Pre-existing autoimmune disease as a risk factor for immune-related adverse events in cancer patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have been widely used as standard therapies for various cancers. However, in 20-30% of cases, ICIs can lead to immune-related adverse events (irAEs), which sometimes require discontinuation of treatment. Due to the increased risk of irAEs, patients with pre-existing autoimmune diseases (AI) are often advised against receiving ICIs. However, there has not been sufficient objective risk assessment for AI. In our study, we conducted logistic regression analysis to assess the risk of irAEs by analyzing 478 cases that received anti-PD-(L)1 Ab and/or anti-CTLA4 Ab at our hospital between April 3, 2017, and May 24, 2022. Among these cases, 28 (5.9%) had pre-existing AI. We selected several independent factors for analysis: gender, age, performance status (PS), cancer type, type of ICI, type of combined anti-cancer agents, best overall response, and pre-existing AI. The adjusted odds ratio (OR) of AI for irAE occurrence was 2.52 [95% CI: 1.08-5.86] (p = 0.033), and the adjusted OR of AI for ICI discontinuation due to irAE was 3.32 [1.41-7.78] (p = 0.006). Patients with pre-existing AI experienced a significantly shorter irAE-free survival time compared to those without AI (median irAE-free survival: 5.7 months [95% CI: 3.5-7.8] vs 10.4 months [95% CI: 7.9-12.9], respectively, p = 0.035). Frequently observed irAEs in full ICI cohort, such as dermatologic issues (7.5%), pneumonitis (7.1%), hepatitis (4.6%), and hypothyroidism (4.2%), were often accompanied by pre-existing AI. Furthermore, pre-existing AI flared up in 6 cases (37.5% in AI-positive irAE-positive cases). The activity of AI was not related to the occurrence of irAEs. Grade 3 or higher irAEs were observed in 6 out of 20 (30.0%) cases in AI-accompanied patients complicated with irAEs. Although having a complicated AI increases the risk of irAEs, it may not necessarily be a contraindication for ICI treatment if closely monitored. (292<300 characters).

CD44-positive Cancer Stem-like Cells as a Potential Source of Peritoneal Metastasis After Surgery.

BACKGROUND/AIM: The role of CD44 in gastric cancer-derived peritoneal metastasis is currently unknown. It was previously shown that viable, tumorigenic cancer cells are spilled into the peritoneal cavity during surgery, providing a potential cause of peritoneal recurrence after surgery. The purpose of this study was to elucidate the mechanism of peritoneal metastasis of gastric cancer through the expression of CD44 and to propose a method for preventing peritoneal recurrence. MATERIALS AND METHODS: Gastric cancer cell line MKN-45 was sorted into CD44+ and CD44- cells and then injected intraperitoneally into NOD/ShiJic-scidJcl mice. Differences in tumor-initiating capacity between the two groups were assessed using in vivo limiting dilution assays. Tumors harvested from both groups were examined for CD44 and ALDH1A1 expression using immunohistochemistry. The effects of CD44 blockade with anti-CD44 antibody on cell invasion and peritoneal metastasis formation in vivo were assessed. RESULTS: CD44+ cells showed significantly higher efficiency in initiating peritoneal tumor than CD44- cells. Blockade of CD44 significantly reduced peritoneal dissemination of CD44+ cells in vivo, indicating that the CD44 function of intraperitoneally disseminated cancer cells helped promote the formation of peritoneal metastasis. The margin of established tumors showed clusters of cells co-expressing CD44 and ALDH1A1. Peritoneally administered CD44- cells resulted in peritoneal metastases consisting of CD44+ and CD44- cancer cells. CONCLUSION: CD44 expressing cells are a potential source of peritoneal metastasis after surgery and could be a promising target for preventing peritoneal recurrence.

Aggressive Intervention of Pancrelipase After Pancreatectomy Prevents Deterioration of Postoperative Nutritional Status.

