Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: Eighth edition.

In 2023, the Japan Pancreas Society (JPS) published the new eighth edition of the Japanese classification of pancreatic carcinoma. We present here an excerpted version in English, based on the latest edition. The major changes in this revision are as follows: In the eighth edition of the Union for International Cancer Control (UICC), the T category was changed to be based on tumor size; however, the eighth edition of the Japanese classification retains the previous T category based on local invasion factors. Lymph nodes have been renamed, and regional lymph nodes have been defined by location. Peritoneal cytology, which was not previously included in distant metastasis (M), has now been included in the M category. Moreover, significant additions have been made regarding the pathological diagnosis of endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) and criteria for histological assessment of the effects after chemotherapy and radiation therapy. Although this classification is aimed at carcinoma originating in the pancreas, not in the bile duct or duodenum, if the differentiation of the primary organ is difficult, this classification should be applied. It is also desirable to describe tumors other than carcinoma and metastatic tumors to the pancreas in accordance with this classification.

Primary anastomosing hemangioma as a preoperative diagnostic mimicker of retroperitoneal cavernous hemangioma: A case report.

Anastomosing hemangioma (AH) is rare and a newly recognized variant of capillary hemangioma that is mostly found in the genitourinary tract. Additionally, AH is sometimes difficult to diagnose without pathological specimens. It is difficult to diagnose preoperatively due to the lack of specific clinical and radiologic appearance. The present report describes the imaging features from a radiological perspective and outlines the clinicopathologic features and treatment options. A 67-year-old woman was referred to Dokkyo Medical University Saitama Medical Center (Koshigaya, Japan) for a retroperitoneal tumor that was identified at a medical checkup 4 years prior. The patient had no symptoms, no abnormal physical signs and no past medical or specific family history. Routine blood tests were all within the normal ranges. A nonenhanced CT scan showed a circular, homogenous, well-circumscribed retroperitoneal tumor that was ~32×23 mm in size, between the abdominal aorta and the inferior vena cava, and just below the left renal vein. On a contrast-enhanced multidetector CT scan, the tumor showed heterogeneous septal enhancement in the arterial phase and persistent enhancement in the portal phase. The tumor was diagnosed as a benign neurogenic tumor or a retroperitoneal cavernous hemangioma at the time, and the patient was intended to be followed up at the outpatient clinic. However, it gradually increased to a maximum diameter of 35 mm over 4 years. Finally, it was completely resected by open laparotomy and pathologically diagnosed as AH. Retroperitoneal hemangioma is extremely rare in adulthood and has been confirmed in only 1-3% of all retroperitoneal tumors. To the best of our knowledge, only 6 cases of para-aortic AH have been reported. The incidence of this variant is very low. However, AH may be included in the differential diagnosis when a slowly progressing heterogeneous mass appears in the para-aortic region that exhibits a CT-enhanced pattern similar to a typical cavernous hemangioma.

Dietary polyamines promote intestinal adaptation in an experimental model of short bowel syndrome.

Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.

Novel Clean End-to-End Anastomosis Method, Without Opening the Stomach Lumen, in Totally Laparoscopic or Robotic Pylorus-Preserving Gastrectomy.

