IQ Motif Containing GTPase-Activating Protein 3 Is Associated with Cancer Stemness and Survival in Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of malignancy, with poor prognosis and rising incidence. IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the IQGAPs family of scaffolding proteins that govern multiple cellular activities like cytoskeletal remodeling and cellular signal transduction. This study aimed to analyze the expression and biological function of IQGAP3 in PDAC. METHODS: We analyzed IQGAP3 expression in 81 PDAC samples by immunohistochemistry. RNA interference was used to inhibit IQGAP3 expression in PDAC cell lines. RESULTS: Immunohistochemical analysis of IQGAP3 showed that 54.3% of PDACs were positive for cytoplasmic expression of IQGAP3, with no expression found in non-neoplastic tissue. Furthermore, IQGAP3 expression was an independent poor prognostic factor in our immunostaining-based studies and analyses of public databases. Our cohort and the Cancer Genome Atlas database indicated that IQGAP3 is co-localized with kinesin family member C1 (KIFC1), which we previously reported as a cancer stem cell-associated protein. IQGAP3 small interfering RNA treatment decreased PDAC cell proliferation and spheroid colony formation via ERK and AKT pathways. DISCUSSION/CONCLUSION: These results suggest that IQGAP3, a transmembrane protein, is involved in survival and stemness and may be a promising new therapeutic target for PDAC.

Effects of transmembrane serine protease 4 on the survival in patients with pancreatic ductal adenocarcinoma undergoing surgery followed by adjuvant chemotherapy.

PURPOSE: The transmembrane serine protease 4 (TMPRSS4) gene is upregulated in various human cancers. However, its biological functions in pancreatic ductal adenocarcinoma remain unclear. We examined the expression of TMPRSS4 in pancreatic ductal adenocarcinoma tissues and its correlation with clinicopathological parameters in patients with pancreatic ductal adenocarcinoma who underwent surgery. METHODS: The TMPRSS4 expression was immunohistochemically examined in 81 PDAC patients with pancreatic ductal adenocarcinoma. We analyzed the association between the TMPRSS4 expression and clinicopathological factors, the recurrence-free survival (RFS), and the overall survival (OS) and examined the effect of TMPRSS4 expression on cell migration and sensitivity to 5-fluorouracil. RESULTS: The expression rate of TMPRSS4 in the samples was 62.9% (51/81). The TMPRSS4 expression was not correlated with any clinicopathological feature. The five-year overall and recurrence-free survival rates were significantly lower in the TMPRSS4-positive group than in the TMPRSS4-negative group. On a multivariate analysis, TMPRSS4 positivity, poorly differentiated histology, and non-adjuvant chemotherapy predicted a poor OS, while TMPRSS4 positivity and poorly differentiated histology predicted a poor RFS. TMPRSS4-silenced pancreatic ductal adenocarcinoma cells showed higher sensitivity to 5- fluorouracil than did the control siRNA-transfected cells. CONCLUSIONS: TMPRSS4 can be considered a prognostic factor and therapeutic target for pancreatic ductal adenocarcinoma.

Effect of body fat mass loss on prognosis of radical resection for pancreatic ductal adenocarcinoma based on bioelectrical impedance analysis.

BACKGROUND: Few reports have performed a prognostic analysis based on bioelectrical impedance analysis in patients with radical resection of pancreatic ductal adenocarcinoma (PDAC), and its usefulness in prognostic analysis remains unclear. This study aimed to evaluate body composition changes in patients undergoing radical resection for PDAC and analyze its impact on prognosis. METHODS: The medical records of radical resection for patients with PDAC were retrospectively reviewed, and the parameters of body composition, including body weight, skeletal muscle mass, body fat mass (BFM), and extracellular water-total body water ratio, from preoperatively to 12 months postoperatively, for each surgical procedure were measured based on direct segmental multifrequency bioelectrical impedance analysis with an InBody 770 (InBody Inc., Tokyo, Japan) device. The clinicopathological and prognostic factors were analyzed. RESULTS: Among 79 patients who underwent radical resection for PDAC, 36 (46%), 7 (8%), and 36 (46%) underwent pancreatoduodenectomy, total pancreatectomy, and distal pancreatectomy, respectively. The multivariate overall survival analysis demonstrated that BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021), lymph node metastasis (p = 0.014), and non-adjuvant chemotherapy (p <  0.001) were independent poor prognostic factors. Multivariate analysis revealed that preoperative BFM < 12 kg and preoperative albumin < 3.5 g/dL were independently associated with BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021 and p = 0.047, respectively). CONCLUSIONS: Loss of BFM in the early postoperative period may have a poor prognosis in radical resection of PDAC.