OBJECTIVES: This study aimed to investigate the effect of early administration of delayed-release high-titer pancrelipase. METHODS: The medical records of 120 patients who had undergone pancreatectomy with computed tomography (CT) before and 6 months after surgery were retrospectively reviewed. Delayed-release high-titer pancrelipase were administered daily starting on postoperative day 3, which was defined as the EP group. The postoperative nutritional status and CT attenuation values of the liver were compared between the EP and control groups. RESULTS: Thirty-three patients (28%) were categorized into the EP group. With regard to the postoperative nutritional status 6 months after surgery, the body mass index, total lymphocyte count, and Onodera's prognostic nutritional index were higher, and controlling nutritional status score was lower in the EP group than that in the control group. The CT attenuation values of the liver were not significantly different. After propensity score matching analysis, body mass index (20.7 vs 19.2, P = 0.049) and Onodera's prognostic nutritional index (47.9 vs 44.2, P = 0.045) were significantly higher, and controlling nutritional status score was significantly lower in the EP group than that in the control group (1 vs 3, P = 0.046). CONCLUSIONS: The early administration of pancrelipase after pancreatectomy improved nutritional status after pancreatectomy.

Pleural empyema caused by dropped gallstones after laparoscopic cholecystectomy for acute cholecystitis: a case report.

BACKGROUND: Dropped gallstones during laparoscopic cholecystectomy (LC) sometimes induce postoperative infectious complications. However, pleural empyema rarely occurs as a complication of LC. CASE PRESENTATION: We present the case of a 66-year-old woman with right pleural empyema. She previously underwent LC for acute gangrenous cholecystitis 11 months ago. The operative report revealed iatrogenic gallbladder perforation and stone spillage. The bacterial culture of the gallbladder bile was positive for Escherichia coli. Chest and abdominal computed tomography revealed right pleural effusion, perihepatic fluid collection, and multiple small radiopaque density masses. Although ultrasound-guided transthoracic drainage was performed, the drainage was incomplete, and systemic inflammatory reaction persisted. Consequently, thoracotomy and laparotomy with gallstone retrieval were performed, and the patient recovered completely. The patient has remained well without complications after 14 months of follow-up. CONCLUSIONS: We report a rare case of pleural empyema caused by dropped gallstones after LC. This case emphasized the importance of completely retrieving the dropped gallstones to prevent late infectious complications after LC.

Impact of Preoperative Muscle Mass Maintenance and Perioperative Muscle Mass Loss Prevention After Pancreatectomy: Association Between Perioperative Muscle Mass and Postoperative Nutritional Status.

OBJECTIVES: We investigated how preoperative sarcopenia and perioperative muscle mass changes affect postoperative nutritional parameters in patients undergoing pancreatectomy. METHODS: This study included 164 patients undergoing pancreatectomy between January 2011 and October 2018. Skeletal muscle area was measured by computed tomography before and 6 months after surgery. Sarcopenia was defined as the lowest sex-specific quartile, and patients with muscle mass ratios less than -10% were classified into the high-reduction group. We examined the relationship between perioperative muscle mass and postoperative nutritional parameters 6 months after pancreatectomy. RESULTS: There were no significant differences in nutritional parameters between the sarcopenia and nonsarcopenia groups at 6 months after surgery. In contrast, albumin (P < 0.001), cholinesterase (P < 0.001), and prognostic nutritional index (P < 0.001) were lower in the high-reduction group. According to each surgical procedure, albumin (P < 0.001), cholinesterase (P = 0.007), and prognostic nutritional index (P < 0.001) were lower in the high-reduction group of pancreaticoduodenectomy. In distal pancreatectomy cases, only cholinesterase (P = 0.005) was lower. CONCLUSIONS: Postoperative nutritional parameters were correlated with muscle mass ratios but not with preoperative sarcopenia in patients undergoing pancreatectomy. Improvement and maintenance of perioperative muscle mass are important to maintain good nutritional parameters.

