Prognostic and diagnostic effects of high serum midkine levels in patients with hepatocellular carcinoma.

Midkine (MK) is a soluble cytokine, and its serum levels strongly correspond to protein expression levels in tumors. The present study aimed to clarify the clinicopathological and prognostic significance of serum MK (s-MK) in patients with hepatocellular carcinoma (HCC). Serum samples were obtained before surgery from 123 patients with HCC who had undergone surgery between January 2012 and December 2020. The receiver operating characteristic curve revealed that the best cut-off value for s-MK in differentiating HCC from healthy cases was 426 pg/ml. The clinicopathological variables and overall survival of patients were compared between the s-MK-positive group and s-MK-negative group. The sensitivity, specificity and accuracy of s-MK were 82.1, 97.4 and 88.0%, respectively. An s-MK-positive status was significantly associated with the number of tumors (≥2). The positivity rate of s-MK was significantly higher compared with that of α-fetoprotein and protein-induced by vitamin K absence-II. In total, only 28% of the patients were positive for s-MK. The s-MK-positive group showed significantly worse overall survival compared with the s-MK-negative group. Moreover, multivariate analysis revealed that an s-MK-positive status was independently associated with poor prognosis. s-MK was useful in detecting early HCC. The findings of this study indicated that the s-MK-positive status is associated with the number of tumors and can act as an independent prognostic risk factor.

Safety of laparoscopic liver resection for high-risk patients.

BACKGROUND/PURPOSE: To investigate the safety of laparoscopic liver resections (LLRs) for high-risk patients (HRs) with preoperative comorbidities affecting the heart, lungs, kidneys, glucose tolerance, and central nervous system. METHODS: This retrospective study included 585 patients who had undergone total hepatectomies from 2006 to 2020. Among them, 239 patients underwent LLRs, and 349 underwent open liver resections (OLRs). The safety and validity of LLRs were analyzed by comparing outcomes and preoperative records between HRs and nonhigh-risk patients (nHRs). HRs were defined as patients with any type of chronic heart disease rated New York Heart Association II or higher, chronic obstructive pulmonary disease rated stage III or higher, chronic kidney disease rated stage III or higher, insulin-dependent diabetes mellitus, or cerebrovascular disease with neurological sequelae. RESULTS: A total of 117 LLRs (49.0%) were performed in HRs, and there were more patients with ASA class III or higher than nHRs. Complications of Clavien-Dindo classification grade 3b or higher were not observed in HRs and in only one nHR. Furthermore, no postoperative exacerbations of the five HRs factors were observed in either group. CONCLUSIONS: Rigorous assessment of surgical indications and perioperative management can promote safe LLRs, even in HRs with comorbidities.

Six autoantibodies as potential differential biomarkers of hepatocellular carcinoma vs. liver cirrhosis and chronic hepatitis: A prospective multi-institutional study.

Serum autoantibodies respond not only to tumor-associated antigens of hepatocellular carcinoma (HCC) but also to those of liver cirrhosis (LC) and chronic hepatitis (CH). The present prospective multi-institutional study evaluated the diagnostic properties of six autoantibodies in distinguishing HCC from LC and CH. A total of 416 participants were enrolled: 149 With HCC, 76 with LC, 103 with CH and 88 healthy controls. Titers of serum autoantibodies to Sui1, RalA, p62, p53, c-myc and NY-ESO-1 were determined using enzyme-linked immunosorbent assays. All six antibodies were positive for HCC: s-Sui1-Abs (44%), s-RalA-Abs (23%), s-p62-Abs (21%), s-p53-Abs (13%), s-c-myc-Abs (11%) and s-NY-ESO-1-Abs (6%). The positivity rates of all six antibodies combined were 5% for healthy controls, 52% for CH, 58% for LC and 66% for HCC. The positivity rates of s-Sui1-Abs, s-RalA-Abs and s-p53-Abs were higher for HCC compared with those of LC and CH. However, the positivity rates of s-p62-Abs, s-c-myc-Abs and s-NY-ESO-1-Abs for HCC were not higher compared with those for LC and CH. Overall, autoantibodies were useful in differentiating patients with HCC from healthy individuals. However, they were not specific to HCC and were also present in the sera of individuals with CH and LC. These autoantibodies may be induced during the development of HCC. Clinical trial registration number: UMIN000014530 (date of registration 2011/07/11).

