Keywords Endoscopic ultrasonography - Gastric cancer - Endoscopy Upper GI Tract - Endoscopic
resection (ESD, EMRc, ...) - Quality and logistical aspects - Performance and complications
Introduction
Endoscopic submucosal dissection (ESD) has become widely accepted as an effective
treatment for early-stage gastric cancer, providing high en bloc resection rates with
relatively low complication rates [1 ]. Compared with gastrectomy, ESD is less invasive and places a lower physical burden
on patients [2 ]
[3 ]. Consequently, ESD has become a viable alternative to surgery for high-risk patients,
such as older individuals [4 ] or those with significant comorbidities [5 ], potentially offering fewer complications than gastrectomy.
Despite these positive findings, patients with comorbid conditions exhibit varying
disease severity and different types of systemic involvement, which may differentially
influence risk of post-ESD complications. One study reported that ESD is effective
across different American Society of Anesthesiologists Physical Status (ASA-PS) categories,
but that higher ASA-PS scores correlate with more frequent complications [6 ]. However, other studies have found no significant increase in adverse events (AEs)
despite varied comorbidity profiles [4 ]
[5 ]. These discrepancies suggest that particular subgroups of patients may warrant closer
attention.
One such subgroup is immunocompromised individuals, especially those receiving glucocorticoids
(GCs) or immunomodulators (IMs). Commonly prescribed for chronic inflammatory diseases,
GCs have been associated with an increased risk of gastric ulcers [7 ], and this risk becomes even more pronounced when combined with non-steroidal anti-inflammatory
drugs (NSAIDs) [8 ]
[9 ]. GC use is also associated with a higher risk of gastrointestinal bleeding and perforation
in hospitalized patients [10 ]. Indeed, in colonic ESD, patients taking GCs or IMs have demonstrated an increased
risk of post-coagulation syndrome [11 ]. These findings raise the concern that a similar pattern of complications, such
as post-procedure pain, fever, delayed bleeding, and delayed perforation, could also
occur following gastric ESD. In light of these considerations, it is crucial to clarify
the influence of GCs and IMs on complication rates associated with gastric ESD.
This information is essential for optimizing procedural techniques and for postoperative
management in this growing patient population. We hypothesized that patients receiving
GC/IM therapy would experience a modest increase in overall incidence of clinically
managed post-ESD events, whereas major complications (delayed bleeding or perforation)
remained uncommon and could be managed with standard rescue measures. Therefore, this
study aimed to elucidate whether treatment with GCs or IMs increases risk of post-gastric
ESD complications, thereby providing valuable insights to improve the care of immunocompromised
patients undergoing gastric ESD.
Patients and methods
Study design and patients
This retrospective, single-center, observational cohort study was conducted using
data from patient medical records and the endoscopic database at our institution.
Between April 2017 and April 2022, we identified 439 consecutive patients who underwent
gastric ESD. Of these, 19 patients who underwent ESD for remnant stomach and nine
patients who underwent complete closure of the post-ESD ulcer were excluded because
these factors could confound the evaluated effects of GCs or IMs on ESD complications.
Consequently, 411 patients were included in the final analysis. Patients receiving
either GCs or IMs were classified as the GC/IM group (n = 32), and patients without
such treatments were allocated to the standard group (n = 379). The patient selection
process and group allocation are summarized in [Fig. 1 ]. This study was reviewed and approved by the institutional review board of our hospital
(approval number: 23C008). The study adhered to the ethical principles of the Declaration
of Helsinki.
Fig. 1 Flowchart of patient selection and propensity-score matching. Of 439 patients undergoing
gastric ESD, 28 were excluded (remnant stomach, n = 19; complete closure of the post-ESD
ulcer, n = 9), leaving 411 eligible patients. Of these, 32 received GC/IM and 379
did not. One-to-three propensity-score matching (covariates: sex, ACCI, antithrombotic
use, lesion size, location, multiplicity, procedure time, and use of PGA sheets with
fibrin glue) yielded matched cohorts of 27 GC/IM and 81 standard patients. ACCI, age-adjusted
Charlson Comorbidity Index; PGA, polyglycolic acid.
