Poor tolerability of lenvatinib in elderly patients ≥80 years old with hepatocellular carcinoma: A multicenter observational study.

INTRODUCTION: Management of elderly patients with cancer has become a global issue. We investigated the safety and tolerability of lenvatinib in hepatocellular carcinoma (HCC) patients ≥80 years old. METHODS: We retrospectively evaluated 61 HCC patients and divided them into 2 groups: an elderly group (n = 13, ≥80 years old) and a younger group (n = 48, <80 years old). We compared the adverse events (AEs), administration period, dose intensity, objective response, and progression-free survival (PFS) between the two groups. RESULTS: The discontinuation of lenvatinib due to AEs was more frequent in the elderly group (8/13, 61.5%) than in the younger group (10/48, 20.8%) (P = 0.0043). Fatigue and appetite loss accounted for half of the cases discontinued due to AEs in the elderly group. The elderly group had a significantly lower 8-week-delivered dose intensity/body surface area ratio (147.2) and 8-week-relative dose intensity (50.0%) than those in the younger group (267.4, 67%) (P = 0.003, 0.029). The objective response rate was significantly lower in the elderly group (15.4%) than in the younger group (61.5%) (P = 0.021). The PFS in the elderly group tended to be shorter than that in the younger group (P = 0.058, hazard ratio [HR] 1.98). The modified albumin-bilirubin (mALBI) grade (hepatic function) (HR, 2.60; P = 0.01) and objective response (HR, 0.41; P = 0.011) were independently associated with the PFS in the multivariate analysis. CONCLUSION: The management of AEs is crucial for adherence and maintaining the dose intensity of lenvatinib in elderly HCC patients.

Analysis of the variation in learning curves for achieving competency in convex EUS training: a prospective cohort study using a standardized assessment tool.

BACKGROUND AND AIMS: The need for mastering standard imaging techniques for convex EUS in the biliopancreatic regions has been increasing; however, large variations in the aptitude for achieving EUS competency hinder expert development. Therefore, we investigated the factors influencing the achievement of expert competency in EUS using a new assessment tool for multiple imaging items. METHODS: Between January 2018 and February 2022, 3277 consecutive EUS procedures conducted by 5 beginners (EUS procedures <250), 7 intermediate trainees (250-749), and 2 experts (≥750) were prospectively evaluated. Immediately after each EUS procedure, the success or failure of imaging for each item was recorded using a newly developed EUS assessment tool that requires 17 items to be photographed. After correcting for missing values using multiple imputation, learning curves of EUS scores were created, and a competency was set based on expert scores. Finally, a comparative analysis between high and low performers was performed to extract factors influencing EUS scores. RESULTS: Although 3 of 7 intermediates (43%; mean, 317 cases) achieved competency, none of the beginners achieved competency. During a comparative analysis, although no significant difference in the number of EUS procedures performed was observed between the high and low performers, the former had significantly higher scores in the written test (theoretical knowledge). CONCLUSIONS: Our results showed that theoretical knowledge, rather than the number of EUS cases, may be a possible influencing factor for distinguishing high and low performers after treating 250 cases. (Clinical trial registration number: UMIN 000043271.).

Potential significance of uncovered self-expandable metal stents for distal malignant biliary obstruction: A propensity score-adjusted competing risk regression analysis.

Objectives: Selection criteria for self-expandable metal stents (SEMSs) with or without cover during palliative treatment of distal malignant biliary obstruction (DMBO) remain unclear. We evaluated factors associated with time to recurrent biliary obstruction (TRBO) in fully covered SEMSs (FCSEMSs) and uncovered SEMSs (UCSEMSs). Methods: We retrospectively analyzed consecutive patients with DMBO who received a SEMS. TRBO was determined using the Kaplan-Meier analysis, and complications were compared between the FCSEMS and UCSEMS groups. After TRBO-associated factors were extracted using multivariate competing-risks regression (CRR), propensity score-adjusted CRRs were performed to verify their robustness. Results: There were 180 patients (66 FCSEMSs and 114 UCSEMSs) enrolled in this study. There was no significant difference between median TRBO in the FCSEMS and UCSEMS groups (275 vs. 255 days, p = 0.67). Complications were more frequent in the FCSEMS than UCSEMS group (21.2% vs. 8.8%; p = 0.023). Multivariate CRR for TRBO-associated factors revealed that "pancreatic ductal carcinoma (PDAC) treated with UCSEMS" was the only independent predictor of TRBO (p = 0.03). Similarly, the propensity score-adjusted CRRs showed no significant difference in TRBO in "FCSEMS" vs "UCSEMS" (p = 0.96); however, there was a significant difference in "PDAC using UCSEMS" vs "other" (p = 0.043). In the palliative care group including any DMBO without chemotherapy, the first quartile of the TRBO of UCSEMS was 100 days. Conclusions: UCSEMSs are a possible option for both patients with DMBO arising from PDAC and for patients with any DMBO receiving palliative care who should avoid SEMS-related complications.