Intraoperative guidance using ICG fluorescence imaging system for safe and precise laparoscopic liver resection.

BACKGROUND: Laparoscopic liver resection (LLR) has been spread as minimally invasive surgery for liver disease. Advances in surgical technique and devices enabled us to perform various procedures of LLR. Indocyanine green (ICG) fluorescence imaging has been suggested as useful tool to identify liver tumors, anatomical territory of liver parenchyma, and cholangiography in open liver surgery. Due to recent development, this technology can be applied in LLR. we describe safe and effective using of the ICG fluorescence imaging during LLR. METHODS: From September 2013 to August 2019, 34 patients were performed LLR using a total of 46 procedures by ICG fluorescence imaging system for purposes including identification of anatomic domain of the liver in 12 LLRs, detection of liver tumors in 30 nodules, or intraoperative cholangiography in 4 LLRs. RESULTS: During the detection of liver tumors, 25 nodules in 30 malignant to benign tumors were positively detected (83.3%). Although there has been no publication regarding information on ICG fluorescence imaging of low grade malignant or benign tumors, we found positive emission in focal nodular hyperplasia, an angiomyolipoma, and an intraductal papillary neoplasm of the bile duct. The identification of anatomic domain in the liver was successful in all 12 LLRs with negative and positive staining techniques. In the intraoperative cholangiography, all 4 tests were successfully performed. One of 4 patients were found to have biliary leakage which was repaired intraoperatively. CONCLUSIONS: The ICG fluorescence imaging could be useful in safe and precise performance of LLR.

Inducing multiple antibodies to treat squamous cell esophageal carcinoma.

BACKGROUND: The positive response and the clinical usefulness of 14 serum antibodies in patients with esophageal squamous cell carcinoma (ESCC) were examined in this study. The Cancer Genome Atlas (TCGA) was used to investigate the frequency of gene expressions, mutations, and amplification of these 14 antigens and also the possible effects of antibody induction. METHODS: Blood serum derived from 85 patients with ESCC was collected and analyzed for the 14 antibodies using ELISA. The prognosis between positive and negative antibodies were then compared. The antibody panel included LGALS1, HCA25a, HCC-22-5, and HSP70. RESULTS: Patient serum was positive for all antibodies, except VEGF, with the positive rates ranging from 1.18 to 10.59%. Positive rates for LGALS1, HCA25a, HCC-22-5, and HSP70 were > 10%. TCGA data revealed that all antigen-related genes had little or no mutation or amplification, and hence an increase in gene expression affected antibody induction. The positive results from the panel accounted for the positive rate comparable to the combination of CEA and SCC. No significant association was observed between the presence of antibodies and disease prognosis. CONCLUSIONS: The detection rates of LGALS1, HCA25a, HCC-22-5, and HSP70 were 10% higher in patients with ESCC. Gene overexpression may be involved in such antibody production. These four antibodies were applied as a panel in comparison with conventional tumor markers. Moreover, it was confirmed that the combination of this panel and the conventional tumor markers significantly improved the positive rate.

Prognostic impact of p53 and/or NY-ESO-1 autoantibody induction in patients with gastroenterological cancers.