ESD procedure
All ESD procedures were performed by 17 therapeutic endoscopists: six experts (each
with
≥ 100 gastric ESD cases) and 11 non-experts (< 100 cases each) under expert supervision,
and some cases were co-performed by an expert and a non-expert operator. Procedures
were
performed on hospitalized patients under sedation with midazolam and dexmedetomidine,
and
analgesia with meperidine using a standard single-channel endoscope (GIF-Q260J or
GIF-290T;
Olympus, Tokyo, Japan). An electrosurgical generator (VIO300D or VIO3; ERBE, Tübingen,
Germany) was used in combination with a Dual Knife (2.0 mm; Olympus, Tokyo, Japan)
or a
Clutch Cutter Long (Fujifilm, Tokyo, Japan). A bipolar coagulation device (Hemo-Stat
Y;
Pentax) was used for hemostasis during the procedure. For submucosal injection,
physiological saline, 20% concentrated glycerin-fructose (Glycerol; Chugai Pharmaceuticals,
Tokyo, Japan), or 0.4% sodium hyaluronic acid (Mucoup; Johnson & Johnson, Tokyo, Japan)
was administered at the discretion of the endoscopist. Antithrombotic management followed
established institutional guidelines: low-dose aspirin was continued peri-procedurally,
whereas other antiplatelet agents were switched to low-dose aspirin. Patients on warfarin
underwent heparin bridging therapy until 2017; thereafter, warfarin was continued
within a
therapeutic prothrombin time/international normalized ratio range of 2.0 to 3.0. Direct
oral
anticoagulants were discontinued on the day of the procedure and resumed 1 to 2 days
post-procedure if no bleeding occurred. All patients received vonoprazan (20 mg/day),
a
potassium-competitive acid blocker (P-CAB), both before and after ESD for a total
of 8
weeks. In the event of intraoperative perforation, initial management consisted of
endoscopic clip closure, followed by application of polyglycolic acid (PGA) sheets
with
fibrin glue if necessary. PGA sheets were also applied prophylactically when the muscularis
propria was significantly exposed or injured, even in the absence of full-thickness
perforation, to support tissue healing. If endoscopic intervention was insufficient,
urgent
surgical consultation was arranged. Second-look endoscopy was not routinely performed
but
was conducted selectively in cases of clinically high risk of delayed bleeding based
on the
operator`s decision.
Data collection
Demographic and clinical data from the patients were collected, including age, sex,
body mass index (BMI), ASA-PS, and age-adjusted Charlson Comorbidity Index (ACCI)
[12 ], as well as use or non-use of GCs and IMs. IMs were defined as thiopurines (e.g.,
azathioprine), methotrexate, calcineurin inhibitors (e.g., tacrolimus), and cytokine-targeted
biologics (e.g., anti-tumor necrosis factor agents), alone or in combination. Use
of antithrombotic drugs was also documented. Lesion characteristics, including size,
location, morphology, and multiplicity, were recorded. In addition, procedure details,
such as procedure time, presence of submucosal fibrosis, injury to the muscularis
propria, and application of PGA sheets with fibrin glue, were collected. We also recorded
post-procedure symptom management, including administration of analgesics, antipyretics,
and antibiotics, and whether second-look endoscopy was performed.
Measured outcomes
The primary outcome was the overall rate of post-ESD complications, defined as the
combined incidence of post-ESD pain, fever, delayed bleeding, and delayed perforation.
We selected a composite outcome to capture the full post-procedure workload, because
even minor events (pain, fever) routinely prompt additional monitoring, imaging, or
analgesic use. Secondary outcomes included individual rates of these post-ESD complications,
incidence of intraoperative perforation, and length of hospital stay. Post-ESD pain
was defined as any abdominal pain reported by patients at any time after ESD until
discharge. Post-ESD fever was defined as a body temperature ≥ 37.5°C persisting from
time of the ESD procedure until discharge. Delayed bleeding was defined as overt bleeding
requiring emergency endoscopic hemostasis or transfusion, or a decrease of ≥ 2 g/dL
in hemoglobin concentration following ESD. Delayed perforation was defined as perforation
occurring ≥ 6 hours after ESD, without evidence of intraoperative perforation during
the procedure. In cases in which multiple lesions were treated, characteristics and
treatment specifics were recorded on the basis of the predominant lesion.
