Tsutomu Mizoshita’s research while affiliated with Nagoya City University and other places

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Publications (171)


Poor Tolerability of Lenvatinib in Elderly Patients with Advanced Hepatocellular Carcinoma after Disease Progression following First-Line Atezolizumab Plus Bevacizumab: A Multicenter Study
  • Article

October 2024

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14 Reads

Oncology

Daisuke Kato

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Takanori Suzuki

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Kentaro Matsuura

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Introduction: We investigated the effectiveness of lenvatinib (LEN) after disease progression following first-line treatment with atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable hepatocellular carcinoma (HCC). Methods: One hundred and ten HCC patients treated with Atez/Bev as first-line systemic chemotherapy were enrolled and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response. We evaluated the treatment efficacy and prognosis after second-line LEN treatment, especially in elderly patients. Results: Of the 110 study patients, 88 patients (80%) were determined to have progressive disease (PD) during the observation periods, and 40 patients received second-line LEN therapy. The 40 patients included 13 patients who were unable to continue LEN until the initial evaluation due to adverse events (AE). The 27 patients who were able to continue LEN therapy (Group A) were significantly younger at initiation of Atez/Bev than those who could not continue (71 vs. 77 years old, p = 0.013). Comparing the OS and PFS between Group A and 44 patients that included 13 patients who were unable to continue LEN and 31 patients did not receive the second-line treatment (Group B), the former had significantly better OS than Group B (31.1 vs. 17.8 months, p = 0.035). Conclusions: The tolerability of second-line LEN therapy was lower in elderly patients, and the OS from the start of Atez/Bev therapy was different depending on the tolerability of second-line LEN therapy.


Table 2 (continued)
Clinical characteristics of patients with pneumatosis intestinalis
Multicenter epidemiological survey of pneumatosis intestinalis in Japan
  • Article
  • Full-text available

May 2022

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34 Reads

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9 Citations

BMC Gastroenterology

Background Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome. Methods We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion. Results We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02–1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04–167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80–152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02–15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82–145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31–144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10–72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07–140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053–131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09–189.48, P = 0.0425). Discussion Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis.

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Summary of demographic factors and baseline characteristics by group in the full analysis set (FAS)
Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial

April 2021

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1,028 Reads

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41 Citations

The Lancet Gastroenterology & Hepatology

Background Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab. Methods We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. Findings Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1–90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0–69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7–44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0–44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI −10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9–90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions. Interpretation Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. Funding Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan. Translation For the Japanese translation of the abstract see Supplementary Materials section.


Efficacies of first and second tumor necrosis factor inhibitors in refractory ulcerative colitis patients in real-world practice

October 2020

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18 Reads

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1 Citation

Indian Journal of Gastroenterology

Background Switching tumor necrosis factor-α inhibitors is an important treatment option for refractory ulcerative colitis (UC) patients who fail the first anti-tumor necrosis factor-α therapy, although many questions about this option remain unanswered.Methods The efficacy of the second anti-tumor necrosis factor-α therapy in refractory UC patients who failed the first anti-tumor necrosis factor-α therapy was examined using the Mayo score as a measure of disease activity at week 8. The efficacy of the first anti-tumor necrosis factor-α therapy before treatment and at weeks 8 and 52 was also evaluated in real-world practice.ResultsThere were no significant differences in remission induction and maintenance between infliximab and adalimumab as the first anti-tumor necrosis factor-α therapy in UC patients. Of 123 UC patients, 21 (17.1%) switched tumor necrosis factor-α inhibitors. Eight (38.1%), 4 (19.0%), 7 (33.3%), and 2 (9.5%) patients switched from infliximab to adalimumab, infliximab to golimumab, adalimumab to infliximab, and adalimumab to golimumab, respectively. Three (100%) with intolerance to the first anti-tumor necrosis factor-α therapy, 5 (41.7%) with loss of response to the first anti-tumor necrosis factor-α therapy, and 1 (20.0%) with no improvement with the first anti-tumor necrosis factor-α therapy had clinical remission at week 8.Conclusions Switching tumor necrosis factor-α inhibitors is more effective for refractory UC patients who are intolerant and lose response to the first anti-tumor necrosis factor-α therapy rather than for those showing no improvement with the first anti-tumor necrosis factor-α therapy. Patients with primary failure of anti-tumor necrosis factor-α therapy should be switched to another class of drug.


