Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab.

BACKGROUND: In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy. METHODS: The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves. RESULTS: During January 2017-June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0-34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0-16.6) and 4.0 (95% CI, 2.6-5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22-0.67; p = 0.001). CONCLUSIONS: Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.

Decision making for anti-VEGF inhibitor continuation: dip stick? or urine protein/creatinine ratio? (VERSiON UP study).

BACKGROUND: Monitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri. METHODS: From January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR < 2.0 (low UPCR) in cases with a QV2+ at the point of the first proteinuria onset. The secondary endpoints were a comparison of low UPCR and worst UPCR ≥2.0 (high UPCR), the concordance rate between UPCR and QV in the Common Terminology Criteria for Adverse Events (CTCAE) grading, and the differences in the decision making for anti-VEGF/Ri continuation. RESULTS: Among the 71 patients enrolled, the proportion of low UPCR in onset QV2+ (n = 53) was 66% (n = 35). In a comparison between low (n = 36) and high UPCR cases (n = 24), body weight (P = 0.036), onset QV status (P = 0.0134), and worst QV status (P < 0.0001) were significantly associated with UPCR levels. The concordance rate for CTCAE Grade 2 of both the QV and UPCR was 83%. Regarding the judgment of anti-VEGF/Ri continuation, treatment was continued in 42.4% of cases when the QV became 3+, whereas only 25% continued treatment when the UPCR value became high. CONCLUSION: Urine dipstick test results may overestimate proteinuria, and the UPCR result tended to be more critical than the QV when deciding the treatment policy. TRIAL REGISTRATION: This study is a multiple institutional retrospectively registered observational trial. CLINICAL TRIAL NUMBER: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol ID UMIN000042545 ).

[A Case of Gastric Cancer with Pericardial Effusion as an Immune-Reactive Adverse Events].

A 67-year-old man diagnosed with clinical Stage Ⅳ gastric cancer was administered nivolumab as fourth-line chemotherapy. After 9 courses, he was emergently admitted with complaints of low blood pressure and general malaise. On the fourth hospital day, he had high-grade fever and elevated serum C-reactive protein. Computed tomography showed a moderate amount of pericardial effusion. He was administered 1.7 mg/kg of methylprednisolone and improved rapidly. A hormonal blood examination showed his adrenal gland disorder. This is the first case in our country of pericardial effusion as an immune-reactive adverse event, which is not well known in Japan.

Gastric xanthelasma may be a warning sign for the presence of early gastric cancer.

BACKGROUND AND AIM: The significance of gastric xanthelasma in relation to gastric disease still remains unclear. We investigated the prevalence and significance of gastric xanthelasma in patients with atrophic gastritis and gastric cancer. METHODS: A total of 3238 patients who underwent endoscopic examinations of the upper gastrointestinal tract were enrolled. We retrospectively investigated the presence of gastric xanthelasma, the severity of gastric atrophy, and the presence of gastric cancer, and examined the relationship between gastric xanthelasma and various clinicopathological features. RESULTS: Gastric xanthelasma was detected in 249 (7.7%) of the 3238 patients and was significantly associated with age ≥ 65 years, male gender, open-type atrophy, and the presence of gastric cancer (P < 0.0001, P = 0.0002, P < 0.0001 and P < 0.0001, respectively). Multivariate analysis revealed that the presence of gastric cancer was independently related to the presence of gastric xanthelasma (odds ratio 6.19 [3.95-9.70], P < 0.0001). Age/sex/atrophy-matched control analysis demonstrated that the presence of gastric xanthelasma was significantly associated with the presence of gastric cancer (P < 0.0001). Moreover, the presence of xanthelasma in the upper region of the stomach was significantly associated with gastric cancer (P = 0.002). Gastric xanthelasma was observed in 50 (47.6%) of 105 patients with gastric cancer. CONCLUSION: Gastric xanthelasma may serve as a warning sign for the presence of gastric cancer.

Dense-type crypt opening seen on magnifying endoscopy with narrow-band imaging is a feature of gastric adenoma.