Statistical analysis
Propensity scores for GC/IM exposure were estimated using multivariable logistic
regression including sex, ACCI, antithrombotic use, lesion size and location, lesion
multiplicity, procedure time, and use of PGA sheets with fibrin glue. Patients were
matched
1:3 (GC/IM: standard) by nearest-neighbor matching within a caliper of 0.2 standard
deviations of the logit propensity score [13 ]. Covariate balance after matching was assessed using the absolute standardized
difference (ASD), with ASD < 0.10 considered acceptable [14 ]. We deliberately excluded age, daily NSAID use, and operator expertise because age
is captured by the ACCI, NSAIDs were uniformly withheld peri-procedurally per institutional
protocol, and all procedures (including trainee cases) were performed under direct
expert
supervision. When modelling exposure status (GC/IM vs standard),
receiver-operating-characteristic (ROC) analyses for individual continuous covariates
indicated limited predictive ability (area under the ROC curve [AUROC] ACCI 0.73;
lesion
size 0.48; procedure time 0.57); therefore, we applied clinically validated thresholds
to
dichotomize these variables: ACCI ≥ 4 (moderate-to-severe comorbidity) [15 ], lesion diameter > 20 mm (odds ratio [OR] 2.70 for post-procedural bleeding)
[16 ], and procedure time ≥ 60 minutes (OR 2.05 for higher bleeding rates) [16 ]. The overall propensity-score model showed good discrimination (AUROC: 0.79, 95%
confidence interval [CI] 0.70–0.87; Supplementary Fig. 1 ). The
study flow and matched sample sizes (27 vs. 81) are shown in [Fig. 1 ].
All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical
University, Saitama, Japan), which serves as a graphical user interface for R (The
R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version
of R Commander that incorporates additional statistical functions commonly used in
biostatistics [17 ]. Continuous variables are presented as the median with interquartile range (IQR)
and were compared using the Mann–Whitney U test. Categorical variables are expressed
as counts and percentages, and intergroup comparisons were performed using Fisher’s
exact test. P < 0.05 was considered statistically significant.
Results
Baseline clinical characteristics of the patients
[Table 1 ] summarizes baseline clinical characteristics of the GC/IM group (n = 32) and the
standard group (n = 379). Significant differences were observed in sex, age, and ASA-PS
between the groups. Compared with the standard group, the GC/IM group included fewer
male patients (46.9% vs. 76.2%, P
< 0.001), had a higher median age 78 years (IQR 75–81) vs. 73 years (IQR 67–79) (P = 0.010), and had a markedly greater proportion of patients with an ACCI ≥ 4 (84.4%
vs. 48.0%, P < 0.001) and ASA-PS ≥ 2 (100% vs. 23.7%, P < 0.001). Other variables, including BMI, antithrombotic agent use, lesion size,
lesion location, lesion multiplicity, procedure time, submucosal fibrosis, muscle
layer injury, and use of PGA with fibrin glue, did not differ significantly between
the two groups.
Table 1 Clinical characteristics of patients in the GC/IM and standard groups.
Variables
GC/IM group (n = 32)
Standard group (n = 379)
P value
ACCI, age-adjusted Charlson Comorbidity Index; ASA-PS, American Society of Anesthesiologist
Physical Status; GC, glucocorticoid; IM, immunomodulator; PGA, polyglycolic acid sheet.
Fisher`s exact test was used for categorical variables and the Mann-Whitney U test
was applied for non-categorical variables.
