Prognostic Significance of NQO1 Expression in Non-neoplastic Esophageal Squamous Epithelium for Patients With Esophageal Cancer.

BACKGROUND/AIM: NAD(P)H dehydrogenase [quinone] 1 (NQO1), an antioxidant enzyme, confers resistance to anticancer agents. NQO1 C609T is a single-nucleotide polymorphism associated with reduced protein expression in the non-neoplastic esophageal squamous epithelium (ESE). This study aimed to investigate immunohistochemical NQO1 expression in non-neoplastic ESE and to elucidate its prognostic significance in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant therapy followed by esophagectomy. MATERIALS AND METHODS: NQO1 expression in non-neoplastic ESE was determined in surgical specimens from 83 patients with ESCC using immunohistochemistry. The association between NQO1 expression and clinicopathological factors, and the prognostic significance of NQO1 expression for relapse-free survival (RFS) were statistically evaluated. RESULTS: Patients with complete loss or weak NQO1 expression and patients with moderate or strong NQO1 expression were classified into the NQO1-negative (n=29) and NQO1-positive (n=54) groups, respectively. The downstaging of T classification status after neoadjuvant therapy was significantly more frequent in the NQO1-negative group than in the NQO1-positive group (59% vs. 33%; p=0.036). The NQO1-negative group had significantly more favorable RFS than the NQO1-positive group (p=0.035). Multivariate survival analysis demonstrated that NQO1 negative expression had a favorable prognostic impact on RFS (HR=0.332; 95%CI=0.136-0.812; p=0.016). CONCLUSION: Immunohistochemical evaluation of NQO1 expression in non-neoplastic ESE has clinical utility for predicting patient prognosis after neoadjuvant therapy followed by esophagectomy and might be helpful for selecting candidates for adjuvant therapy to treat ESCC.

Macroscopic type is implicated in the prognostic impact of initial chemotherapy on peritoneal lavage cytology-positive gastric cancer with no other noncurative factors.

BACKGROUND: Initial chemotherapy (Initial-C) followed by surgery is a promising treatment strategy for peritoneal lavage cytology-positive gastric cancer (CY1 GC) with no other noncurative factors. The aim of this study was to investigate the survival advantage of Initial-C compared to initial surgery (Initial-S) for this disease according to the macroscopic type, which was associated with prognosis and the efficacy of chemotherapy in GC. METHODS: One hundred eighty-nine patients who were diagnosed with CY1 GC with no other noncurative factors at four institutions from January 2007 to December 2018 were enrolled. The patients were divided into a macroscopic type 4 group (N = 48) and a non-type 4 group (N = 141). The influence of initial treatment on overall survival (OS) in each group was evaluated. RESULTS: In the type 4 group, the 5-year OS rates of Initial-C (N = 35) and Initial-S (N = 13) were 11.6% and 0%, respectively (P = 0.801). The multivariate analysis could not show the survival advantage of Initial-C. In the non-type 4 group, the 5-year OS rates of Initial-C (N = 41) and Initial-S (N = 100) were 48.4% and 29.0%, respectively (P = 0.020). The multivariate analysis revealed that Initial-C was independently associated with prolonged OS (hazard ratio, 0.591; 95% confidence interval, 0.375-0.933: P = 0.023). CONCLUSIONS: Initial-C improves the prognosis of non-type 4 CY1 GC with no other noncurative factors. On the other hand, further development of effective chemotherapeutic regimens and innovative treatment strategies are required for type 4 CY1 GC.

Surgical Outcomes of Ipsilateral Inguinal Hernia After Kidney Transplantation.