Dysbiosis of the Fecal and Biliary Microbiota in Biliary Tract Cancer.

Characteristic bile duct and gut microbiota have been identified in patients with chronic biliary tract disease. This study aimed to characterize the fecal and bile microbiota in biliary tract cancer (BTC) patients and their relationship. Patients with BTC (n = 30) and benign biliary disease (BBD) without cholangitis (n = 11) were included. Ten healthy, age-matched subjects were also recruited for fecal microbiota comparison. The fecal and bile duct microbiotas were analyzed by sequencing the 16S rRNA gene V3-V4 region. Live bacteria were obtained in the bile from three BTC patients by culture, and metagenomics-based identification was performed. Linear discriminant analysis effect size showed a higher Enterobacteriaceae abundance and a lower Clostridia abundance, including that of Faecalibacterium and Coprococcus, in the BTC patients than in the other subjects. Ten of 17 operational taxonomic units (OTUs) assigned to Enterobacteriaceae in the bile were matched with the OTUs found in the BTC subject fecal samples. Furthermore, a bile-isolated strain possessed the carcinogenic bacterial colipolyketide synthase-encoding gene. Enterobacteriaceae was enriched in the BTC feces, and more than half of Enterobacteriaceae in the bile matched that in the feces at the OTU level. Our data suggests that fecal microbiota dysbiosis may contribute to BTC onset.

Diagnostic Dilemma of Biliopancreatic Contrast-Enhanced Harmonic Endoscopic Ultrasonography.

Background: The utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) alone in the biliopancreatic region appears to be limited because it is highly dependent on the experience and skill of the endoscopist. Therefore, the present study aimed to validate the efficacy of CH-EUS in clinical practice. Methods: Between January 2018 and March 2019, 301 consecutive patients who underwent CH-EUS were prospectively enrolled in this study. The diagnostic performance of CH-EUS was compared with that of dynamic computed tomography (CT), magnetic resonance imaging (MRI), and all combinations (i.e., CH-EUS, dynamic CT, and MRI) using a Bonferroni correction. A multiple logistic regression analysis was performed to extract each disease that allowed the CH-EUS diagnosis to be consistent with the final diagnosis. Results: In multiple comparisons of diagnostic performance, no significant differences were observed among dynamic CT, MRI, and CH-EUS (p = 1.00), but the diagnostic performance was significantly higher when all modalities were combined (p < 0.001). Moreover, only intraductal papillary mucinous neoplasm comprising adenoma or carcinoma (IPMN, n = 161) showed significance with respect to the agreement with the final diagnosis (p = 0.006). Conclusions: Our results showed that CH-EUS-based diagnosis of IPMN may be possible in clinical practice. On the contrary, to accurately diagnose biliopancreatic diseases other than IPMN, comprehensive diagnosis using multiple modalities may be necessary, rather than relying on CH-EUS alone.

The Geriatric Nutritional Risk Index Predicts Tolerability of Lenvatinib in Patients With Hepatocellular Carcinoma.

BACKGROUND/AIM: We aimed to investigate the association between The Geriatric Nutritional Risk Index (GNRI) and the tolerability of lenvatinib in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively evaluated 61 HCC patients treated with lenvatinib and compared those with low GNRI (≤98, n=26) to those with high GNRI (>98, n=35). RESULTS: The discontinuation of lenvatinib due to adverse events was more frequent in the low GNRI group (46.2%) than in the high GNRI group (17.1%) (p=0.014). Multivariate analysis revealed that low GNRI (p=0.014), hypothyroidism (model 1 p=0.021, model 2 p=0.013), and advanced age (p=0.026) were independently associated with the discontinuation of lenvatinib. The progression-free survival in the low GNRI group was significantly shorter than that in the high GNRI group (p=0.047). CONCLUSION: The GNRI might be independently associated with the tolerability of lenvatinib in patients with HCC.