Pathological complete response in a patient with metastatic pancreatic acinar cell carcinoma who received a chemotherapy regimen containing cisplatin and irinotecan.

Pancreatic acinar cell carcinoma is a rare tumor of the pancreas, and patients with such tumors rarely have a pathological complete response to treatment. Herein, we present a case involving a 48-year-old woman with a pancreatic tail mass. The pancreatic mass was connected to splenic and portal vein thrombosis. Distal pancreatectomy and removal of portal vein tumor thrombosis were performed. Ten months after surgery, multiple liver metastases and local recurrence in the pancreatic bed were detected, and chemotherapy was administered through the administration of a regimen containing both cisplatin and irinotecan. After seven courses of the cisplatin-plus-irinotecan regimen had been administered, computed tomography revealed that the patient had a partial response to treatment. Radical resection of multiple liver metastases and the locally recurrent tumor was performed. Pathological examination did not reveal the presence of carcinoma in any of the resected specimens. Thus, this case involves a pathological complete response in a patient with metastatic pancreatic acinar cell carcinoma who received a regimen containing both cisplatin and irinotecan. Our findings reveal that the administration of the cisplatin-plus-irinotecan regimen may be an option for the management of such tumors.

Cancer-derived Exosomes Activate Immune Surveillance and Suppress Peritoneal Metastasis of Murine Colonic Cancer.

BACKGROUND: Colonic cancer is associated with a low incidence of peritoneal metastasis compared with gastric cancer; however, the reason for this remains unclear. In this study, a model of peritoneal dissemination using the CT26 murine colon cancer cell line was used to analyze the physiological roles of cancer-derived exosomes. MATERIALS AND METHODS: Exosomes were collected from the supernatant of CT26 cell culture by ultracentrifugation. The number of peritoneal disseminations in two mouse models of colonic cancer pre-administered exosomes or phosphate-buffered saline were compared. RESULTS: Cancer-derived exosomes suppressed peritoneal dissemination compared to phosphate-buffered saline. After administration of exosomes, the number of intraperitoneal macrophages and the expression of inducible nitric oxide synthase increased. Furthermore, cancer-derived exosomes increased activated natural killer cells and interferon-γ expression. CONCLUSION: Tumor-derived exosomes from colonic cancer may suppress peritoneal metastasis via an immunological mechanism.

Attenuation around the gallbladder on plain abdominal computed tomography as a predictor of surgical difficulty in laparoscopic cholecystectomy.

PURPOSE: This study examined whether abdominal plain computed tomography (CT) can predict surgical difficulty in acute cholecystitis. METHODS: We retrospectively analyzed 84 consecutive patients who underwent laparoscopic cholecystectomy for acute cholecystitis between January 2015 and December 2018. We distinguished three degrees of surgical difficulty based on the operative time and blood loss: difficult, both ≥120 minutes and ≥ 100 mL, respectively (n = 27); moderate, either ≥120 minutes or ≥ 100 mL, respectively (n = 30); and easy, both <120 minutes and < 100 mL, respectively (n = 27). We calculated the attenuation around the gallbladder on CT before surgery and compared the values among the three groups. RESULTS: Mean age, albumin levels, C-reactive protein levels, and the CT attenuation around the gallbladder (P < .001) were significantly different between groups. The surgical difficulty was unrelated to the timing of surgery. The postoperative complications were more frequent in operations more than 72 hours after disease onset (P = .04) and with CT attenuation around the gallbladder of ≥1.4 (P = .036). CONCLUSION: High attenuation around the gallbladder on plain CT predicted a high surgical difficulty of laparoscopic cholecystectomy. We recommend measuring the CT attenuation around the gallbladder in patients with acute cholecystitis.

Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population.