PURPOSE: Intra-abdominal infection is a common postoperative complication of laparoscopic pylorus-preserving gastrectomies (PPGs). Many studies have reported that intra-abdominal infectious complications after gastrectomy adversely affect patient survival outcomes. To prevent gastric fluid leakage into the abdominal cavity, we developed a novel anastomosis method in which the stomach lumen is not opened (termed the non-opened clean end-to-end anastomosis method [NoCEAM]) and evaluated its feasibility. MATERIALS AND METHODS: Subsequent to lymphadenectomy, the oral and anal resection lines were sutured using an intraoperative endoscope. After closing the stomach circumferentially with clips, the specimen was rolled outward like a "donut." We resected the specimen circumferentially using a linear stapler, and anastomosis was completed simultaneously. We examined the feasibility of this procedure ex vivo, using three porcine stomachs, and in vivo, using one pig. Subsequently, we applied the procedure to 13 consecutive patients with middle-third early gastric cancer utilizing laparotomic, laparoscopic, and robotic PPG. RESULTS: NoCEAM was completed in all porcine models and human cases. In the human cases, the mean operation time (±standard deviation) was 279±51 minutes, and mean blood loss volume was 22±45 mL. The mean number of linear staples used was 5.06±0.76. None of the patients had complications, and all were discharged on the eighth postoperative. The serum total protein, serum albumin, and hemoglobin levels did not change significantly after surgery. CONCLUSIONS: NoCEAM is feasible and safe for performing totally laparoscopic or robotic PPG. It may reduce postoperative complications, such as intra-abdominal infections.

Lymph node involvement is rare in mucinous cystic neoplasms of the pancreas: Role of minimally invasive surgery.

Mucinous cystic neoplasm (MCN) is a premalignant cystic tumor of the pancreas. Resection of MCN in the distal pancreas is a standard treatment; however, at present, there is no consensus on the necessity or extent of lymph node dissection, and minimally invasive pancreatectomy is commonly the preferred surgical technique. Thus, the present study aimed to assess the efficacy of minimally invasive surgery and the extent of lymph node metastasis as factors in determining an appropriate surgical treatment for MCN. The present study retrospectively analyzed 21 consecutive patients who underwent distal pancreatectomy (DP) for MCN under general anesthesia at Chiba University Hospital (Chiba, Japan) between April 2011 and July 2019. All 21 patients were female. DP with a splenectomy was performed in all the patients. A total of 14 patients underwent laparoscopic DP (LDP). No lymph node metastasis was found in any of the patients. The minimally invasive surgery group had lower operative blood loss and a shorter hospital stay than the open surgery group. There was no significant difference in the number of dissected lymph nodes between the open surgery group and the minimally invasive surgery group. Preoperative findings of malignancy in MCN included solid components on enhanced CT and endoscopic ultrasonography, high carbohydrate antigen 19-9 values and large tumor size. In conclusion, DP with spleen preservation, which is minimally invasive, may be preferentially considered as a surgical technique for MCN without malignant findings because lymph node metastases are rare in MCN and were not observed in the present study.

Primary hepatic neuroendocrine neoplasm presenting as a massive cystic liver tumor mimicking mucinous cystic neoplasm of the liver: A case report and literature review.

Neuroendocrine neoplasms (NENs) preferentially arise in the bronchopulmonary tree or the gastrointestinal tract. Notably, primary hepatic NENs are extremely rare. The present study describes a case of hepatic NEN presenting as a giant hepatic cystic lesion. A 42-year-old woman presented with a large liver tumor. Contrast-enhanced abdominal computed tomography revealed a cystic tumor (18 cm) in their left liver. The tumor exhibited liquid components and mural solid nodules with enhanced effects. The lesion was diagnosed as mucinous cystic carcinoma (MCC) preoperatively. The patient underwent a left hepatectomy, and the postoperative course was uneventful. The patient has been alive without recurrence for 36 months postoperatively. The pathological diagnosis was NEN G2. This patient had ectopic pancreatic tissue in the liver and thus the ectopic pancreatic origin of the tumor was suspected. The present study describes a case of resected cystic primary NEN of the liver that was difficult to differentiate from mucinous cystic neoplasms. As primary liver NENs are extremely rare, further studies are needed to establish their diagnosis and treatment.

Tumor Budding as a Predictive Marker of Relapse and Survival in Patients With Stage II Colon Cancer.