OBJECTIVES: We aimed to clarify the clinical features and outcomes of ipsilateral inguinal hernias after kidney transplantation. PATIENTS AND METHODS: Eleven patients diagnosed with inguinal hernia on the ipsilateral side after kidney transplantation between 2011 and 2022 were analyzed. Clinical data were retrospectively reviewed from the medical records. RESULT: Eleven patients were included in the analysis (median age, 68 [range, 28-75] years, male, n = 11). The time from kidney transplantation to hernia surgery was 107 (6-393) months. Eight patients had direct-type inguinal hernias. Three had indirect-type inguinal hernias. Hernia contents included the small intestine (n = 5), transplanted ureter and bladder (n = 2), only bladder (n = 1), transplanted kidney, ureter, and small intestine (n = 1), transplanted kidney and small intestine (n = 1), and transplanted ureter (n = 1). Six patients (55%) were diagnosed with urinary tract obstruction due to inguinal hernia. All hernias were repaired using mesh. The plug method was used in 9 cases. The Lichtenstein method was used in 2 cases. The median operative time was 110 (73-155) minutes, and the median blood loss was 3 (1-85) mL. The median postoperative hospital stay was 4 (2-7) days. In the 6 patients with urinary obstruction, the serum creatinine levels improved (P = .028), and the transplanted urinary tract obstruction disappeared after surgery. There was no recurrence of inguinal hernia. One patient experienced chronic pain in the groin area (Clavien-Dindo grade II) during follow-up. CONCLUSION: Surgical intervention for inguinal hernia after kidney transplantation is safe and effective for preventing worsening of the kidney graft function.

Malignancy After Living Donor Liver Transplantation.

OBJECTIVES: De novo malignancy (DNM) is a major cause of death in long-term recipients of liver transplantation (LT). We herein report our experience with DNM after living-donor LT (LDLT). PATIENTS AND METHODS: A total of 111 LDLT procedures were performed in our institute from 1999 to 2022. Among them, 70 adult (>13 years old) LDLT recipients who survived for more than 1 year were included in this study. RESULTS: During a median follow-up of 146 (range, 12-285) months, 7 out of 70 recipients developed 8 DNMs, including lung cancer in 4, post-transplant lymphoproliferative disease in 3, and skin cancer in 1. One patient developed metachronal skin cancer and post-transplant lymphoproliferative disease. The pre-LT smoking history rate in patients with DNM was higher than in patients without DNM (P = .004). The survival time after DNM was 6 (1-166) months. Only 2 patients underwent R0 resection. DNM did not recur during follow-up. Other patients who underwent R1 resection and/or chemotherapy and/or radiotherapy all died due to DNMs during the follow-up. The cumulative DNM incidence was 3.5% at 10 years and 18.4% at 20 years after LDLT. The cumulative survival rate in patients with DNM was significantly worse than that in patients without DNM after LDLT (P = .049). CONCLUSION: The survival rate of patients with DNM was lower than that of those without DNM. A pre-LT smoking history is a risk factor for DNM. R0 resection is effective for improving the prognosis of patients with DNM. Regular cancer screening is important for detecting DNM early after LDLT.

Multimodal prehabilitation program in patients with resectable perihilar cholangiocarcinoma: keypoints for an implementation protocol and literature review.

BACKGROUND: Postoperative complications after perihilar cholangiocarcinoma surgical procedure are still very high. The implementation of a multimodal prehabilitation program could improve these outcomes. Based on our experience and that of the literature in hepatobiliary and pancreatic surgery, we propose a protocol to promote its implementation. METHODS: First, we performed a retrospective analysis of the implementation feasibility of a multimodal prehabilitation program in patients' candidates for elective perihilar cholangiocarcinoma surgery in our center. Second, we conducted a literature search of publications in PubMed until December 2022. Relevant data about hepato-pancreato-biliary surgery and prehabilitation programs in features and postoperative outcomes was analyzed. RESULTS: Since October 2020, 11 patients were evaluated for prehabilitation in our hospital. Two of them could not be resected intraoperatively due to disease extension. The median hospital stay was 10 days (iqr, 7-11). There were no major complications and 1 patient died. Of a total of 17 articles related to prehabilitation in hepato-biliary-pancreatic surgery, no reports focusing exclusively on perihilar cholangiocarcinoma were found. Six of the studies had nutritional therapies in addition to physical interventions, and 12 studies used home-based exercise therapy. CONCLUSIONS: Based on our experience and the data obtained from other studies, a prehabilitation program could be useful to improve perioperative physical and mental fitness in patients' candidates for elective perihilar cholangiocarcinoma surgery. However, more well-designed studies are needed to allow us to obtain more evidence.