BACKGROUND: Magnifying endoscopy with narrow-band imaging (ME-NBI) can visualize crypt openings (CO) as slit-like structures in gastric epithelial neoplasia. Visualization of numerous CO is characteristic of low-grade adenoma (LGA). The aim of the present study was to investigate whether visualization of CO by ME-NBI is useful for discriminating between LGA and early gastric cancer (EGC). PATIENTS AND METHODS: Fifty-one superficial elevated-type gastric neoplasias (10 LGA and 41 EGC) were retrospectively evaluated. The presence of CO and the number of CO were evaluated in endoscopic photos obtained at high-power endoscopic magnification by ME-NBI. The optimal cut-off value for the number of CO visualized to discriminate between LGA and EGC was determined by receiver operating characteristic curve analysis. RESULTS: The mean number of CO visualized was significantly larger in the LGA group than in the EGC group (31.2, 95% confidence interval [CI] 16.3-46.1 vs 6.3, 95% CI 3.6-9.0; P < 0.001). When the cut-off for the number of CO visualized was set at 20, the sensitivity, specificity, and accuracy of dense-type CO for discriminating between LGA and EGC were 90.0%, 87.8%, and 88.2%, respectively. CONCLUSION: Determining the number of CO visualized in superficial elevated-type gastric neoplasias by ME-NBI appears to be a useful method for discriminating between LGA and EGC.

Clinical characteristics of collagenous colitis with linear ulcerations.

BACKGROUND: The relationship between the thickness of subepithelial collagen bands (CB) and the development of linear ulcerations (LU) in collagenous colitis (CC) remains unclear. The aim of the present study was to compare the clinical and pathological features, including the thickness of CB, in CC patients with and without LU. PATIENTS AND METHODS: Twenty-five patients with CC diagnosed by pathological examination of biopsy specimens were analyzed. Eleven patients with LU (LU group) and 14 patients without LU (non-LU group) were compared. RESULTS: Ten patients in the LU group and seven in the non-LU group were taking lansoprazole (P = 0.038). Seven patients in the LU group and one in the non-LU group were taking non-steroidal anti-inflammatory drugs (NSAIDs) (P = 0.004). All LU were locatedin the transverse or left colon. Patients in the LU group were older than those in the non-LU group (P = 0.015). CB were significantly thicker in the LU group than in the non-LU group (mean ± SD, 40 ± 21 µm vs 20 ± 11 µm, P = 0.004). Multivariate analysis showed that NSAIDs use (odds ratio, 19.236; 95% confidence interval, 1.341-275.869) and CB thickness (odds ratio, 0.893; 95% confidence interval, 0.804-0.999) were independently associated with the development of LU. CONCLUSION: Use of lansoprazole and NSAIDs, thick CB, and advanced age are associated with the development of LU in CC patients.

[A case of α-fetoprotein-producing hepatoid adenocarcinoma of the stomach with spontaneous rupture of multiple liver metastases].

An 85-year-old man with epigastric pain and anorexia was admitted to our hospital. His serum α-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA II) levels were markedly elevated. Gastrointestinal endoscopy revealed a large mass near the fundus, and computed tomography revealed multiple liver tumors. Intraperitoneal bleeding followed rupture of a liver tumor and was successfully stopped by transarterial embolization; however, regrowth of multiple tumors followed, resulting in liver failure and death within a short period. Autopsy revealed hepatoid adenocarcinomas originating in the stomach that had metastasized to the liver. Hepatoid adenocarcinomas are hypervascular, rapidly growing tumors that may result in the spontaneous rupture of metastatic liver lesions. Transarterial embolization may be a feasible option for the treatment of these ruptured tumors.

Precision Medicine of Hepatobiliary and Pancreatic Cancers: Focusing on Clinical Trial Outcomes.

Tumor-agnostic precision medicine employing comprehensive genome profiling (CGP) and using next-generation sequencing (NGS) has been progressing recently. This review focuses on precision medicine for advanced unresectable hepatobiliary and pancreatic cancers. In this paper, for biliary tract cancer (BTC), therapies that target several regulators of cancer cell growth, including isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2) fusion, proto-oncogene B-Raf (BRAF), and human epidermal growth factor receptor 2 (HER2) alterations, are reviewed. For pancreatic ductal adenocarcinoma (PDAC), therapies for Kirsten rat sarcoma virus (KRAS) gene mutation G12C, neuregulin (NRG)1, and breast cancer type 1 and 2 susceptibility (BRCA1/2), gene alterations are summarized. On the other hand, precision medicine targets were not established for hepatocellular carcinoma (HCC), although telomerase reverse transcriptase (TERT), tumor protein P53 (TP53), and Wnt/ß catenin signaling alterations have been recognized as HCC driver oncogenes. Tumor-agnostic therapies for microsatellite instability-high (MSI-H) and neurotropic tyrosine receptor kinase (NTRK) fusion cancers effectively treat biliary and pancreatic cancers. Precision medicine methods developed using NGS of circulating tumor DNA (ctDNA) and utilizing a liquid biopsy technique are discussed.

Prospective comparison of diagnostic performance of magnifying endoscopy and biopsy for sessile serrated adenoma/polyp.