Endoscopic ultrasound-guided fine-needle biopsy histology with a 22-gauge Franseen needle and fine-needle aspiration liquid-based cytology with a conventional 25-gauge needle provide comparable diagnostic accuracy in solid pancreatic lesions.

BACKGROUND AND AIM: Fine-needle biopsy (FNB) needles obtain more core samples and support the shift from cytologic to histologic evaluation; however, recent studies have proposed a superior diagnostic potential for liquid-based cytology (LBC). This study compared the diagnostic ability of endoscopic ultrasound (EUS)-guided FNB histology with a 22-gauge Franseen needle (22G-FNB-H) and fine-needle aspiration (FNA) LBC with a conventional 25-gauge needle (25G-FNA-LBC). METHODS: We analyzed 46 patients who underwent both 22G-FNB-H and 25G-FNA-LBC in the same lesion during the same endoscopic procedure. This study evaluated the diagnostic ability of each needle, diagnostic concordance between needles, and incremental diagnostic effect of both needles compared to using each needle alone. RESULTS: The agreement rate for malignancy between both techniques was 93.5% (kappa value = 0.82). There was no significant difference in the diagnostic ability of both methods. 22G-FNB-H and 25G-FNA-LBC provided an incremental diagnostic accuracy in two (4.3%) cases and one (2.2%) case, respectively. CONCLUSION: Our study demonstrated that the diagnostic accuracy of 25G-FNA-LBC and 22G-FNA-H for solid pancreatic lesions were comparable. A conventional 25-gauge needle that punctures lesions with ease can be used in difficult cases and according to the skill of the endoscopist.

Cancerous pericarditis presenting as cardiac tamponade in a 68-year-old man with pancreatic adenocarcinoma: a case report.

INTRODUCTION: Pericardial effusion is a rare complication of pancreatic cancer. We report a case of cardiac tamponade secondary to pancreatic cancer. CASE PRESENTATION: A 68-year-old Japanese man was diagnosed as having pancreatic cancer during surgery and received chemotherapy for 28 months after the diagnosis. He was admitted to the emergency room with severe dyspnea. Echocardiography revealed pericardial effusion with severe hypofunction. Emergency pericardial drainage was performed to maintain hemodynamics, which resulted in the elimination of 450 mL of blood and the maintenance of circulatory dynamics. Cytological examination of the pericardial fluid revealed atypical cells and tumor cells suggesting adenocarcinoma. CONCLUSIONS: To our knowledge, pancreatic cancer complicated with cancerous pericarditis has not been previously documented. This case highlights the extreme severity of pericardial effusion, a sign of progressive disease, secondary to pancreatic cancer. In the case of neoplastic pericardial effusion, an extremely poor prognosis must be considered.

Clinical Significance of Tumor-Infiltrating T Cells and Programed Death Ligand-1 in Patients with Pancreatic Cancer.

The associations of the immunological status of the pancreatic ductal adenocarcinoma (PDA) microenvironment with prognosis were assessed. A high tumor-infiltrating lymphocyte (TIL) density was associated with a better prognosis. Importantly, even with a high density of TILs, the PDA cells with programed cell death-ligand 1 (PD-L1) expression showed a worse prognosis than the patients with negative PD-L1 expression. A significant association between a better prognosis and a tumor microenvironment with a high TIL density/negative PD-L1 expression was observed. Assessments of a combined immunological status in the tumor microenvironment may predict the prognosis of PDA patients following surgical resection.

Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1.