Risk factors for death from other diseases after curative gastrectomy and lymph node dissection for gastric cancer.

BACKGROUND: Recent advances in treatment are expected to bring a cure to more patients with gastric cancer (GC). Focusing on the risk of death from other diseases (DOD) has become a crucial issue in patients cured of GC. The aim of this study was to elucidate the risk factors for DOD in patients who underwent curative gastrectomy with lymph node dissection for GC. METHODS: We enrolled 810 patients who underwent curative gastrectomy with lymph node dissection for GC from January 1990 to December 2014 and had no recurrence or death of GC until December 2019. We investigated the risk factors for DOD defined as death excluding death from a malignant neoplasm, accident, or suicide after gastrectomy, focusing on the perioperative characteristics at gastrectomy. RESULTS: Among 315 deaths from any cause, 210 died from diseases other than malignancy, accidents and suicide. The leading cause of DOD was pneumonia in 54 patients (25.7%). The actual survival period in 167 patients (79.5%) with DOD was shorter than their estimated life expectancy at gastrectomy. Multivariate analysis revealed that a high Charlson Comorbidity Index score (score 1-2: hazard ratio [HR] 2.192, 95% confidence interval [CI] 1.713-2.804, P < 0.001 and score ≥ 3: HR 4.813, 95% CI 3.022-7.668, P < 0.001), total gastrectomy (HR 1.620, 95% CI 1.195-2.197, P = 0.002) and the presence of postoperative complications (HR 1.402, 95% CI 1.024-1.919, P = 0.035) were significant independent risk factors for DOD after gastrectomy for GC, in addition to age of 70 years or higher, performance status of one or higher and body mass index less than 22.0 at gastrectomy. CONCLUSIONS: Pneumonia is a leading cause of DOD after curative gastrectomy and lymph node dissection for GC. Paying attention to comorbidities, minimizing the choice of total gastrectomy and avoiding postoperative complications are essential to maintain the long-term prognosis after gastrectomy.

Extent of regional lymphadenectomy and number-based nodal classification for non-ampullary duodenal adenocarcinoma.

BACKGROUND: This study aimed to evaluate the adequate extent of regional lymphadenectomy according to tumor location and the impact of number-based nodal classification on survival in patients with non-ampullary duodenal adenocarcinoma (NADAC). METHODS: A total of 85 patients with NADAC who underwent surgery were enrolled. The frequency of metastasis was calculated for each node group in the respective tumor locations for 63 patients who underwent lymphadenectomy for pT2-pT4 tumor. RESULTS: The frequency of metastasis in the pancreaticoduodenal (nos. 13 and 17) and superior mesenteric artery (no. 14) nodes was high (16.7 %-52.3 %) regardless of tumor location. Metastasis in the perigastric (nos. 3 and 4d) and right celiac artery (no. 9) nodes was not uncommon (14.3 %-22.2 %) for tumors in the first portion. The frequency of metastasis in the pyloric (nos. 5 and 6) and the other peripancreaticoduodenal (nos. 8 and 12) nodes varied depending on tumor location but could not be ignored for staging. When these nodes were classified as regional nodes, the 5-year survival in patients with pN0, pN1 (1-2 positive nodes), and pN2 (≥3 positive nodes) were 82.9 %, 51.7 %, and 19.2 %, respectively (p < 0.001). pN classification independently predicted survival (pN1, p = 0.022; pN2, p < 0.001). CONCLUSIONS: Nos. 5, 6, 8, 12, 13, 14, and 17 nodes in all advanced NADAC and nos. 3, 4d, and 9 nodes in advanced NADAC in the first portion should be considered as regional nodes for accurate staging. The number-based nodal classification allows good patients' prognostic stratification.

Oral Administration of Glucosylceramide Suppresses Tumor Growth by Affecting the Ceramide/Sphingosine-1-Phosphate Balance in Breast Cancer Tissue.