Patient characteristics
Age
78 (75–81)
73 (67–79)
0.010
Sex (male)
15 (46.9%)
289 (76.2%)
0.001
BMI
21.6 (19.0–24.4)
22.7 (20.6–24.6)
0.134
ACCI (≥ 4)
27 (84.4%)
182 (48.0%)
< 0.001
ASA-PS (≥ 2)
32 (100%)
90 (23.7%)
< 0.001
Antithrombotic agents
10 (31.0%)
92 (24.2%)
0.406
NSAID daily use
3 (9.4%)
16 (4.2%)
0.177
Lesion characteristics
Lesion size
16 (10–26)
15 (10–25)
0.697
Location (Upper)
18 (56.3%)
205 (54.1%)
0.236
Multiplicity of lesions
5 (15.6%)
53 (14.0%)
0.792
Procedure details
Submucosal fibrosis
6 (18.8%)
51 (13.5%)
0.423
Injury to the muscle layer
3 (9.4%)
40 (10.6%)
1.000
Operator skill (expert)
3 (9.4%)
93 (24.5%)
0.052
Procedure time
62 (42–120)
85 (55–130)
0.161
PGA with fibrin glue
6 (18.7%)
38 (10.0%)
0.130
Within the GC/IM group, 30 patients (93.7%) received GC, seven patients (21.8%) received
GCs and IMs, and two patients (6.3%) received IMs alone. Median daily GC dose was
5 mg (IQR 4–5), with a maximum dose of 10 mg/day. Among the IMs, methotrexate was
most frequently prescribed (six patients, 60.0%), followed by tacrolimus (two patients,
20.0%), a combination of methotrexate and tacrolimus (one patient, 10.0%), and azathioprine
(one patient, 10%).
In the GC/IM group, rheumatoid arthritis was the most prevalent comorbidity (43.8%),
followed by polymyalgia rheumatica (12.5%) and systemic lupus erythematosus (9.4%).
Other autoimmune and inflammatory conditions, including membranous nephropathy, microscopic
polyangiitis, autoimmune pancreatitis, mixed connective tissue disease, immunoglobulin
A nephropathy, giant cell arteritis, psoriasis, sarcoidosis, and scleroderma, collectively
affected 34.4% of patients ([Table 2 ]).
Table 2 Comorbidities in patients in the GC/IM group.
Comorbidity
Number of cases
Percentage (%)
GC, glucocorticoid; IM, immunomodulator.
Rheumatoid arthritis
12
43.8
Polymyalgia rheumatica
4
12.5
Systemic lupus erythematosus
3
9.4
Others
13
34.4
Total
32
100
Propensity score matching
[Table 3 ] shows clinical characteristics of the GC/IM group and the standard group after propensity-score
matching (PSM). Following matching, the GC/IM group (n = 27) and the standard group
(n = 81) showed good balance across most key variables. For instance, the ASD for
sex decreased from 0.630 before matching to 0.075 after matching, and the ASD for
the ACCI declined from 0.830 to 0.100. Although the ASD for age and ASA-PS remained
above the ideal threshold of 0.100, other variables, such as use of antithrombotic
agents (ASD: 0.060) and lesion size (ASD: 0.080), demonstrated good balance. These
findings indicate that PSM successfully minimized potential confounding factors, resulting
in a more balanced comparison between the groups.
Table 3 Clinical characteristics of patients in the GC/IM and standard groups after propensity
score matching.
Propensity-score matched cases (n = 108)
Variable
GC/IM (n = 27)
Standard (n = 81)
P value
ASD
ACCI, age-adjusted Charlson Comorbidity Inex; ASA-PS, American Society of Anesthesiologists
physical status; ASD, absolute standardized difference; GC, glucocorticoid; IM, immunomodulator;
NSAID, nonsteroidal anti-inflammatory drug; PGA, polyglycolic acid.