BACKGROUND: We have developed a Wilms' tumor 1 (WT1)-targeting dendritic cell (DC)-based cancer vaccine combined with standard chemotherapy for patients with advanced pancreatic ductal adenocarcinoma (PDA). METHODS: We evaluated predictive markers of overall survival (OS) in PDA patients treated with multiple major histocompatibility complex class I/II-restricted, WT1 peptide-pulsed DC vaccinations (DC/WT1-I/II) in combination with chemotherapy. Throughout the entire period of immunochemotherapy, the plasma levels of soluble factors derived from granulocytes of 7 eligible PDA patients were examined. Moreover, systemic inflammatory response markers (neutrophil-to-lymphocyte ratio [NLR], monocyte-to-lymphocyte ratio [MLR], and granulocyte-to-lymphocyte ratio [GLR]) were assessed. In addition, cytoplasmic WT1 expression in PDA cells was examined. RESULTS: Compared to the 4 non-super-responders (OS <1 year), the remaining 3 super-responders (OS ≥1 year) showed significantly decreased low plasma matrix metalloproteinase-9 levels throughout long-term therapy. The NLR, MLR, and GLR after 5 DC/WT1-I/II vaccinations and 3 cycles of gemcitabine were significantly lower in the super-responders than in the non-super-responders. Furthermore, the cytoplasmic WT1 expression in the PDA cells of super-responders was relatively weak compared to that in the PDA cells of non-super-responders. CONCLUSIONS: Prolonged low levels of a granulocyte-related systemic inflammatory response after the early period of therapy and low cytoplasmic WT1 expression in PDA cells may be markers predictive of OS in PDA patients receiving WT1-targeting immunochemotherapy.

Metagenomic analyses of the gut microbiota associated with colorectal adenoma.

Recent studies have suggested an association between certain members of the Fusobacterium genus, especially F. nucleatum, and the progression of advanced colorectal carcinoma (CRC). We assessed such an association of the gut microbiota in Japanese patients with colorectal adenoma (CRA) or intramucosal CRC using colonoscopy aspirates. We analyzed samples from 81 Japanese patients, including 47 CRA and 24 intramucosal CRC patients, and 10 healthy subjects. Metagenomic analysis of the V3-V4 region of the 16S ribosomal RNA gene was performed. The linear discriminant analysis (LDA) effect size (LEfSe) method was used to examine microbial dysbiosis, revealing significant differences in bacterial abundances between the healthy controls and CRA or intramucosal CRC patients. In particular, F. varium was statistically more abundant in patients with CRA and intramucosal CRC than in healthy subjects. Here, we present the metagenomic profile of CRA and intramucosal CRC and demonstrate that F. varium is at least partially involved in the pathogenesis of CRA and intramucosal CRC.

Clinical characteristics and short-term outcomes in patients with acute cholecystitis over aged >80 years.

AIM: We investigated the clinical characteristics and short-term outcomes in acute cholecystitis (AC) patients aged ≥80 years. We therefore sought to determine the ideal treatment for elderly patients with AC. METHODS: We retrospectively evaluated 253 patients with AC. The patients were divided into two groups according to their age: elderly group (n = 77, aged ≥80 years) and non-elderly group (n = 176, aged <80 years). We compared the clinical characteristics, in-hospital mortality and recurrence of cholecystitis within 6 months between the two groups. The predictive factors for in-hospital mortality were also assessed. RESULTS: The elderly group had more severe comorbidities (P = 0.0055), higher severity grade of AC (P = 0.00071) and higher in-hospital mortality (P = 0.029) than the non-elderly group. The multivariate analysis showed that the serum creatinine level (hazard ratio 12.43; P = 0.002) was independently associated with the in-hospital mortality. The elderly group (20.8%) underwent subsequent cholecystectomy less frequently than the non-elderly group (63.2%; P < 0.0001). The recurrence rate of AC was comparable between the two groups (P = 0.89). The proportion of patients in the elderly group who received percutaneous drainage in the latter period (64.3%) was significantly higher than in the former period (33.3%; P = 0.015). CONCLUSIONS: More attention should be paid to AC patients with chronic renal disease after treatment. Percutaneous drainage might serve as a definitive treatment without subsequent cholecystectomy in elderly AC patients with various comorbidities. Geriatr Gerontol Int 2019; 19: 208-212.

[A Case of Advanced Gastric Cancer with Bladder Metastasis].