Background: Ceramide and sphingosine-1-phosphate (S1P) play opposing roles in cell death and survival, and maintain a dynamic balance called the sphingolipid rheostat. Glucosylceramide is a substrate to generate ceramide but its effect on breast cancer by oral administration was never tested. The purpose of this study was to reveal the anticancer activity of glucosylceramide and its potential as a new therapeutic agent in breast cancer. Methods: E0771 cells were inoculated into the breast tissue of female C57BL/6NJcl mice. Glucosylceramide was administered orally to the mice for nine consecutive days. The concentrations of sphingolipid mediators including ceramide, glucosylceramide, and S1P in tumor tissues and serum were determined by mass spectrometry. Results: Oral administration of glucosylceramide significantly suppressed E0771 tumor growth compared with the control group (P = 0.006). There were no significant differences in the serum concentrations of sphingolipid mediators including ceramide and S1P between the mice treated with glucosylceramide and control-treated mice. The ceramide concentration was significantly lower in tumor tissues (P = 0.026), and the S1P concentration was significantly higher than that in paired non-tumor tissues (P = 0.009). The S1P concentration in tumor tissues was significantly lower in mice treated with glucosylceramide than in control-treated mice (P = 0.001). The ceramide-to-S1P concentration ratio in tumor tissues was significantly higher in mice treated with glucosylceramide than in control-treated mice (P = 0.034). Conclusions: Breast tumors could enhance their survival by increasing S1P conversion from ceramide. Oral administration of glucosylceramide suppressed tumor growth by affecting the ceramide/S1P balance. Oral administration of glucosylceramide is a promising basis for a new therapeutic approach.

Clinical Significance of Phosphorylated Sphingosine Kinase 1 Expression in Pancreatic Ductal Adenocarcinoma.

BACKGROUND/AIM: Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive, lipid mediator, produced by sphingosine kinase 1 (SphK1). In this study, we evaluated the expression of phosphorylated SphK1 (pSphK1) in patients with pancreatic ductal adenocarcinoma (PDAC) and investigated its clinical significance. MATERIALS AND METHODS: A total of 111 patients who underwent curative-intent resection for PDAC were enrolled. We investigated pSphK1 (Ser-225) expression in surgically resected specimens of PDAC using immunohistochemistry. The patients were divided into two groups according to pSphK1 immunoreactive expression: a pSphK1-high group (n=63) and a pSphK1-low group (n=48). RESULTS: Logistic regression analyses revealed that lymphatic invasion (p=0.007) was a significantly independent factor associated with high pSphK1 immunoreactive expression. The pSphK1-high group showed significantly worse disease-specific survival (DSS) than the pSphK1-low group (5-year DSS rate, 19.6% vs. 58.7%; p=0.001). High pSphK1 immunoreactive expression (hazard ratio=2.547; 95% confidence interval= 1.434-4.527; p=0.001) was an independent prognostic factor for DSS. CONCLUSION: High pSphK1 expression is independently associated with lymphatic invasion and unfavorable prognosis in PDAC patients. Thus, the SphK1-S1P axis may be important in mechanisms of tumor progression, such as lymphatic invasion, in PDAC patients.

Impact of rapid hypertrophy of tourniquet associating liver partition and portal vein ligation in the tumor progression pathways compared to two stage hepatectomy in patients with colorectal liver metastases.

BACKGROUND: It is not known if the inflammatory phenomena related to highly accelerated regeneration activate any signaling pathways that are associated with a major stimulus to colorectal liver metastases (CRLM) disease in tourniquet associating liver partition and portal vein ligation for staged hepatectomy (T-ALPPS) compared to two stage hepatectomy (TSH). METHODS: Between January 2012 and April 2018, we prospectively performed biopsies from future liver remnant and deportalized lobe in CRLM patients undergoing T-ALPPS in both stages. Immunohistopathological analysis was performed on the above tissue samples and compared to biopsy samples from patients who underwent TSH for CRLM at our center between September 2000 and August 2011. RESULTS: A total of 42 patients (20 TSH and 22 T-ALPPS) were included. There were no differences in the rates of recurrence, overall survival or any of the factors analyzed relating to tumor progression between stages 1 and 2. Regarding the anti-tumor effect, there was a significant reduction in the number of T-CD8 infiltrates in the second stage of TSH (12.5 vs. 5.5, p = 0.02). CONCLUSION: The results suggest that liver regeneration with T-ALPPS does not induce higher tumor progression or significant immunological changes in the tumor environment when compared to classical TSH.