BACKGROUND: The tumor microenvironment, including cancer-associated fibroblasts (CAFs), plays various clinical roles in cancer growth. CAFs are a heterogeneous population and express a variety of mesenchymal markers. However, the clinical roles for CAFs expressing different markers in pancreatic ductal adenocarcinoma (PDAC) remain unknown. METHODS: We reviewed 67 resected PDAC patients who had not received preoperative therapy. Each primary tumor was analyzed for vimentin and α-smooth muscle actin (α-SMA) expression by immunohistochemical and dual immunofluorescence staining. RESULTS: There was no correlation between the percentage of cells expressing vimentin and α-SMA in the tumor stroma (Pearson's correlation coefficient: r = 0.171). Higher vimentin expression (p = 0.018) was associated with significantly shorter overall survival in PDAC patients. Using dual immunofluorescence staining, vimentin-positive CAFs were divided into two subpopulations: co-expression of α-SMA, and no co-expression of α-SMA. In PDAC, the level of co-expression had no effect on survival using univariate analysis (median survival time, 33.3 months for low co-expression vs. 18.2 months for high co-expression; log-rank, p = 0.143). However, multivariate analysis clarified that CAFs expressing vimentin alone was an independent predictor of poor survival (p = 0.014; hazard ratio, 2.305; 95% confidence interval, 1.181-4.497). CONCLUSIONS: Vimentin-positive CAFs without co-expression of α-SMA were associated with poor survival in PDAC, and CAFs possessed molecular and functional heterogeneity in this disease.

Fibrosis in metastatic lymph nodes is clinically correlated to poor prognosis in colorectal cancer.

BACKGROUND: Tumor microenvironment including fibrosis has a pivotal role in cancer growth and distant metastasis. Fibrosis is a known risk factor for carcinogenesis, but its biological role in disease invasion and metastasis in colorectal cancer (CRC) remains unclear. In particular, there is no report on how fibrosis of metastatic lymph nodes (MLNs) in CRC contributes to prognosis. METHODS: We reviewed 94 colorectal adenocarcinoma patients with MLNs who underwent colectomy. Both the primary tumors and MLNs were analyzed for alpha-smooth muscle actin (α-SMA) expression and collagen deposition. RESULTS: Higher α-SMA expression and collagen deposition in MLNs were associated with significantly shorter relapse-free survival and overall survival in CRC patients. α-SMA expression in MLNs (HR, 1.53; p = 0.034) was independent predictive factor of overall survival in multivariate Cox proportional hazards regression analysis of clinicopathological factors. In the Stage III patient subgroup, α-SMA expression in MLNs was a strong prognostic marker (HR, 3.01; p = 0.006). On the other hand, higher α-SMA expression and collagen deposition in primary tumors were associated with short overall survival, but they were not significant factors in multivariate Cox regression analyses. In MLNs, the podoplanin signals co-localized with α-SMA expression and were confirmed by the dual immunofluorescence staining, implying that the MLN stromal cells were fibroblastic reticular cells. CONCLUSION: Both high collagen deposition and high α-SMA expression in MLNs predicted poor prognosis in CRC.

[A case of breast cancer with repeated cardiac dysfunction due to trastuzumab].

Here we present a case of breast cancer in which cardiac dysfunction had previously been observed on trastuzumab(TRS) administration; the condition then improved but reoccurred on readministration of TRS. A 52-year-old woman received preoperative chemotherapy for StageIIIC left breast cancer(fluorouracil, epirubicin and cyclophosphamide followed by docetaxel and TRS), and then underwent partial mastectomy and axillary lymph node dissection. For adjuvant therapy, she received endocrine therapy and TRS. Radiation therapy was administered to the left residual breast. The patient complained about palpitation in the 5th cycle of TRS, and left ventricle ejection fraction(LVEF)decreased to 45.3% from 64%. Therefore, we stopped TRS administration. Palpitation improved, and LVEF increased to 53% after 2 months. TRS was administered again; however, palpitation reoccurred and LVEF decreased to 44%. TRS administration was once again discontinued. However, according to the HERA trial report regarding patients with a history of anthracycline and radiation therapy, TRS administration could be resumed when LVEF is greater than 50%, but we should be more careful during readministration of TRS.