BACKGROUND AND AIM: We evaluated the clinicopathological and prognostic significance of serum p53 (s-p53-Abs) and serum NY-ESO-1 autoantibodies (s-NY-ESO-1-Abs) in esophageal squamous cell carcinoma (ESCC), gastric cancer and hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 377 patients, 85 patients with ESCC, 248 patients with gastric cancer, and 44 patients with HCC were enrolled to measure s-p53-Abs and s-NY-ESO-1-Abs titers by the enzyme-linked immunosorbent assay before treatment. The clinicopathological significance and prognostic impact of the presence of autoantibodies were evaluated. Expression data based on the Cancer Genome Atlas and the prognostic impact of gene expression was also examined for discussion. RESULTS: The positive rates of s-p53-Abs were 32.9% in ESCC, 15% in gastric cancer, and 4.5% in HCC. The positive rates of s-NY-ESO-1-Abs were 29.4% in ESCC, 9.7% in gastric cancer, and 13.6% in HCC. The presence of s-p53-Abs was not associated with tumor progression in these three cancer types. On the other hand, the presence of s-NY-ESO-1-Abs was significantly associated with tumor progression in ESCC and gastric cancer. The presence of s-p53-Abs and/or s-NY-ESO-1-Abs was significantly associated with poor prognosis in gastric cancer but not in ESCC nor HCC. CONCLUSIONS: The presence of s-p53-Abs and/or s-NY-ESO-1-Abs was associated with tumor progression in ESCC and gastric cancer. These autoantibodies might have poor prognostic impacts on gastric cancer (UMIN000014530).

Six autoantibodies as potential serum biomarkers of hepatocellular carcinoma: A prospective multicenter study.

Serum autoantibodies have been reported to react with tumor-associated antigen (TAA) in various cancers. This multicenter study evaluated the diagnostic and prognostic value of six autoantibodies against a panel of six hepatocellular carcinoma (HCC)-associated antigens, including Sui1, p62, RalA, p53, NY-ESO-1 and c-myc. A total of 160 patients with HCC and 74 healthy controls were prospectively enrolled from six institutions. Serum antibody titers were determined by enzyme-linked immunosorbent assays. The sensitivities were 19% for Sui1, 18% for p62, 17% for RalA, 11% for p53, 10% for NY-ESO-1 and 9% for c-myc. Overall sensitivity of the TAA panel (56%) was higher than that of α-fetoprotein (41%, P < .05). The combined sensitivity of the TAA panel and α-fetoprotein was significantly higher than that of α-fetoprotein alone (P < .001). The difference in overall survival of TAA panel-positive and panel-negative patients was significant when the Stage I/II patients were combined (P = .023). Overall survival was worse in NY-ESO-1 antibody-positive than in NY-ESO-1 antibody-negative patients (P = .002). Multivariate analysis found that positivity for the TAA panel was independently associated with poor prognosis (P = .030). This TAA panel may have diagnostic and prognostic value in the patients with HCC.

Serum p53 antibody as a potential tumor marker in extrahepatic cholangiocarcinoma.

PURPOSE: Only a few studies have evaluated the clinicopathological significance of the p53 protein expression and s-p53-Abs level in patients with cholangiocarcinoma. We therefore analyzed the clinicopathological and prognostic significance of s-p53-Abs in patients with extrahepatic cholangiocarcinoma. METHODS: We prospectively evaluated s-p53-Abs levels before and after surgery in 61 patients with extrahepatic cholangiocarcinoma to determine the relationship between clinicopathological factors and the prognostic significance of s-p53-Abs. RESULTS: Among a total of 61 primary extrahepatic cholangiocarcinoma cases, 23% were positive for s-p53-Abs. Combination of s-p53-Abs with the conventional serum markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) significantly increased the rate of positive extrahepatic cholangiocarcinoma cases (57% for CEA and/or CA19-9 vs. 75% for CEA and/or CA19-9 and/or s-p53-Abs, P = 0.035). There were no significant differences in clinicopathological factors between the p53-seropositive and p53-seronegative patients. An immunohistochemical analysis showed the presence of significant associations between the intensity (P = 0.003) and extent (P = 0.001) of p53 immunoreactivity and p53-seropositivitly. Although s-p53-Abs was not a significant prognostic factor for the survival in either univariate or multivariate analyses, p53 immunoreactivity was independently associated with a poor survival. Among patients positive for s-p53-Abs before surgery, the s-p53-Abs levels were reduced after surgery in most. CONCLUSION: These findings suggested that s-p53-Abs might be associated with p53 immunoreactivity. In addition, s-p53-Abs may be useful for a diagnosis, but was not useful for predicting tumor recurrence or the survival. This study was registered as UMIN000014530.