Impact of anatomic resection on long-term survival in patients with hepatocellular carcinoma with T1-T2 disease or microscopic vascular invasion.

BACKGROUND: This study aimed to clarify potential candidates for anatomic resection (AR) among patients with pathological T1-T2 (pT1-T2) hepatocellular carcinoma (HCC) and to determine whether AR is effective for HCC with microscopic vascular invasion (MVI). METHODS: We retrospectively analyzed 288 patients with pT1a (n = 50), pT1b (n = 134) or pT2 (n = 104) HCC who underwent curative-intent resection between 1990 and 2010. Surgical outcomes were compared between patients who underwent AR (n = 189) and those who underwent nonanatomic resection (NAR; n = 99) according to pT category and MVI status. RESULTS: Patients who underwent AR were more likely to have good hepatic functional reserve and an aggressive primary tumor than those who underwent NAR. When patients were stratified according to pT category, AR had a more favorable impact on survival than NAR only in patients with pT2 HCC in univariate (5-year survival, 51.5% vs. 34.6%; p = 0.010) and multivariate analysis (hazard ratio 0.505; p = 0.014). However, AR had no impact on survival in patients with pT1a or pT1b HCC. In patients with MVI (n = 57), AR achieved better survival than NAR (5-year survival, 52.0% vs. 16.7%; p = 0.019) and was an independent prognostic factor (hazard ratio 0.335; p = 0.020). In patients without MVI (n = 231), there was no significant difference in survival between the two groups (p = 0.221). CONCLUSION: AR was identified as an independent factor in improved survival in patients with pT2 HCC or HCC with MVI.

Selecting the Appropriate Downstaging and Bridging Therapies for Hepatocellular Carcinoma: What Is the Role of Transarterial Radioembolization? A Pooled Analysis.

BACKGROUND: Transarterial radioembolization in HCC for LT as downstaging/bridging has been increasing in recent years but some indication criteria are still unclear. METHODS: We conducted a systematic literature search of primary research publications conducted in PubMed, Scopus and ScienceDirect databases until November 2022. Relevant data about patient selection, HCC features and oncological outcomes after TARE for downstaging or bridging in LT were analyzed. RESULTS: A total of 14 studies were included (7 downstaging, 3 bridging and 4 mixed downstaging and bridging). The proportion of whole liver TARE was between 0 and 1.6%. Multiple TARE interventions were necessary for 16.7% up to 28% of the patients. A total of 55 of 204 patients across all included studies undergoing TARE for downstaging were finally transplanted. The only RCT included presents a higher tumor response with the downstaging rate for LT of TARE than TACE (9/32 vs. 4/34, respectively). Grade 3 or 4 adverse effects rate were detected between 15 and 30% of patients. CONCLUSIONS: TARE is a safe therapeutic option with potential advantages in its capacity to necrotize and reduce the size of the HCC for downstaging or bridging in LT.

Rational Extent of Regional Lymphadenectomy and the Prognostic Impact of the Number of Positive Lymph Nodes for Perihilar Cholangiocarcinoma.