Patient characteristics
Age (≥ 65)
23 (85.2)
80 (98.8)
0.013
0.520
Sex (male)
15 (55.6)
42 (59.3)
0.823
0.075
BMI (≥ 21)
18 (66.7)
57 (70.4)
0.810
0.080
ACCI (≥ 4)
22 (81.5)
69 (85.2)
0.761
0.100
ASA-PS (≥ 2)
27 (100)
69 (85.2)
0.035
0.590
Antithrombotic agents
8 (30.8)
16 (20.2)
0.290
0.060
NSAID daily use
3(11.1)
8(9.9)
1.000
0.040
Lesion characteristics
Lesion size (≥ 21)
8 (29.6)
27 (33.3)
0.815
0.080
Location (Upper)
3 (11.1)
6 (7.4)
0.688
0.128
Multiplicity of lesion
4 (15.4)
10 (12.8)
0.750
0.074
Procedure details
Submucosal fibrosis
5 (18.5)
14 (17.3)
1.000
0.032
Injury to the muscle layer
3 (11.1)
9 (11.1)
1.000
< 0.001
Operator skill (Expert)
2 (7.4)
18 (22.2)
0.150
0.426
Procedure time (≥ 61)
15 (55.6)
55 (67.9)
0.255
0.256
PGA with fibrin glue
3 (11.1)
6 (7.4)
0.688
0.128
Primary and secondary outcomes after propensity score matching
[Table 4 ] presents primary and secondary outcomes for the GC/IM group and the standard group
after PSM. The overall post-ESD complication rate was significantly higher in the
GC/IM group than in the standard group (44.4% vs. 21.0%, P = 0.024; relative risk [RR] 2.11; 95% CI 1.16–3.84). Specifically, post-ESD pain
(40.7% vs. 18.5%, P = 0.035; RR 2.2; 95% CI 1.15–4.19) and post-ESD fever (11.1% vs. 1.2%, P = 0.047; RR 9.0; 95% CI 0.98–82.9) occurred more frequently in the GC/IM group. By
contrast, there were no significant differences between the two groups in rates of
delayed bleeding (3.7% vs. 2.5%, P = 1.000), delayed perforation (0.0% vs. 0.0%, P = 1.000), or intraoperative perforation (7.4% vs. 3.7%, P = 0.162). Similarly, median length of hospital stay did not differ significantly
between the two groups (9 days [IQR 7–10] vs. 8 days [IQR 7–9]; P = 0.064). Regarding laboratory data, the standard group showed a significantly greater
change in logarithmic WBC count (0.09 vs. 0.17, P = 0.022), although changes in logarithmic C-reactive protein concentration did not
differ significantly between the two groups (0.54 vs. 0.65, P = 0.668).
Table 4 Post-ESD outcomes after propensity-score matching (GC/IM vs standard): complications,
hospital stay, labs, and management.
Variable
GC/IM (n = 27)
Standard (n = 81)
RR (95%CI)
P value
CRP, C-reactive protein; ESD, endoscopic submucosal dissection; GC, glucocorticoid;
IM, immunomodulator; WBC, white blood cell.
Complications
Overall complications
12 (44.4)
17 (21.0)
2.1 (1.2–3.9)
0.024
Post ESD pain
11 (40.7)
15 (18.5)
2.2 (1.2–4.2)
0.035
Post ESD fever
3 (11.1)
1 (1.2)
9 (0.98–83)
0.047
Delayed bleeding
1 (3.7)
2 (2.5)
1.5 (0.14–16)
1.000
Delayed perforation
0 (0)
0 (0)
NA
1.000
Intraoperative perforation
2 (7.4)
3 (3.7)
2 (0.35–11)
0.162
Resource use
Hospital stay
9 (7–11)
8 (7–9)
NA
0.064
Second look endoscopy
2 (7.4)
3 (3.7)
2 (0.35–11)
0.597
Laboratory changes
△log-CRP
0.54 (0.15–1.17)
0.65 (0.35–0.95)
NA
0.668
△log-WBC
0.09 (0.02–0.2)
0.17 (0.08–0.25)
NA
0.022
Symptom management
Analgesic use
7 (25.9)
3 (3.7)
4.5 (1.8–11)
0.002
Antipyretic use
2 (7.4)
2 (2.5)
3 (0.44–20)
0.270
Antibiotic use
2 (7.4)
3 (3.7)
2 (0.35–11)
0.597
On-demand analgesics for pain were given to 25.9 % of GC/IM patients vs 3.7% of controls
(P = 0.002), antipyretics for fever to 7.4% vs 2.5% (P = 0.270), and antibiotics to 7.4% vs 3.7% (P = 0.597) ([Table 4 ]). To examine how early symptoms influenced subsequent treatment requirements and
clinical course, we grouped patients according to initial symptom burden. In the pain-only
subgroup (n = 24), analgesics were administered in eight of 24 (33 %) and median hospital
stay was 9 days (IQR 7–12); in the fever ± pain subgroup (n = 4), antipyretics and
analgesics were each used in two of four (50%) and median hospital stay was 18 days
(IQR 13–25); no-symptom patients (n = 80) required neither analgesics nor antipyretics
and stayed a median of 8 days (IQR 7–8) ([Fig. 2 ]).