Background: Magnifying narrow-band imaging (M-NBI) has recently improved the accuracy of endoscopic diagnosis of gastrointestinal tumors, including colorectal polyps. However, it can be difficult to distinguish between sessile serrated adenoma/polyps (SSA/Ps) and other polyps, especially hyperplastic polyps (HPs), by histological biopsy, because diagnostic features of SSA/Ps can be detected around the colon crypt bases. We aimed to evaluate the accuracy of endoscopic diagnosis of SSA/Ps using M-NBI compared with histological biopsy. Methods: We prospectively enrolled patients diagnosed with SSA/Ps by preoperative endoscopy and assessed the diagnostic accuracy. The primary outcome was the diagnostic accuracy of endoscopy and biopsy. Results: Between August 2015 and October 2017, 295 lesions were resected by polypectomy or endoscopic mucosal resection, and 79 endoscopically resected specimens that were endoscopically diagnosed as SSA/P underwent biopsy for histological examination. Two lesions were excluded because the specimens were too small for histological examination. Finally, 77 endoscopically resected specimens and 77 biopsy specimens were included in the analysis. Histopathological examination showed 67 SSA/Ps, 8 HPs, and 2 adenomas. The sensitivity, specificity and accuracy of endoscopic M-NBI diagnosis for SSA/Ps were 95.7%, 95.5% and 95.6%, respectively. The sensitivity, specificity and accuracy of histological diagnosis of a single biopsy specimen were 71.6%, 90.0% and 74.0%, respectively. The McNemar test showed significant differences between biopsy and endoscopy diagnoses (P=0.001). Conclusion: This study shows that biopsy may be avoided by using M-NBI in patients with suspected SSA/Ps.

Real-World Data of Trastuzumab Deruxtecan for Advanced Gastric Cancer: A Multi-Institutional Retrospective Study.

Trastuzumab deruxtecan (T-DXd) has shown promising efficacy against HER2-positive advanced gastric cancer (AGC). However, data on its real-world efficacy in AGC patients are insufficient, and the predictive marker of T-DXd is unclear. In this multi-center retrospective study, we collected clinical information of 18 patients with HER2-positive AGC who received T-DXd after intolerant or refractory responses to at least two prior regimens and analyzed predictive factors. The median age was 71 years (range: 51-85), 13 men were included, and ECOG performance status (PS): 0/1/2/3 was 9/6/2/1. A total of 11 patients (61%) received prior immune checkpoint inhibitors (ICIs), 14 patients were HER2 3+, and 4 patients were HER2 2+/FISH positive. The median trastuzumab (Tmab)-free interval was 7.7 months (range: 2.8-28.6). The overall response rate was 41%, and the disease control rate was 76%. Median progression-free survival (PFS) was 3.9 months (95% CI: 2.6-6.5), and median overall survival (OS) was 6.1 months (95% CI: 3.7-9.4). PFS (6.5 vs. 2.9 months, p = 0.0292) and OS (9.2 vs. 3.7 months, p = 0.0819) were longer in patients who received prior ICIs than in those who had not. PFS (6.5 vs. 3.4 months, p = 0.0249) and OS (9.4 vs. 5.7 months, p = 0.0426) were longer in patients with an 8 month or longer Tmab-free interval. In patients with ascites, PFS (6.5 vs. 2.75 months, p = 0.0139) and OS (9.4 vs. 3.9 months, p = 0.0460) were shorter. T-DXd showed promising efficacy in HER2-positive AGC patients in a real-world setting. Pre-administration of ICIs and a sufficient Tmab-free interval may be predictive factors of T-DXd efficacy.

Real-World Data of Trifluridine/Tipiracil for Patients With Advanced Gastric Cancer: A Multi-Institutional Retrospective Study.

Background: A trial with trifluridine/tipiracil (FTD/TPI) versus placebo in patients with heavily pretreated metastatic gastric cancer showed that FTD/TPI is effective with manageable toxicity in these patients. However, real-world data on the effects of FTD/TPI in patients with advanced gastric cancer (AGC) are limited. Methods: We retrospectively collected and analyzed the clinicopathological data of patients with AGC who received FTD/TPI monotherapy at our institutions (Kobe City Medical Center General Hospital, Osaka Red Cross Hospital, Himeji Red Cross Hospital, and Kansai Medical University Hospital) between September 2019 and July 2021. Tumor responses were evaluated based on the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 53 patients were included in the study. The median age was 70 (range, 37-85) years; 39 patients (74%) were men; the numbers of patients with Eastern Cooperative Oncology Group performance status scores of 0, 1, and 2 were 10 (19%), 39 (74%), and 4 (8%), respectively; and 27 patients (51%) had diffuse-type histology. A total of 29 patients (56%) had ascites. Prior nivolumab therapy was administered to 49 patients (92%). The response rate and disease control rate (DCR) were 2% and 35%, respectively. The median progression-free survival was 2.4 months, and OS was 5.8 months. Patients with ascites exhibited significantly shorter OS (8.6 vs 4.7 months, P = .0291) than those without ascites, and DCR (54% vs 18%, P = .0055) was significantly worse in patients with ascites. There was no significant difference in the frequency of adverse events of grade 3 or higher between patients with and without ascites. Conclusion: In a real-world setting, FTD/TPI has similar effectiveness as late-line chemotherapy for patients with AGC, including those who previously had received nivolumab.