Severe Fournier's gangrene in a patient with rectal cancer: case report and literature review.

BACKGROUND: Fournier's gangrene in the setting of rectal cancer is rare. Treatment for Fournier's gangrene associated with rectal cancer is more complex than other cases of Fournier's gangrene. We report on a patient with severe Fournier's gangrene in the setting of locally advanced rectal cancer who was treated with a combined modality therapy. CASE PRESENTATION: A 65-year-old man presented with general fatigue and anal pain. The medical and surgical histories were unremarkable. A black spot on the perineal skin surrounded by erythema was found on physical examination, suspicious for Fournier's gangrene. Computed tomography scan showed a rectal tumor invading into the bladder (clinically T4bN2M0) and abscess formation with emphysema around the rectum. He was thus diagnosed with locally advanced rectal cancer and Fournier's gangrene with a severity index score of 12 points. We created a diverting loop colostomy of the transverse colon and performed extensive debridement of the perineum and perianal area. Fifty days later, the patient underwent radical total pelvic exenteration with sacrectomy. In addition, reconstruction of the soft tissue defect was performed using the rectus muscle, the gluteus maximus muscle, and the femoral muscle. Histopathological findings of the specimen were as follows: the tumor was a moderately adenocarcinoma with invasion to the bladder and the prostate (T4b), metastases to four resected lymph nodes (N2), and lymphovascular invasion. There were no major postoperative complications, and the patient was discharged 108 days postoperatively. CONCLUSIONS: We report a rare case of locally invasive rectal cancer associated with Fournier's gangrene. This case highlights a usual cause of Fournier's gangrene. Physicians should be cognizant not only of the more common condition but also of the rare presentations including those associated with rectal cancer.

A resected case of intraductal tubulopapillary neoplasm of the pancreas: report of a case.

The patient was a 61-year-old male who was referred to our hospital after dilatation of the main pancreatic duct was detected by screening ultrasonography. Computed tomography revealed a protruding lesion measuring 15 mm in diameter within the main pancreatic duct in the head of the pancreas, and magnetic resonance cholangiopancreatography revealed interruption of the duct at the tumor site. We performed pancreaticoduodenectomy under a suspected diagnosis of invasive ductal carcinoma. Gross examination of the resected specimen showed that the tumor invaginated into the main pancreatic duct, and no mucin was found. Histological examination revealed proliferation of high-grade dysplastic cells in a tubulopapillary growth pattern. Immunohistochemically, cytokeratin 7 expression was detected, but not trypsin expression. Based on these morphological features, we diagnosed the tumor as intraductal tubulopapillary neoplasm (ITPN). We report the case with bibliographic consideration, together with a review of intraductal neoplasms of the pancreas encountered at our institution.

A case of mucinous cystic neoplasm of the liver: a case report.

A 71-year-old woman was referred to our institution for further investigation of epigastric pain. The patient had been detected to have a multilocular cyst in the medial segment of the liver measuring 69 mm in diameter at another hospital 2 years ago, and the diameter of the cyst had increased to 90 mm. Although the cyst had gradually increased in size, there was no evidence of mural nodules. As we were concerned about the malignant potential of the lesion, a left hepatic segmentectomy was performed. Pathologically, the cyst was lined by columnar and cuboidal epithelium with low-grade atypia. The epithelium covered an ovarian-like stroma, and the diagnosis was mucinous cystic neoplasm of the liver (MCN-L) with low-grade intraepithelial neoplasia. MCN-L is a rare disease and its characteristics are still poorly understood. MCN-L occurs at a lower frequency as compared to the counterpart of MCN of the pancreas, further investigations are necessary to clarify the biological malignancy of MCN-L.