BACKGROUND/AIM: Tumor budding (TB) has recently been recognized worldwide as a prognostic predictor in several solid cancers. The objective of this study was to explore the relationship between TB and clinicopathological characteristics, postoperative relapse, and survival in patients with stage II colon cancer. PATIENTS AND METHODS: A total of 213 patients with stage II colon cancer were retrospectively enrolled at Saitama Medical Center, Dokkyo Medical University from 2010 to 2016. TB was evaluated in hotspot areas on hematoxylin and eosin-stained slides at the invasive front of the tumor to define a low-grade group (BD1) and a high-grade group (BD2 or BD3). RESULTS: High-grade TB was found in 38.3% of cases, and was associated with pT4, presence of lymphovascular invasion, and tumor relapse (p=0.02, p=0.03, p=0.002, respectively). Patients with highgrade TB showed worse relapse-free survival (RFS) and overall survival (OS) rates than patients with low-grade TB (5-year RFS: High 75.6% vs. Low 92.1%, p=0.001; 5-year OS: High 93.7% vs. Low 93.7%, p=0.001). On multivariate analysis for predictors of RFS and OS, high-grade TB was significant for both RFS and OS (RFS, p=0.003; OS, p=0.005). Patients with high-grade TB experienced lung and liver relapses significantly more frequently than patients with low-grade TB (p=0.03 each). Among patients who received adjuvant chemotherapy (AC), no patients showed lung or liver relapse even in the presence of high-grade TB. CONCLUSION: TB may offer a useful predictor of relapse in patients with stage II colon cancer after surgery, and AC should be considered for patients with high-grade TB.

Surgical site infection after laparoscopic resection of colorectal cancer is associated with compromised long-term oncological outcome.

BACKGROUND: We evaluated the influence of infectious complications, particularly surgical site infection (SSI), on long-term oncological results after elective laparoscopic resection of colorectal cancer. METHODS: A total of 199 patients who underwent laparoscopic elective resection with negative resection margins for stage I-III colorectal cancer were retrospectively examined. The postoperative course was recorded based on hospital records, and cancer relapse was diagnosed based on radiological or pathological findings under a standardized follow-up program. The severity of complications was graded using Clavien-Dindo (CD) classification. RESULTS: SSI was found in 25 patients (12.6%), with 12 (6.0%) showing anastomotic leak. The postoperative relapse-free survival (RFS) rate was significantly lower in patients with SSI (49.2%) than in patients without SSI (87.2%, P<0.001). Differences in RFS were found after both colectomy and rectal resection (P<0.001 and P<0.001, respectively). RFS did not differ between patients who had major SSI CD (grade III) and those who had minor SSI CD (grades I or II). Multivariate Cox regression analysis identified the occurrence of SSI and pathological stage as independent co-factors for RFS (P<0.001 and P=0.003). CONCLUSION: These results suggest that postoperative SSI compromises long-term oncological results after laparoscopic colorectal resection. Further improvements in surgical technique and refinements in perioperative care may improve long-term oncological results.

Randomized phase III trial of intravenous and intraperitoneal paclitaxel with S-1 versus gemcitabine plus nab-paclitaxel for pancreatic ductal adenocarcinoma with peritoneal metastasis (SP study).

The prognosis of pancreatic ductal carcinoma (PDAC) with peritoneal metastasis remains dismal. Systemic chemotherapy alone may not be effective, and the combination of intraperitoneal chemotherapy with systemic chemotherapy is expected to prolong the overall survival in patients with peritoneal metastasis. We have designed a randomized phase III trial to confirm the superiority of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel (PTX) with S-1 relative to gemcitabine plus nab-PTX (GnP), which is the current standard therapy for patients with metastatic PDAC. A total of 180 patients will be accrued from 30 institutions within 3 years. Patients will be randomly assigned in a 1:1 ratio to receive either i.v. and i.p. PTX with S-1 or GnP (target of 90 patients per group). The primary endpoint is overall survival; secondary endpoints are progression-free survival, response rate, proportion with negative peritoneal washing cytology during chemotherapy, proportion requiring conversion surgery, and adverse event profiles. Japan Registry of Clinical Trials jRCTs051180199 ( https://jrct.niph.go.jp/ ).