[Seven cases of gemcitabine-induced lung injury during treatment for pancreatic or biliary tract cancers].

Gemcitabine is an anti-cancer drug known to be safe and effective for pancreatic or biliary tract cancers, but lung injury is also known to be a rare side effect that sometimes becomes severe. Here we report seven cases of lung injury during gemcitabine treatment. Drug-induced lung injury was suspected in all cases. The male: female ratio was 5:2, and the average patient age was 71. Four had pancreatic cancers and three had biliary tract cancers. Gemcitabine had been administered an average 5.9 times at a dose of 1,141 mg. Patients showed a diffuse or patchy shadow mainly in the lower lung on computed tomography examination. Grades of adverse events were greater than 3 in all cases. Three patients died of the lung injury. Five cases had pulmonary emphysema, 2 had metastatic lung tumor as underlying pulmonary lesions, and these were assumed to have been important risk factors for drug-induced interstitial lung injury during gemcitabine treatment.

[Case of moderately differentiated hepatocellular carcinoma with gastric metastasis].

A solitary liver nodule about 1cm in diameter was detected in a 68-year-old male HBV carrier during therapy for advanced lung cancer. A multiple IIc-like depressed lesion originating in the stomach soon became elevated as the liver lesion progressed. HE staining produced hepatoma-like histological findings for the tumors of the lung, liver and stomach, while immunohistochemical staining showed them to be positive for PIVKA-II and weakly positive for HP-1. Autopsy led to a diagnosis of a moderately differentiated hepatocellular carcinoma producing bile juice with metastasis to the lung and stomach. It is not clear why advanced metastasis in the lung occurred while the hepatocellular carcinoma in the liver was still small, but one possible explanation lies in the localization of the hepatic cancer: the tumor was located near a branch of the hepatic vein and vascular invasion may have caused early pulmonary metastasis via the hepatic venous flow.

Gastric atrophy and xanthelasma are markers for predicting the development of early gastric cancer.

BACKGROUND: The significance of gastric xanthelasma in relation to gastric cancer still remains unclear. We investigated whether gastric xanthelasma would be a useful marker for predicting the development of early gastric cancer. METHODS: A total of 1823 patients who underwent a medical health checkup were enrolled. We examined the relationship between gastric xanthelasma and various clinical features, and in an endoscopic follow-up study investigated whether the presence of gastric xanthelasma was predictive of the development of early gastric cancer. RESULTS: In the initial endoscopic examination, gastric xanthelasma was detected in 107 (5.9 %) of the 1823 patients. The presence of gastric xanthelasma was significantly associated with age ≥65 years, male gender, open-type atrophy, and the presence of diabetes mellitus (DM) (p < 0.0001, p < 0.0001, p < 0.0001, and p < 0.0001, respectively). During the endoscopic follow-up period, early gastric cancer was found in 29 (1.6 %) of the 1823 patients. Gastric cancer occurred in 15 (14.0 %) of 107 patients with gastric xanthelasma, whereas it occurred in 14 (0.8 %) of 1716 patients without (p < 0.0001). Multivariate analysis revealed that open-type atrophy and gastric xanthelasma were independently related to the development of gastric cancer (odds ratio 7.19 [2.50-20.83]; p = 0.0003 and 5.85 [2.67-12.82]; p < 0.0001, respectively). The presence of gastric xanthelasma was significantly predictive of gastric cancer development even in the selected high-risk groups with open-type atrophy or DM (p < 0.0001 or p < 0.0001, respectively). CONCLUSIONS: Gastric xanthelasma is a useful marker for predicting the development of gastric cancer.

A Case of Myelodysplastic Syndrome with Intestinal Behçet's Disease-Like Symptoms Treated by Prednisolone and Azacitidine.