Clinical features and images of malignant lymphoma localized in the pancreatic head to differentiate from pancreatic ductal adenocarcinoma: a case series study.

BACKGROUND: Pathological examination by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been reported to be useful in diagnosing pancreatic malignant lymphoma (ML), but some ML cases are difficult to be differentiated from pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective study included 8 patients diagnosed with ML that had a pancreatic-head lesion at initial diagnosis and 46 patients with resected PDAC in the pancreatic head between April 2006 and October 2021 at our institute. ML and PDAC were compared in terms of patients' clinical features and imaging examinations. RESULTS: The median tumor size was larger in ML than in PDAC (45.8 [24-64] vs. 23.9 [8-44] mm), but the median diameter of the caudal main pancreatic duct (MPD) was larger in PDAC (2.5 [1.0-3.5] vs. 7.1 [2.5-11.8] mm), both showing significant differences between these malignancies (both, P < 0.001). In the analysis of covariance, MLs showed a smaller caudal MPD per tumor size than PDACs, with a statistical difference (P = 0.042). Sensitivity and specificity using sIL-2R ≥ 658 U/mL plus CA19-9 < 37 U/mL for the differentiation of ML from PDAC were 80.0% and 95.6%, respectively. CONCLUSIONS: Diagnosing pancreatic ML using cytohistological examination through EUS-FNA can be difficult in some cases. Thus, ML should be suspected if a patient with a pancreatic tumor has a small MPD diameter per tumor size, high serum sIL-2R level, normal CA19-9 level. If the abovementioned features are present and still cannot be confirmed as PDAC, re-examination should be considered.

[Unresectable Esophageal Cancer on the Elderly Woman Which Was Treated Effectively with Ipilimumab plus Nivolumab-A Case Report].

Until now, the standard treatment regimen was cisplatin plus 5-FU as the chemotherapy for unresectable advanced esophageal cancer. Immune checkpoint inhibitors have brought about changes to the cancer treatment. Ipilimumab plus nivolumab was approved in June 2022 for unresectable advanced esophageal cancer. An 86-year-old woman who was normal ADL and cognitive function was diagnosed with unresectable esophageal cancer with multiple lymph node metastasis. We thought surgery or chemotherapy is impossible because of her age and health status, so we treated with ipilimumab plus nivolumab. After 2 cycles, tumor became reduced in size on endoscopic examination and accumulation in primary lesion and lymph node metastases was decreased considerably on positron emission tomography/computed tomography(PET-CT). Though the cycle after initiation of chemotherapy was uneventful, tumor regrowth on the examinations at 5 months. The patient's condition of the disease was improved temporarily after change chemotherapy to paclitaxel as the second-line therapy, but she died due to disease progression at 11.4 months from initiation of treatment. Ipilimumab plus nivolumab can become one of the effective treatments for patients who are impossible to treat with conventional chemotherapy.

[Surgical Resection and Adjuvant Chemotherapy for Early Multiple Peritoneal Recurrence after Rejection of Hepatocellular Carcinoma-A Case Report].

Thus far, no consensus has been reached regarding the treatment of peritoneal dissemination of hepatocellular carcinoma (HCC). Here, we report a case of surgical resection and postoperative adjuvant chemotherapy for early multiple peritoneal recurrences of HCC. A 74-year-old man was found to have hepatic mass of 80 mm in size in S7 and 57 mm in S8, and was diagnosed with HCC. The patient underwent an open anterior segmentectomy and S7 subsegmentectomy of the liver. Peritoneal washing cytology revealed the presence of malignant cells. The tumor strongly adhered to the diaphragm, necessitating partial resection of the diaphragm. Six months after surgery, multiple disseminated recurrences were found on the CT scan. Atezolizumab plus bevacizumab combination therapy was initiated, but tumor size enlargement and elevation of tumor markers were observed after 3 courses. Resection of the dissemination(2 on the surface of the lung right lower lobe, 1 on the right renal superior retroperitoneum, 1 on the omentum, and 1 invading the jejunum)was performed. Considering the high risk of recurrence, postoperative adjuvant chemotherapy with lenvatinib was administered for 1 year. No recurrence has been found for 16 months after the resection. Although more cases are needed to conclude, this case report suggests that surgical resection and postoperative administration of lenvatinib may be effective in the treatment of disseminated HCC lesions at a high risk of recurrence.