Successful salvage treatment with paclitaxel, ifosfamide, and cisplatin in a patient with methotrexate-resistant gestational trophoblastic neoplasia who developed hypersensitivity reaction to etoposide.

We report a 34-year-old woman with recurrent gestational trophoblastic neoplasia (GTN) who showed hypersensitivity to etoposide. Computed tomography (CT) revealed a 32-mm solid mass in the right lung and a 101-mm cystic mass with solid components in the left side of the liver. The patient's serum human chorionic gonadotropin (HCG) level was 689 439 mIU/mL. After eight cycles of combined paclitaxel 175 mg/m2 on day 1, ifosfamide 1 g/m2 on days 2-5, and cisplatin 20 mg/m2 on days 2-5 (TIP) every 3 weeks, the serum HCG level decreased to 2.4 mIU/mL. CT scan revealed disappearance of the lung tumor and significant reduction in the solid components of the liver tumor. Then, left hemihepatectomy was performed. After 3 months, there was no evidence of the disease, and the serum HCG level normalized. Thus, TIP chemotherapy, followed by residual mass resection, might be effective for methotrexate-resistant GTN.

Complement factor B regulates cellular senescence and is associated with poor prognosis in pancreatic cancer.

BACKGROUND: The interplay between cancer cells and stromal components, including soluble mediators released from cancer cells, contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we set out to identify key secreted proteins involved in PDAC progression. METHODS: We performed secretome analyses of culture media of mouse pancreatic intraepithelial neoplasia (PanIN) and PDAC cells using Stable Isotope Labeling by Amino acid in Cell culture (SILAC) with click chemistry and liquid chromatography-mass spectrometry (LC-MS/MS). The results obtained were verified in primary PDAC tissue samples and cell line models. RESULTS: Complement factor B (CFB) was identified as one of the robustly upregulated proteins, and found to exhibit elevated expression in PDAC cells compared to PanIN cells. Endogenous CFB knockdown by a specific siRNA dramatically decreased the proliferation of PDAC cells, PANC-1 and MIA PaCa-II. CFB knockdown induced increases in the number of senescence-associated-ß-galactosidase (SA-ß-gal) positive cells exhibiting p21 expression upregulation, which promotes cellular senescence with cyclinD1 accumulation. Furthermore, CFB knockdown facilitated downregulation of proliferating cell nuclear antigen and led to cell cycle arrest in the G1 phase in PDAC cells. Using immunohistochemistry, we found that high stromal CFB expression was associated with unfavorable clinical outcomes with hematogenous dissemination after surgery in human PDAC patients. Despite the presence of enriched CD8+ tumor infiltrating lymphocytes in the PDAC tumor microenvironments, patients with a high stromal CFB expression exhibited a significantly poorer prognosis compared to those with a low stromal CFB expression. Immunofluorescence staining revealed a correlation between stromal CFB expression in the tumor microenvironment and an enrichment of immunosuppressive regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We also found that high stromal CFB expression showed a positive correlation with high CD8+/Foxp3+ Tregs populations in PDAC tissues. CONCLUSIONS: Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.

Usefulness of the MALDI-TOF MS technology with membrane filter protocol for the rapid identification of microorganisms in perioperative drainage fluids of hepatobiliary pancreatic surgery.