A 61-year-old man was referred to the urology department in our hospital with gross hematuria and hydro nephrosis. Cystoscopy revealed a smooth mass lesion in his bladder, and a transurethral biopsy was performed. Signet ring cell carcinoma was found in the submucosa. Upper gastrointestinal endoscopy revealed an ulcerated lesion in his gastric body. Biopsy specimens obtained from the ulcerated lesion showed signet ring cell carcinoma. No other primary lesions were detected using colonoscopy, gallium scintigraphy, or computed tomography of the chest. He was ultimately diagnosed with advanced gastric cancer with bladder metastasis. He was prescribed combination chemotherapy of cisplatin and tegafur, gimeracil, oteracil potassium, and trastuzumab. After 2 courses of chemotherapy, there was a decrease in the size of both the gastric and bladder lesions. There was also a significant decrease in the tumor marker levels. He is currently alive after 7 courses of chemotherapy.

Inflammation-based prognostic scores predict disease severity in patients with acute cholecystitis.

BACKGROUND: Although several investigators have reported that inflammation-based prognostic scores can predict disease severity in patients with various inflammatory diseases, whether or not these scores are associated with disease severity in patients with acute cholecystitis (AC) has not yet been fully clarified. PATIENTS AND METHODS: Two hundred and sixty-two patients with AC were reviewed retrospectively. We evaluated the correlations between demographic or clinical variables, including the neutrophil-to-lymphocyte ratio (NLR), the Glasgow Prognostic Score (GPS), the modified Glasgow Prognostic Score (mGPS), and the C-reactive protein/albumin (CRP/Alb) ratio, as well as the disease severity grade on the basis of the revised Tokyo guidelines. Multivariate analyses were carried out to identify the clinical parameters associated with disease severity grade. RESULTS: The NLR (P<0.0001), GPS (P<0.0001), mGPS (P<0.0001), and CRP/Alb ratio (P<0.0001) were all elevated according to the severity grade. Multivariate analyses showed that the NLR [odds ratio (OR)=3.41-4.77; P<0.005], GPS (OR=2.49; P=0.012), mGPS (OR=2.79; P=0.005), and the CRP/Alb ratio (OR=12.53; P<0.0001) were associated independently with grade II/III AC. The value of the area under the curve of the CRP/Alb ratio (continuous 0.759) or NLR (continuous 0.753) was higher than that of other inflammation-based prognostic scores for diagnosing ≥grade II AC, grade III AC, respectively. CONCLUSION: Inflammation-based prognostic scores could predict the severity grade independently in patients with AC. These scores may play a complementary role in predicting disease severity in patients with AC in conjunction with the Tokyo guidelines severity grade.

Endoscopic submucosal dissection in a patient with esophageal adenoid cystic carcinoma.

We report the first use of endoscopic submucosal dissection (ESD) for the treatment of a patient with adenoid cystic carcinoma of the esophagus (EACC). An 82-year-old woman visited our hospital for evaluation of an esophageal submucosal tumor. Endoscopic examination showed a submucosal tumor in the middle third of the esophagus. The lesion partially stained with Lugol's solution, and narrow band imaging with magnification showed intrapapillary capillary loops with mild dilatation and a divergence of caliber in the center of the lesion. Endoscopic ultrasound imaging revealed a solid 8 mm × 4.2 mm tumor, primarily involving the second and third layers of the esophagus. A preoperative biopsy was non-diagnostic. ESD was performed to resect the lesion, an 8 mm submucosal tumor. Immunohistologically, tumor cells differentiating into ductal epithelium and myoepithelium were observed, and the tissue type was adenoid cystic carcinoma. There was no evidence of esophageal wall, vertical stump or horizontal margin invasion with pT1b-SM2 staining (1800 µm from the muscularis mucosa). Further studies are needed to assess the use of ESD for the treatment of patients with EACC.

Liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids.

We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.

A case of adenosquamous cell carcinoma of the gallbladder with markedly elevated PTHrP and G-CSF levels.

A 76-year-old woman was referred to our hospital with anorexia. Computed tomography revealed a tumor lesion measuring 110mm in the liver at S4/5 with calcification and swelling of a paraaortic lymph node. The gallbladder was not visualized. Histological examination of a biopsy specimen from the liver tumor revealed squamous cell and undifferentiated carcinomas, and several tumor markers were elevated. Therefore, we diagnosed the patient with gallbladder adenosquamous cell carcinoma T3N2M0 stage III. Because the serum parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels were significantly elevated, we suspected that PTHrP and G-CSF production occurred because of adenosquamous cell carcinoma in the gallbladder. We initiated chemotherapy with S-1.