[A Case of Anal Canal Cancer with Pagetoid Spread and a Significant Response to Preoperative Chemoradiotherapy].

Perianal Pagetoid spread is a rare condition for which there is no proven therapy. We experienced a case of anal canal cancer with Pagetoid spread which exhibited a significant response to preoperative chemoradiotherapy(CRT). A 76-year-old man with anal stenosis was referred to our hospital. He was diagnosed with anal canal cancer with Pagetoid spread. No infiltration into the surrounding tissue was observed, but metastasis to the left inguinal lymph node was noted. The patient received preoperative CRT(oral S-1, 1.8 Gy×25 Fr, a total dose of 45 Gy)including the bilateral inguinal region. After CRT, the main tumor size was reduced and PET-CT showed disappearance of the abnormal accumulation in the left inguinal lymph nodes. Laparoscopic abdominoperineal resection and left inguinal trans lymphadenectomy were performed. The macroscopic findings of the surgical specimen confirmed no residual carcinoma or lymph node metastasis. Although more proof is needed, this case suggested that CRT may be effective for anal canal cancer with pagetoid spread.

[A Case of Laparoscopic Surgery for Colon Metastasis of Renal Cancer].

A 67-year-old man underwent laparoscopic partial left nephrectomy for renal cell carcinoma 2.5 years ago. CT showed a well-defined 3 cm mass with contrast effect bordering on the descending colon, and PET-CT showed an accumulation of SUVmax 6.01 in the same area. Colonoscopy revealed a submucosal tumor-like mass in the descending colon. The patient was diagnosed with a local recurrence of renal cell carcinoma and invasion of the descending colon, and laparoscopic colectomy was performed. The excised specimen was a pale yellowish submucosal tumor measuring 4.5×3.8 cm, which was histologically diagnosed as metastasis of clear cell renal cell carcinoma. Surgical resections for metastases of renal carcinoma have been reported and expected prolong survival. We report a case of laparoscopic colon resection for recurrence of descending colon metastasis of renal cell carcinoma.

[Two Cases of Alpha-Fetoprotein Producing Gastric Cancer].

Case 1: A 51-year-old man underwent total gastrectomy for esophagogastric junction cancer. Pathological diagnosis was alpha-fetoprotein(AFP)producing cancer. One month after the surgery, lung metastasis was found on CT. Despite systemic chemotherapy, he died 4 months after the surgery. Case 2: A 79-year-old man underwent open distal gastrectomy for gastric cancer. Pathological diagnosis was AFP producing cancer. Six months after the surgery, multiple lymph node metastases were found on CT. He received chemotherapy and radiation therapy. He is currently alive 9 years 8 months after the surgery.

[Lung Metastasis from Alpha-Fetoprotein Resulting in Esophagogastric Junction Cancer-A Case Report].

A 51-year-old male underwent total gastrectomy for esophagogastric junction cancer(T3N0M0, Stage ⅡA). He was diagnosed with an alpha-fetoprotein(AFP) producing tumor and hepatoid adenocarcinoma. One month after radical surgery, computed tomography(CT) showed lung metastasis, and the patient's serum AFP level was high. He underwent chemotherapy( S-1 and wPTX/RAM)and eventually died 4 months after surgery.

Surgical resection of double advanced pancreatic neuroendocrine tumors with multiple renal cell carcinoma associated with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46 year-old man with a 35 mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55 mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36 mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6 months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22 months after primary surgery. The patient remains alive 41 months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL.

Utility of Machine Learning in the Prediction of Post-Hepatectomy Liver Failure in Liver Cancer.

Background: Posthepatectomy liver failure (PHLF) is a serious complication associated with high mortality rates. Machine learning (ML) has rapidly developed and may outperform traditional models in predicting PHLF in patients who have undergone hepatectomy. This study aimed to predict PHLF using ML and compare its performance with that of traditional scoring systems. Methods: The clinicopathological data of 334 patients who underwent liver resection were retrospectively collected. The Pycaret library, a simple, open-source machine learning library, was used to compare multiple classification models for PHLF prediction. The predictive performance of 15 ML algorithms was compared using the mean area under the receiver operating characteristic curve (AUROC) and accuracy, and the best-fit model was selected among 15 ML algorithms. Next, the predictive performance of the selected ML-PHLF model was compared with that of routine scoring systems, the albumin-bilirubin score (ALBI) and the fibrosis-4 (FIB-4) index, using AUROC. Results: The best model was extreme gradient boosting (accuracy:93.1%; AUROC:0.863) among the 15 ML algorithms. As compared with ALBI and FIB-4, the ML PHLF model had higher AUROC for predicting PHLF. Conclusion: The novel ML model for predicting PHLF outperformed routine scoring systems.