[A case of home parenteral nutrition therapy associated with some problems in exchanging of a popular TPN one bag solution to a new type one bag TPN solution containing all elements of essential nutritionals].

This case was a 62-year-old female patient who had received a home parenteral nutrition therapy for the past 15 years.In order to simplify a management of home parenteral nutritional therapy, she tried to exchange a current use of popular TPN one bag solution to a new type one bag solution containing all elements of essential nutritionals, which could reduce a number of mixing procedures.However, she unfortunately encountered a new problem increasing a number of solution contained boxes(from 7 popular solution bags per box to 5 bags per box)to be brought into her house.Consequently, her living space was limited with more new boxes in the house.Moreover, a new solution bag was not easy to mix all elements of nutritionals, and a 1, 500 mL bag was too heavy for her to lift.In conclusion, there are many different problems associated with each patient, so that we ought to consider each patient's living environment as one of the important issues.

[Pathological complete response in advanced gastric carcinoma by S-1/CDDP combination chemotherapy].

A59 -year-old woman was referred to our hospital for a close examination and treatment of an advanced gastric carcinoma. A physical examination and CT scan showed that the right cervical and axillar lymph nodes were swelling, and a histopathological examination of the axillar lymph node revealed metastatic growth of the gastric carcinoma (Stage IV). Then, we started S-1/CDDP combination chemotherapy. S-1 (80 mg/m2/day)was orally administered for 3 weeks followed by 2 weeks of rest, and CDDP (60 mg/m2) was administered by drip on day 8. Since the distant metastases were greatly reduced after 6 courses of combination therapy, a distal gastrectomy with lymph nodes dissection (D2) was performed. Histopathological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. The clinical course after the operation went well without any complications, and the patient is alive with no evidence of recurrence 1 year after surgery. S-1/CDDP combination chemotherapy appears to be one of the effective treatments for advanced gastric carcinoma.

Comparison of clinical effectiveness between surgical and endovascular treatment for thrombotic obstruction in hemodialysis access.

PURPOSE: Endovascular treatment (ET) is widely used for thrombotic complications of vascular access (VA) for hemodialysis. We evaluated the effectiveness of both ET and surgical interventions for thrombotic complications. METHODS: We studied 533 patients who underwent surgical procedures (a total of 879 procedures) and 54 patients who received ET (a total of 156 procedures) for VA obstruction (endovascular group; group 1). The 533 patients who underwent surgical procedures were further divided into two groups: the surgical balloon-angioplasty group (the thrombus was surgically removed and the stenotic lesions were dilated by balloon angioplasty; 189 procedures; group 2) and the surgical repair group (the stenotic lesions were bypassed with additional graft diversion or creation of a new access; 690 procedures; group 3). The three groups were evaluated for VA patency. RESULTS: Using the Kaplan-Meier method, the 2-yr patency for groups 1, 2, and 3 were 11.1%, 11.5%, and 34.0% (p<0.0001). The 2-yr patency rates in patients in whom arteriovenous grafts were used were 5.9% (group 1), 9.2% (group 2), and 22.8% (group 3) (p<0.0001), whereas in patients with arteriovenous fistulae they were 33.7% (group 1), 35.7% (group 2), and 59.8% (group 3) (p=0.0005). CONCLUSIONS: A surgical approach may cause difficulty in creating a new VA, because useful access vessels are limited. Our results indicate surgical balloon-angioplasty and ET provide the same patency. ET is less invasive and can be repeated, which makes it beneficial for the patients. We concluded ET could be considered as the first-line treatment for thrombotic complications.