasia (AGD) is an important cause of lower gastrointestinal bleeding. However, most episodes of bleeding from colonic AGD stop spontaneously. To date, few data are available regarding the endoscopic findings of bleeding colonic AGD. In order to clarify the clinical features and endoscopic findings of actively bleeding colonic AGD, we conducted a retrospective study of patients treated with colonoscopy at our hospital. From November 2006 to March 2013 inclusive, 32,586 colonoscopies were performed at this hospital, among which 13 patients with bleeding colonic AGD were enrolled in the current study. The mean age was 84 years (range: 69-90 years). All patients had chronic heart disease and were currently using anticoagulant and/or antiplatelet drugs. Sites of bleeding AGD were localized in the left colon in two patients (15 %) and in the right colon in the remaining patients (85 %). A total of 77 % of the lesions (10/13) were 1-2 mm in size and two lesions were 4 mm in size; only one lesion was larger than 5 mm. Endoscopic treatment resulted in a therapeutic success rate of 100 %, and no recurrence of bleeding was observed in 85 % of the patients (11/13) after treatment. During the study period, two patients presented with bleeding from residual AGD and underwent endoscopic treatment. In the present study, most sites of bleeding colonic AGD were very small, termed “micro-angiodysplasia”, and targeted endoscopic treatment for actively bleeding AGD was found to be effective and safe. It is essential that physicians consider the potential for actively bleeding colonic AGD, especially “micro-angiodysplasia”, when performing colonoscopy in elderly patients with a history of cardiovascular disease and/or treatment with anticoagulant or antiplatelet therapy.

We performed perfusion computed tomography (P-CT) and angiography of the pancreas in patients with severe acute pancreatitis (SAP) and compared the usefulness of these two methods in predicting the development of pancreatic necrosis. We compared P-CT and angiography results taken within 3 days after symptom onset in 21 SAP patients. We divided the pancreas into three areas, the head, body, and tail, and examined each area for perfusion defects (via P-CT) and arterial vasospasms (by angiography). Three weeks later, all patients underwent contrast-enhanced CT to determine whether pancreatic necrosis had developed. Of the 21 SAP patients, 16 exhibited perfusion defects, while 17 proved positive for vasospasms in at least one area. Fourteen patients developed pancreatic necrosis. Of the 63 pancreatic areas from the 21 SAP patients, perfusion defects appeared in 25 areas (39.7%), 24 of which showed vasospasms (96.0%). Angiography showed 33 areas with vasospasms (52.4%), of which 24 showed perfusion defects (72.7%). Of the 25 areas with perfusion defects, 21 developed pancreatic necrosis (84.0%). Of the 33 areas with vasospasms, 21 developed necrosis (63.6%). Pancreatic necrosis developed only in the areas positive both for perfusion defects and for vasospasms. No areas without perfusion defect or vasospasms developed pancreatic necrosis. P-CT predicted the development of pancreatic necrosis with significantly higher accuracy than angiography. While both P-CT and angiography are useful in predicting the development of pancreatic necrosis in patients with SAP, P-CT appears to be more accurate for this purpose.

Darbepoetin alfa, which has a much longer half-life than recombinant human erythropoietin, is used to treat renal anemia. However, there are few reports investigating the efficacy of darbepoetin alfa administered every 2 weeks (Q2W).We performed the single-center, prospective, and randomized study in chronic hemodialysis patients. Clinically stable patients on hemodialysis were recruited, and darbepoetin alfa 15-40 microg/week was administered intravenously once a week (QW) to achieve a hemoglobin (Hb) level of 10.5-12.0 g/dl for 8 weeks prior to randomization. The patients were randomly assigned to 2 different dosing frequency groups: once a week (QW) or every 2 weeks (Q2W). We switched to a double dose in the Q2W group. We measured Hb level every 2 weeks and administered darbepoetin alfa to achieve an Hb level of 10.5-11.5 g/dl. The primary endpoints were the weekly dose of darbepoetin alfa administered at week 24.We assigned 19 and 20 patients into QW and Q2W, respectively. There were no significant differences between the groups in Hb, transferrin saturation, ferritin, and weekly dose of darbepoetin alfa at end of the baseline period. There was no significant difference in Hb level at week 24, at which time the weekly dose requirement and dose per dry body weight were much higher in the Q2W than in the QW group.Administration of darbepoetin alfa Q2W could maintain Hb level similarly to to that obtained QW, but we did not confirm efficiency at a higher dose requirement or blood pressure elevation.

Glu35 in chicken lysozyme has an abnormally high pKa (6.1) partly due to the hydrophobic environment provided by Trp108. The relationship between protein stability and abnormal pKa was investigated in detail by using mutant lysozymes in which Glu35 was replaced by undissociable residues and an oppositely ionizable residue. It was found that lysozyme was stabilized at alkaline pH range by the replacement of Glu35 with an undissociable residue, Gln (E35Q lysozyme) or Al (E35A lysozyme). On the other hand, when Glu35 was replaced by His (E35H lysozyme), which could have an opposite charge to Glu by ionization, the introduced His35 was found to have an abnormally low pKa (3.6), leading to the destabilization of lysozyme at acidic pH. These observations are completely consistent with the situation that the environment around Glu35 is highly hydrophobic and therefore the placement of either a positive or negative charge in such an environment leads to destabilization of lysozyme. These observations also indicate that the replacement of an acidic residue having abnormally high pKa or a basic residue having abnormally low pKa by an undissociable residue is a very efficient and general method for stabilization of a protein.