Transmembrane serine protease 4 expression in the prognosis of radical resection for biliary tract cancer.

BACKGROUND: Recent advancements in biliary tract cancer (BTC) treatment have expanded beyond surgery to include adjuvant therapy, yet the prognosis remains poor. Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC. AIM: To determine transmembrane serine protease 4 (TMPRSS4) utility as a prognostic biomarker of radical resection for BTC. METHODS: Medical records of patients who underwent radical resection for BTC, excluding intrahepatic cholangiocarcinoma, were retrospectively reviewed. The associations between TMPRSS4 expression and clinicopathological factors, overall survival, and recurrence-free survival were analyzed. RESULTS: Among the 85 patients undergoing radical resection for BTC, 46 (54%) were TMPRSS4-positive. The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9 (CA19-9) values and greater lymphatic invasion than the TMPRSS4-negative group (P = 0.019 and 0.039, respectively). Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group (median survival time: 25.3 months vs not reached, P < 0.001; median survival time: 28.7 months vs not reached, P = 0.043, respectively). Multivariate overall survival analysis indicated TMPRSS4 positivity, pT3/T4, and resection status R1 were independently associated with poor prognosis (P = 0.032, 0.035 and 0.030, respectively). TMPRSS4 positivity correlated with preoperative CA19-9 values ≥ 37 U/mL and pathological tumor size ≥ 30 mm (P = 0.016 and 0.038, respectively). CONCLUSION: TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.

High-grade pancreatic intraepithelial neoplasia diagnosed based on changes in magnetic resonance cholangiopancreatography findings: A case report.

BACKGROUND: High-grade pancreatic intraepithelial neoplasia (PanIN) exhibits no mass and is not detected by any examination modalities. However, it can be diagnosed by pancreatic juice cytology from indirect findings. Most previous cases were diagnosed based on findings of a focal stricture of the main pancreatic duct (MPD) and caudal MPD dilatation and subsequent pancreatic juice cytology using endoscopic retrograde cholangiopancreatography (ERCP). We experienced a case of high-grade PanIN with an unclear MPD over a 20-mm range, but without caudal MPD dilatation on magnetic resonance cholangiopancreatography (MRCP). CASE SUMMARY: A 60-year-old female patient underwent computed tomography for a follow-up of uterine cancer post-excision, which revealed pancreatic cysts. MRCP revealed an unclear MPD of the pancreatic body at a 20-mm length without caudal MPD dilatation. Thus, course observation was performed. After 24 mo, MRCP revealed an increased caudal MPD caliber and a larger pancreatic cyst. We performed ERCP and detected atypical cells suspected of adenocarcinoma by serial pancreatic juice aspiration cytology examination. We performed a distal pancreatectomy and obtained a histopathological diagnosis of high-grade PanIN. Pancreatic parenchyma invasion was not observed, and curative resection was achieved. CONCLUSION: High-grade Pan-IN may cause MPD narrowing in a long range without caudal MPD dilatation.

Expression of kinesin family member C1 in pancreatic ductal adenocarcinoma affects tumor progression and stemness.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer and the third leading cause of cancer-related deaths. Therefore, there is an urgent need for a novel molecular target for the treatment of PDAC. Kinesin family member C1 (KIFC1) belongs to the kinesin superfamily proteins and has been reported to be involved in the pathogenesis of a wide variety of carcinomas. However, the role of KIFC1 in PDAC remains unknown. This study aimed to analyze the expression and biological function of KIFC1 in PDAC. Immunohistochemically, KIFC1 was found in 37 of 81 PDAC cases (46%). A high expression of KIFC1 was significantly related to tumor size (p = 0.023) and poor overall survival (p = 0.011). Univariate and multivariate analysis indicated that KIFC1 expression was a prognostic factor in PDAC cases. As for cancer stem cell markers, KIFC1 expression tended to co-express significantly with CD44 (p < 0.01). The growth and spheroid colony formation of KIFC1 small interfering RNA (siRNA)-transfected PDAC cells were significantly lower than those of negative control siRNA-transfected cells. Therefore, our findings suggest that KIFC1 is an independent prognostic factor in PDAC and may represent a new promising therapeutic target in PDAC.