BACKGROUND Intestinal Behçet's disease-like symptoms are rare complications of myelodysplastic syndrome and are often refractory to immunosuppressive therapies. We described a case of myelodysplastic syndrome complicated by Behçet's disease-like symptoms treated with prednisolone and azacitidine. CASE REPORT A 68-year-old Japanese woman was admitted to our hospital because of persistent high fever and lower abdominal pain. Oral ulcerations developed after admission, and multiple ulcers were found in her terminal ileum by endoscopic examination. She was diagnosed with myelodysplastic syndrome with trisomy 8 by bone marrow examination. Her symptoms diminished after administration of prednisolone, but relapsed afterwards. She began azacitidine therapy and her symptoms have been controlled for at least 10 months. CONCLUSIONS This case might suggest the possibility of azacitidine as a treatment option for myelodysplastic syndrome complicated by Behçet's disease-like symptoms.

Diabetes mellitus increases the risk of early gastric cancer development.

BACKGROUND: The significance of diabetes mellitus (DM) in gastric carcinogenesis still remains unclear. We investigated whether DM would be a risk factor for the development of early gastric cancer. METHODS: Factors related to the presence of gastric cancer were examined in patients undergoing medical health checkups. We then investigated whether DM was related to the development of early gastric cancer during an endoscopic follow-up study. RESULTS: Gastric cancer was detected in 14 (1.0%) of 1463 patients at the first endoscopic examination and was significantly associated with the severity of gastric atrophy and the presence of DM. During the follow-up period (range 36-108 months; mean 70.0 months), early gastric cancer was newly detected in 26 (1.8%) of the 1449 patients in whom gastric cancer had not been detected at the first examination. Gastric cancer was detected in 17 (1.3%) of 1301 patients without DM, and in 9 (6.1%) of 148 patients with DM (P < 0.0001). Multivariate analyses demonstrated that open-type gastric atrophy and DM were independently related to the development of early gastric cancer (P < 0.0001 and P = 0.020, respectively). Gastric cancer was identified in 14 (5.1%) of 274 patients who had open-type atrophic gastritis without DM, whereas it was identified in 8 (16.0%) of 50 patients who had both open-type atrophic gastritis and DM (P = 0.0042). CONCLUSION: DM increases the risk of early gastric cancer development.

Prominent hypereosinophilia with disseminated intravascular coagulation as an unusual presentation of advanced gastric cancer.

A 78-year-old woman was admitted to our hospital complaining of anorexia and purpura of the extremities. She presented with prominent peripheral eosinophilia and disseminated intravascular coagulation (DIC). Despite receiving intensive therapy for DIC, her illness worsened. Esophagogastroduodenoscopy revealed advanced gastric cancer (AGC), and a bone marrow biopsy led to a diagnosis of disseminated carcinomatosis of the bone marrow caused by AGC. We initiated combination chemotherapy with S-1 and cisplatin, which lead to a significant improvement of the DIC and eosinophilia, and the patient was finally discharged. The primary symptoms of DIC and eosinophilia were both considered to be caused by AGC, and we successfully treated the patient's critical condition.

Risk factors associated with recurrent hemorrhage after the initial improvement of colonic diverticular bleeding.

We elucidated risk factors contributing to recurrent hemorrhage after initial improvement of colonic diverticular bleeding. 172 consecutive hospitalized patients diagnosed with colonic diverticular bleeding were analyzed. Recurrent hemorrhage after initial improvement of colonic diverticular bleeding is main outcome measure. We analyzed factors contributing to recurrent hemorrhage risk in univariate and multivariate analyses. The length of the observation period after improvement of colonic diverticular bleeding was 26.4 +/- 14.6 months (range, 1-79 months). The cumulative recurrent hemorrhage rate in all patients at 1 and 2 years was 34.8% and 41.8%, respectively. By univariate analysis, age > 70 years (P = 0.021), BMI > 25 kg/m2 (P = 0.013), the use of anticoagulant drugs (P = 0.034), the use of NSAIDs (P = 0.040), history of hypertension (P = 0.011), history of smoking (P = 0.030) and serum creatinine level > 1.5 mg/dL (P < 0.001) were found to be significant risk factors for recurrent colonic diverticular bleeding. By multivariate analysis, age > 70 years (Hazard ratio (HR), 1.905, 95% confidence interval (CI), 1.067-3.403, P = 0.029), history of hypertension (HR, 0.493, 95% CI, 0.245-0.993, P = 0.048) and serum creatinine level > 1.5 mg/dL (HR, 95% CI, 0.288-0.964, P = 0.044) were shown to be significant independent risk factors. Close observation after the initial improvement of colonic diverticular bleeding is needed, especially in elderly patients or patients with history of hypertension or renal deficiency.