Fig. 2 Post-ESD symptom subgroups and subsequent management/outcomes in the propensity-matched
cohort. Patients were stratified into three symptom categories after gastric ESD:
1) abdominal pain only; 2) fever ± pain; and 3) no pain or fever. For each subgroup,
the chart displays counts of patients requiring antibiotics, antipyretics, or analgesics
(shown as total % and GC/IM vs standard counts) and downstream outcomes—delayed bleeding
and median [IQR] length of stay. Arrows illustrate the descriptive flow from symptoms
→ management → outcomes and do not imply causality. GC/IM, glucocorticoid or immunomodulator;
IQR, interquartile range.
Finally, an exploratory look within the GC/IM cohort showed no clear pattern by agent
type (overall complications: GC only 50%, GC + IM 40 %, IM only 0%; P = 0.389) or by GC dose (≤ 5 mg 57% vs > 5 mg 0%; P = 0.096), and no individual outcome reached significance (Supplementary Table 1 , Supplementary Table 2 ).
Discussion
This study evaluated the impact of GC and IM on risk of post-ESD complications. The
findings showed that patients receiving GC/IM had a significantly higher overall post-ESD
complication rate than the standard group. However, the increase in post-ESD complications
in the GC/IM group was attributed to minor complications, such as abdominal pain and
fever, but not to severe complications, such as delayed bleeding and perforation.
Therefore, ESD appeared to be a clinically feasible option for immunocompromised individuals,
provided that early warning signs such as abdominal pain were closely monitored and
appropriately managed.
We chose a composite primary endpoint because even “minor” symptoms—pain or fever—immediately
prompt additional monitoring, imaging, or analgesic use. Combining these frequent
actions with rarer major complications provides the most sensitive gauge of total
post-ESD workload and matches our a priori hypothesis that overall events might rise
while catastrophic events remain uncommon.
Abdominal pain is one of the most common complications associated with gastric ESD.
The inflammatory response after mucosal injury is considered a primary cause of such
pain [18 ], involving activation of intramuscular sensory nerves by mechanical stimulation
from mucosal defects, thermal injury, and peritoneal irritation during the ESD procedure.
The higher frequency of abdominal pain observed in the GC/IM group may be explained
by the fact that chronic GC/IM therapy can dampen the normal inflammatory cascade
and impair tissue repair, potentially leading to atypical or prolonged postoperative
inflammation [19 ]. This may manifest as more pronounced or persistent pain, because deeper tissue
injury is not fully contained by an efficient immune response.
Fever is another common complication associated with gastric ESD. The inflammatory
response due to mucosal injury is also a primary cause of fever [20 ], typically involving a localized inflammatory response to thermal injury rather
than bacterial infection or bacteremia under normal conditions [20 ]
[21 ], and it usually resolves with conservative management [22 ]. Extensive submucosal dissection accompanied by thermal injury can trigger release
of inflammatory cytokines through activation of macrophages, endothelial cells, and
the reticuloendothelial system [23 ]. In the GC/IM group, subclinical bacterial infection and/or bacterial translocation
may be more likely due to immunosuppression, potentially contributing to increased
frequency of post-gastric ESD fever observed in this study.
Although abdominal pain and fever associated with gastric ESD were more common in
the GC/IM group, major complications such as delayed bleeding and perforation were
not increased. Routine use of P-CABs and prophylactic use of PGA sheets may have contributed
to reduced risk of these serious complications, particularly in the GC/IM group. P-CABs
have been reported to help prevent delayed bleeding [24 ], and prophylactic use of PGA sheets is known to support the healing process [25 ]. In addition, we made every effort to perform gastric ESD using a meticulous technique
to minimize thermal injury to the muscular layer. As a result, incidence of abdominal
pain in both the standard group and the GC/IM group was lower than the previously
reported rates of 53.8% to 98% [18 ]
[26 ]. Similarly, incidence of fever in both groups was also lower than the previously
reported rates of 23.1% to 24.8% [22 ]
[27 ]. A large-scale, multicenter, prospective study is needed to validate our observation
that incidence of major complications, including delayed bleeding and/or perforation,
is not increased in patients receiving GC/IM treatment.