Baseline Demographic Data of Seven Cases That Received Combination Therapy With TOF and Intensive GMA for Refractory UC
Combination Therapy With Tofacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction Therapy for Refractory Ulcerative Colitis

January 2020

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40 Reads

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10 Citations

Journal of Clinical Medicine Research

Background: The use of monotherapy with intensive granulocyte and monocyte adsorptive apheresis (GMA) or a Janus kinase (JAK) inhibitor has been limited to patients with refractory ulcerative colitis (UC). The efficacy and safety of combination therapy with tofacitinib (TOF) plus intensive GMA (two sessions per week) for refractory UC have not been evaluated. Methods: This retrospective study evaluated the 10-week efficacy of combination therapy with TOF plus intensive GMA in patients with refractory UC. Results: Of seven patients who received a combination therapy with TOF plus intensive GMA, 71.4% achieved clinical remission at 10 weeks. The percentages of patients with mucosal healing and complete mucosal healing at 10 weeks were 100% and 42.9%, respectively. The mean full Mayo score and endoscopic subscore at baseline were 8.71 ± 0.80 and 2.4 ± 0.2, respectively, and the corresponding values at 10 weeks were 1.57 ± 0.48 and 0.6 ± 0.2 (P < 0.01), respectively. Adverse events of an orolabial herpes and temporary increase in creatinine phosphokinase (CK) and triglyceride were observed in three patients. Conclusions: Based on these outcomes, combination therapy with TOF plus intensive GMA was well tolerated and may be useful for induction of clinical remission in patients with refractory UC.



Table 1 . Characteristics of the Study Cohort
Figure 3. Correlation between urinary trefoil factor 3 and disease stage of colorectal cancer. Data were analyzed using the Spearman rank correlation.
Table 4 . Urinary Protein Level in the Validation Cohort
Urinary Cysteine-Rich Protein 61 and Trefoil Factor 3 as Diagnostic Biomarkers for Colorectal Cancer

March 2019

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34 Reads

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22 Citations

Translational Oncology

Since a fecal occult blood test for colorectal cancer (CRC) does not offer sufficient diagnostic power for CRC, novel non-invasive biomarkers are hopeful for CRC screening. We conducted the current study to discover non-invasive urinary biomarkers for diagnosing CRC. Among urine samples from 258 patients (CRC, n = 148; healthy controls, n = 110), a cohort of 176 patients composed of 88 patients with GC and 88 healthy controls was selected after age- and sex-matching using propensity score. This cohort was then randomly divided into 2 groups: 53 pairs (106 patients) in the training cohort, and 35 pairs (70 patients) in the validation cohort. No significant differences were found for baseline characteristics between the CRC and healthy control groups in both training and validation cohorts. On multivariate analysis in the training cohort, urinary levels of cysteine-rich protein 61 (uCyr61) and trefoil factor 3 (uTFF3) were identified as independent significant diagnostic markers for CRC. Moreover, uCyr61 alone and the combination of uCyr61 and uTFF3 allowed significant differentiation between healthy controls and CRC groups in the training set (uCyr61: area under the curve (AUC) = 0.745 [95% CI, 0.653–0.838]; uCyr61 + uTFF3: AUC = 0.753 [95% CI, 0.659–0.847]). In the validation cohort, uCyr61 and uTFF3 were significantly higher in the CRC group than in the healthy control group, and they also allowed significant differentiation between healthy control and CRC groups (uCyr61: AUC = 0.696 [95% CI, 0.571–0.822]; uTFF3: AUC = 0.639 [95% CI, 0.508–0.770]; uCyr61 + uTFF3: AUC = 0.720 [95% CI, 0.599–0.841]), as in the training cohort. A panel combining uCyr61 and uTFF3 offers a promising non-invasive biomarker for diagnosing CRC.


The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor‐α inhibitor

February 2019

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48 Reads

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4 Citations

Background and Aim Tacrolimus (TAC) is an important therapeutic option for remission induction in patients with refractory ulcerative colitis (UC). However, there is little evidence available on long‐term outcomes and maintenance treatments after TAC therapy, especially in cases with previous tumor necrosis factor‐α (TNF‐α) inhibitor therapy. Methods Long‐term outcomes and remission induction after TAC treatment were retrospectively examined in refractory UC patients with and without previous TNF‐α inhibitor therapy. Results The mean disease activity index and the endoscopic activity index scores decreased significantly during the 12‐week treatment after TAC therapy in both groups, showing a significantly greater decrease in the group without TNF‐α inhibitor therapy than in the group with previous TNF‐α inhibitor therapy. One year or more after TAC therapy, TNF‐α inhibitor and/or azathioprine was used as maintenance therapy in most cases in the group without previous TNF‐α inhibitor treatment, while azathioprine was primarily used in the group with previous TNF‐α inhibitor treatment. Colectomy was performed in 45.5% (5/11) and 15.6% (7/45) of the groups with and without previous TNF‐α inhibitor therapy, respectively, and the group without previous TNF‐α inhibitor treatment had a better colectomy‐free rate than the group with previous TNF‐α inhibitor treatment after TAC therapy on Kaplan–Meier analysis. Conclusions TAC is effective for remission induction in refractory UC patients with and without previous TNF‐α inhibitor treatment. Maintenance medication after TAC therapy is an issue for the future, especially in UC cases with previous TNF‐α inhibitor treatment failure.