Micro-lymph node metastasis in intrahepatic cholangiocarcinoma showing pathological complete response to primary tumor and intrahepatic metastasis treated by gemcitabine plus cisplatin chemotherapy and radical surgery.

Surgical resection is the only curative treatment option for achieving long-term survival in biliary tract cancer patients. However, regional lymph node dissection in intrahepatic cholangiocarcinoma (ICC) is controversial. Herein, we document our experience with a 76-year-old man who had a 70 mm mass in liver segments 6 and 7 and a 10 mm mass in liver segment 3, which were diagnosed as poorly differentiated adenocarcinomas by needle biopsy. Lymphadenopathy was not evident on multidetector computed tomography scanning. Twenty courses of gemcitabine plus cisplatin chemotherapy were administered to the patient. The tumor masses shrunk and exhibited a partial response to chemotherapy as per the Response Evaluation Criteria in Solid Tumors version 1.1. Although tumor markers were all within normal limits, renal function parameters showed deterioration due to systemic chemotherapy. Therefore, continuing systemic chemotherapy was deemed unfeasible and we decided to perform a radical resection using extended posterior segmentectomy and partial liver resection with regional lymph node dissection. Postoperative histopathological examination revealed complete response of primary tumor and intrahepatic metastases; however, a micro-lymph node metastasis was found. The patient is still alive, without recurrence, more than 30 months after treatment initiation and 15 months after surgery. Even if remarkably effective pathological findings may be observed in the primary tumor, there are cases in which a micro-lymph node metastasis remains that are not identified on imaging examinations. Thus, regional lymphadenectomy may be useful in obtaining the exact state of disease progression and evaluation of chemotherapeutic effect in radical surgery.

Analysis of Acquisition of COVID-2019 Neutralizing Antibodies in Organ Transplant Recipients.

BACKGROUND: This study confirmed the kinetics of antibodies acquired by SARS-CoV-2 vaccination in solid-organ transplant recipients and examined their association with the development of COVID-19 and immunosuppressive status in organ transplant recipients. METHODS: We measured COVID-19 neutralizing antibody titer in 21 organ transplant recipients vaccinated with the COVID-19 vaccine and 14 nontransplant recipients (control group) 3 times before and at 1 and 6 months after the third dose of vaccine. By confirming the kinetics of the acquired antibodies, we examined the relevance of the background characteristics of organ transplant recipients, such as the development of infectious diseases and immunosuppressive status. RESULTS: The proportion of patients with neutralizing antibodies was significantly higher in the nontransplant group than in the transplant group. Neutralizing antibody titers were significantly lower in transplant recipients when they were compared before the third dose and 1 month later. In the transplant recipient group, 11 patients were positive, and 10 were negative for neutralizing antibodies. When the causal relationship between the neutralizing antibody titer and background was examined, a positive correlation was found between the antibody titer and the number of years since transplantation, and a negative correlation was found between the tacrolimus trough values, amount of mycophenolate mofetil or steroids taken internally, and antibody titer. CONCLUSION: This study suggests that the effectiveness of vaccination in transplant recipients is associated with the post-transplant period before vaccination and the dose of immunosuppressive agents.

Falciform ligament hernia with specific abdominal symptom.

Falciform ligament hernia is a very rare internal hernia and is difficult to diagnose before surgery. We report a case of falciform ligament hernia with a specific symptom and image findings, which led to an accurate diagnosis and subsequent laparoscopic surgery. A 15-year-old adolescent boy with no previous medical history showed epigastric pain and was referred to our hospital. The abdominal pain was strong in the supine position and was alleviated in the knee-chest position. Contrast-enhanced computed tomography showed that the round ligament was recognized as a cord-like structure, and the mesentery of the small intestine was located at the cranioventral side of the ligament. He was diagnosed as having falciform ligament hernia, and emergency laparoscopic surgery was performed. The small intestine passed through the falciform ligament; however, it showed no sign of ischemia, and bowel resection was not required. The malposed intestine was repositioned, and the falciform ligament was cut to prevent hernia recurrence. The specific abdominal symptom and computed tomography image finding were useful to make the correct diagnosis in this case.