In addition, several endoscopic closure techniques such as clipping devices, endoscopic
suturing, and over-the-scope clips have been developed recently [28 ]. Although our study employed prophylactic PGA sheets and fibrin glue, robust evidence
demonstrating their effectiveness in preventing perforation remains limited. Future
studies should investigate the efficacy of these various closure techniques.
By contrast, incidence of intraprocedure perforation was numerically higher in the
GC/IM group, although the difference was not statistically significant (P = 0.162) and was based on only five events in total; therefore, a modest drug-related
effect cannot be excluded, and these findings should be interpreted with caution.
Although our data confirm a higher rate of minor events in GC/IM patients, these events
were effectively managed with on-demand medication and close observation, supporting
the notion of clinical—rather than universal—feasibility. Although the overall median
length of stay differed by only 1 day (9 days [7–12] in GC/IM vs 8 days [7–9] in controls),
the small fever ± pain subgroup stayed much longer (18 days [13–25]). Minor symptoms,
therefore, added a modest workload in most cases, yet occasionally required substantial
extra observation. Consistent with this pattern, on-demand medication use was three-
to seven-fold higher in GC/IM patients (analgesics 25.9% vs 3.7%; antipyretics 7.4%
vs 2.5%), reflecting the additional bedside care triggered by pain and fever. Importantly,
this burden remained manageable: a proactive, symptom-directed protocol contained
resource use to extra medication and monitoring without increasing serious AEs or
extending hospitalization beyond what symptoms dictated.
Beyond overall GC/IM exposure, we explored whether specific agents or doses modified
risk; no clear agent‑ or dose‑dependent signal emerged. Complication rates were similar
in GC‑only users (50%) and in GC+IM users (40%) and were absent in the two IM‑only
cases (P = 0.389). Dose stratification likewise showed 57% complications with≤5mg GC vs none
with > 5 mg (P = 0.096). The limited sample sizes in certain subgroups constrain the precision of
these estimates.
These clinical symptoms observed in the GC/IM group were not mirrored in the next-day
laboratory findings; WBC count tended to be lower in the GC/IM group than in the standard
group, likely owing to pharmacologic immunosuppression masking or delaying the typical
inflammatory response. Tailored care is essential for managing minor events and for
preventing escalation into more serious adverse outcomes.
This study has several limitations. As a single-center, retrospective cohort study,
generalizability of the findings is limited, and the small sample size, particularly
in the GC/IM group, reduced the statistical power. In addition, patients at higher
risk of perforation or those with lesions in anatomically challenging locations may
have been preferentially directed toward surgery rather than ESD, introducing potential
selection bias. We included only patients receiving GC doses ≤ 10 mg/day, without
accounting for treatment duration or cumulative dosage. As a result, the safety of
ESD in patients on higher doses or prolonged GC therapy remains unclear. Future research
with larger cohorts and varying GC doses is needed to provide a more comprehensive
assessment. Finally, matching for the ACCI was imperfect (ASD: 0.100), reflecting
the difficulty of identifying comparable controls for GC/IM patients with complex
comorbidities. Despite these limitations, PSM offered a reasonable approach to evaluate
the impact of glucocorticoids and immunomodulators on gastric ESD outcomes.
Conclusions
In patients receiving glucocorticoids or immunomodulators, gastric ESD was associated
with increased incidence of minor post-procedural complications—chiefly abdominal
pain and transient fever—leading to greater use of symptom-directed medication and
slightly longer observation. Nonetheless, with careful technique, vigilant postoperative
monitoring, and prompt symptom management, these minor events were readily controlled
and major complications remained uncommon. Thus, gastric ESD appeared clinically feasible
in this immunosuppressed population when undertaken with proactive management strategies.
Data Availability Statement
Data Availability Statement
All data used in this study are securely stored at Kyushu Medical Center. Access to
these data may be granted upon reasonable request to the corresponding author or the
institutional review board, in accordance with applicable regulations and institutional
guidelines.
Bibliographical Record