BACKGROUND: The definition and classification of regional nodes are not standardized for perihilar cholangiocarcinoma. This study aimed to clarify the rational extent of regional lymphadenectomy and to elucidate the impact of number-based regional nodal classification on survival of patients with this disease. METHODS: Data of 136 patients with perihilar cholangiocarcinoma who underwent surgery were reviewed. The incidence of metastasis and the survival of patients with metastasis were calculated for each node group. RESULTS: The incidence of metastasis for the node groups in the hepatoduodenal ligament (denoted as no. 12) ranged from 3.7% to 25.4%, with 5-year disease-specific survival of 12.9% to 33.3% for patients with metastasis. The incidences of metastasis in the common hepatic artery (no. 8) and posterior superior pancreaticoduodenal (no. 13a) node groups were 14.4% and 11.2%, respectively, with 5-year disease-specific survival rates of 16.7% and 20.0% for the patients with metastasis. When these node groups were defined as regional nodes, the 5-year disease-specific survival rates for the patients with pN0 (n = 80), pN1 (1-3 positive nodes, n = 38), and pN2 (≥ 4 positive nodes, n = 18) were 61.4%, 22.9%, and 17.6%, respectively (p < 0.001). The pN classification was independently associated with disease-specific survival (p < 0.001). When only the no. 12 node groups were regarded as regional nodes, pN classification failed to stratify the patients prognostically. CONCLUSIONS: No. 8 and no. 13a node groups should be considered regional nodes in addition to no. 12 node groups and should be dissected. The number-based regional nodal classification allows patients with this disease to be stratified prognostically.

New challenges in cholangiocarcinoma candidates for elective surgery: harnessing the microbiome dysbiosis.

BACKGROUND: The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery. METHODS: A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development. RESULTS: Bacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA's biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment. CONCLUSION: The correct use of nutrition for microbiota modulation according to each patient's needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.

[Radical Resection Followed by Chemotherapy for Intrahepatic Cholangiocarcinoma with Lymph Node Metastases-Report of a Long-Term Survivor].

We report a case of intrahepatic cholangiocarcinoma(ICC)with lymph node metastases in which long-term survival was achieved after surgery followed by chemotherapy. A 69-year-old man underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection for ICC located mainly in segment 4 of the liver with enlarged lymph nodes in the hepatoduodenal ligament. The histopathologically confirmed diagnosis was ICC(T2N1M0, Stage ⅣA)with 3 positive lymph nodes(No. 12a1, No. 12p1, and No. 12p2). He received chemotherapy with gemcitabine(GEM)plus cisplatin(CDDP)for 9 months, followed by GEM monotherapy for 4 months, and then S-1 monotherapy was started. A right lung nodule was detected 12 months after the initiation of S-1 monotherapy. He received GEM plus S-1 therapy for 28 months, followed by S-1 monotherapy, leading to disappearance of the lung nodule. He remains alive and well without disease 78 months after surgery. Our experience in this case suggests that radical resection followed by chemotherapy may provide a survival benefit in selected patients who have ICC with nodal disease.

Ulcer Scarring in the Gastric Conduit Is a Risk Factor for Anastomotic Leakage After Esophagectomy for Esophageal Cancer.

BACKGROUND: Anastomotic leakage (AL) is a serious complication after esophagectomy for esophageal cancer. The objective of this study was to identify the risk factors for AL. METHODS: Patients with esophageal cancer who underwent curative esophagectomy and cervical esophagogastric anastomosis between 2009 and 2019 (N = 346) and those between 2020 and 2022 (N = 17) were enrolled in the study to identify the risk factors for AL and the study to assess the association between the risk factors and blood flow in the gastric conduit evaluated by indocyanine green (ICG) fluorescence imaging, respectively. RESULTS: AL occurred in 17 out of 346 patients (4.9%). Peptic or endoscopic submucosal dissection (ESD) ulcer scars were independently associated with AL (OR 6.872, 95% CI 2.112-22.365) in addition to diabetes mellitus. The ulcer scars in the anterior/posterior gastric wall were more frequently observed in patients with AL than in those without AL (75.0% vs. 17.4%, P = 0.042). The median flow velocity of ICG fluorescence in the gastric conduits with the scars was significantly lower than in those without the scars (1.17 cm/s vs. 2.23 cm/s, P = 0.004). CONCLUSIONS: Peptic or ESD ulcer scarring is a risk factor for AL after esophagectomy in addition to diabetes mellitus. The scars in the anterior/posterior gastric wall are significantly associated with AL, impairing blood flow of the gastric conduit. Preventive interventions and careful postoperative management should be provided to minimize the risk and severity of AL in patients with these risk factors.