Adalimumab Dose-Escalation Therapy Is Effective in Refractory Crohn’s Disease Patients with Loss of Response to Adalimumab, Especially in Cases without Previous Infliximab Treatment

February 2019

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78 Reads

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9 Citations

Case Reports in Gastroenterology

Background/aims: Adalimumab dose escalation is one of the most important options in refractory Crohn's disease patients with loss of response to adalimumab. The goal of this study was to evaluate the effectiveness of adalimumab dose escalation in Crohn's disease patients with loss of response to adalimumab, since there are few reports of adalimumab dose escalation, especially in East Asia. Methods: The clinical response to adalimumab dose escalation in Crohn's disease patients with loss of response to adalimumab was evaluated retrospectively, using the Crohn's disease activity index score, serum C-reactive protein levels, and endoscopic analyses. Results: Of the 203 Crohn's disease patients treated with anti-tumor necrosis factor, 14 refractory Crohn's disease patients with loss of response to adalimumab received adalimumab dose-escalation therapy. The C-reactive protein level was significantly reduced from the start to weeks 12 and 52 of adalimumab dose escalation in the whole group, although there were no significant reductions of Crohn's disease activity index scores. Both Crohn's disease activity index scores and C-reactive protein levels were significantly reduced from the start to weeks 12 and 52 of adalimumab dose escalation in patients without previous infliximab treatment, although C-reactive protein levels were positive in all cases with previous infliximab exposure at weeks 12 and 52. Endoscopic mucosal healing was achieved with adalimumab dose escalation in 2 cases without previous infliximab treatment. Conclusions: Adalimumab dose-escalation therapy is effective in refractory Crohn's disease patients with loss of response to adalimumab, especially in cases without previous infliximab treatment.


Real-world efficacy of adalimumab and infliximab for refractory intestinal Behçet's disease

February 2019

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30 Reads

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20 Citations

Digestive and Liver Disease

Background: Anti-tumor necrosis factor-α agents are important for managing refractory intestinal Behçet's disease. Few studies have reported the efficacy of anti-tumor necrosis factor-α monoclonal antibodies for intestinal Behçet's disease due to its rarity. Aims: The aim was to examine the efficacy of anti-tumor necrosis factor-α antibodies for intestinal Behçet's disease in real-world practice. Methods: This was a retrospective review of medical records at 4 hospitals in Japan. Global gastrointestinal symptom and endoscopic assessment scores were analyzed in intestinal Behçet's disease patients given anti-tumor necrosis factor-α agents at 3 and 12 months after the start of therapy. Results: Of 53 intestinal Behçet's disease patients, 22 received anti-tumor necrosis factor-α monoclonal antibody treatment. At the first line, 14 were given adalimumab, and 8 were given infliximab. After 3 and 12 months of treatment, 7 and 11 patients showed complete response of gastrointestinal symptom scores, respectively, and 5 and 9 showed complete remission of the endoscopic assessment score, respectively. Three patients switched anti-tumor necrosis factor-α agents. Conclusion: Anti-tumor necrosis factor-α monoclonal antibodies are effective for refractory intestinal Behçet's disease in real-world situations. Switching anti-tumor necrosis factor-α agents may be useful for failure of first-line anti-tumor necrosis factor-α therapy in some refractory cases.


Citations (76)


... The most common symptoms in patients with colonic pneumatosis include constipation, diarrhea, distention, abdominal pain and hematochezia (Sperling et al., 2023). Some other symptoms are flatulence, a decrease in appetite and tenesmus (Ohmiya et al., 2022). Physical exams are usually normal unless there are signs of peritoneal issues from intestinal perforation in cases of PI caused by serious conditions. ...

Reference:

A Case Report on Pneumatosis Intestinalis Complicated by Pneumoperitoneum
Multicenter epidemiological survey of pneumatosis intestinalis in Japan

BMC Gastroenterology

... The available data comparing de-escalation of treatment versus continuation is mainly for the agents that have been in use longer such as TNFi [150,151]. Studies of TNFi dose reduction showed feasibility in patients who have been doseescalated and achieved deep remission. In TAXIT RCT, IBD patients who had stable responses to infliximab were randomized to dose escalation or de-escalation aimed at achieving target trough concentrations, based on either clinical features or trough concentrations. ...

Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial

The Lancet Gastroenterology & Hepatology

... Despite an increasing therapeutic armamentarium, it is advisable to optimize therapy within class when possible [9]. Marutani and colleagues report from Nagoya Memorial Hospital, Nagoya, Japan a retrospective experience of effectiveness of a second anti-TNF therapy after "failure" of first anti-TNF agent in patients with ulcerative colitis (UC) [10]. Among 123 UC patients, 21 switched within class. ...

Efficacies of first and second tumor necrosis factor inhibitors in refractory ulcerative colitis patients in real-world practice
  • Citing Article
  • October 2020

Indian Journal of Gastroenterology

... The use of upadacitinib monotherapy has been limited when higher induction remission rates are the goal. In addition, combination therapy with JAK inhibitor plus intensive GMA was well tolerated and may be useful for inducing clinical remission and mucosal healing in patients with refractory UC [43]. Such evidence suggests that the addition of intensive GMA to upadacitinib may be more effective than upadacitinib monotherapy because GMA depletes elevated and activated myeloid lineage leucocytes and has been associated with a marked downregulation of inflammatory cytokines, including the IL-1β, IL-6, IL-8, and TNF-α released by myeloid leucocytes and lymphocytes [44]. ...

Combination Therapy With Tofacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction Therapy for Refractory Ulcerative Colitis

Journal of Clinical Medicine Research

... Previously, we have developed several PSs containing heavy metals, especially platinum (Pt) or palladium (Pd) 39,41,42 . However, these PSs are limited by their low water solubility. ...

Antitumor Effect of a Novel Photodynamic Therapy With Acetylated Glucose-conjugated Chlorin for Gastrointestinal Cancers
  • Citing Article
  • August 2019

Anticancer Research

... Anti-TNF agents, such as infliximab and adalimumab, have proven efficacy in azathioprine-refractory cases [111,112] and have become primary treatments for severe cases. Switching between anti-TNF agents can be beneficial when the initial agent fails [113]. ...

Real-world efficacy of adalimumab and infliximab for refractory intestinal Behçet's disease
  • Citing Article
  • February 2019

Digestive and Liver Disease

... Our search identified several studies that used the CDEIS and SES-CD indices for the assessment of mucosal inflammation published since 2014, but none used them to make treatment escalation decisions. In all studies, the indices were used for assessing treatment outcomes after escalation [14,26,36,41,55]. The Organization for the Study of Inflammatory Bowel Disease (IOIBD) used a Delphi process to define such thresholds, and ranked the following as their top 4 definitions of endoscopic remission [97]: ...

Adalimumab Dose-Escalation Therapy Is Effective in Refractory Crohn’s Disease Patients with Loss of Response to Adalimumab, Especially in Cases without Previous Infliximab Treatment

Case Reports in Gastroenterology

... Li et al. [22] observed that Cyr61 was elevated in the very early stages of the disease by studying a rat matrix of renal ischemia-reperfusion injury. Shimura et al. [23] also concluded that urinary Cyr61 may be a noninvasive diagnostic criterion for colon cancer. Besides, Cyr61 is also closely associated with heart failure [24], coronary artery disease [25], and myocardial injury [26]. ...

Urinary Cysteine-Rich Protein 61 and Trefoil Factor 3 as Diagnostic Biomarkers for Colorectal Cancer

Translational Oncology

... 9,10 Additionally, GMA has been widely recognized as a safe and well-tolerated treatment for UC. 15,16 Thus, intensive GMA is considered an effective treatment in patients with CD with mild to moderately active disease although clinical e cacy of GMA for patients with CD was controversial. GMA has also demonstrated a safe pro le in patients with CD; however, securing blood vessels is considered the most important issue to complete intensive GMA, especially in patients with dehydration, undernourishment, and anemia. ...

Combination Therapy With Intensive Granulocyte and Monocyte Adsorptive Apheresis Plus Ustekinumab in Patients With Refractory Crohn's Disease: UST and Intensive GMA for CD
  • Citing Article
  • May 2018

Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy

... Yamane et al. reported that five of six cases involved women (6). Similarly, the current case and those reported by Nishie et al. (7) also involved women. Furthermore, all pa-Intern Med Advance Publication DOI: 10.2169/internalmedicine.2554-23 tients were their 50s or older. ...

Refractory gastric antral ulcers without Helicobacter pylori infection and non-steroidal anti-inflammatory drugs
  • Citing Article
  • February 2018

Clinical Journal of Gastroenterology