Surgical site infections (SSIs) are significant and frequent perioperative complications, occurring due to the contamination of the surgical site. The late detection of SSIs, especially organ/space SSIs which are the more difficult to treat, often leads to severe complications. An effective method that can identify bacteria with a high accuracy, leading to the early detection of organ/space SSIs, is needed. Ninety-eight drainage fluid samples obtained from 22 patients with hepatobiliary pancreatic disease were analyzed to identify microorganisms using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) with a new membrane filtration protocol and rapid BACpro® pretreatment compared to sole rapid BACpro® pretreatment. The levels of detail of rapid BACpro® pretreatment with or without filtration were also evaluated for the accuracy of bacterial identification. We found that reliable scores for E. coli and E. faecalis were obtained by inoculation with 1.0 × 104 CFU/ml after preparation of the membrane filter with rapid BACpro®, indicating approximately 10-folds more sensitive compared to sole rapid BACpro® pretreatment in drainage fluid specimens. Among 60 bacterial positive colonies in drainage fluid specimens, the MALDI-TOF MS and the membrane filtration with rapid BACpro® identified 53 isolates (88.3%) with a significantly higher accuracy, compared to 25 isolates in the rapid BACpro® pretreatment group (41.7%) (p < 0.001). Among the 78 strains, 14 enteric Gram-negative bacteria (93.0%) and 55 Gram-positive cocci (87.3%) were correctly identified by the membrane filtration with rapid BACpro® with a high reliability. This novel protocol could identify bacterial species within 30 min, at $2-$3 per sample, thus leading to cost and time savings. MALDI-TOF MS with membrane filter and rapid BACpro® is a quick and reliable method for bacterial identification in drainage fluids. The shortened analysis time will enable earlier selection of suitable antibiotics for treatment of organ/space SSIs to improve patients' outcomes.

Early detection of infectious complications using C-reactive protein and the procalcitonin levels after laparoscopic colorectal resection: a prospective cohort study.

PURPOSE: The predictive values of the C-reactive protein (CRP) and procalcitonin (PCT) levels for postoperative infectious complications were investigated in patients who underwent elective laparoscopic resection of colorectal cancer. METHODS: A total of 154 consecutive patients who underwent elective laparoscopic resection for colorectal cancer (CRC) were prospectively studied. The CRP and PCT levels on the first postoperative day (POD1) and the fourth postoperative day (POD4) were measured. Any correlations between the CRP and PCT levels on POD1 and POD4 with the occurrence of infectious complications were examined. RESULTS: Infectious complications occurred in 18 (11.7%) patients. CRP on POD1 and CRP and PCT on POD4 were significantly higher in patients who developed infectious complications than in those who did not. The areas under the receiver operating characteristic curves of CRP on POD1 and CRP and PCT on POD4 were 0.597, 0.763 and 0.768, respectively. The cut-off values of CRP and PCT levels on POD4 were 14.33 mg/dl and 0,264 ng/ml, respectively. Whereas the positive predictive value of an elevated CRP level was high, the negative predictive value of an elevated PCT was high. CONCLUSION: The CRP and PCT levels on POD4 are both considered to be useful for the early detection of infectious complications after laparoscopic resection of CRC.

Effect of immunonutrition on infectious complications in low skeletal muscle mass patients after pancreaticoduodenectomy.

BACKGROUND & AIMS: Sarcopenia is considered a risk factor of postoperative complications among patients undergoing abdominal surgery. However, few studies have demonstrated an effective strategy for reducing complications in sarcopenic patients. This study aimed to examine retrospectively the effect of preoperative immunonutrition on postoperative complications, especially infectious complications, in low skeletal muscle mass patients undergoing pancreaticoduodenectomy (PD). METHODS: This was a retrospective, consecutive cohort study conducted in our institution. Skeletal muscle mass was assessed using preoperative computed tomography images in 298 consecutive patients who underwent PD between May 2009 and May 2016. Cross-sectional areas at the third lumbar vertebrae normalized for stature (cm2/m2) were defined as the skeletal muscle mass index (SMI). Low SMI was defined as the lowest sex-specific quartile of SMI. Risk factors for postoperative infectious complications and the effect of preoperative immunonutrition on low SMI patients who underwent PD were evaluated. RESULTS: Results of multivariate analysis showed that the presence of low SMI and absence of preoperative immunonutrition were independent risk factors for postoperative infectious complications after PD (odds ratio [OR], 3.17 and 3.10, respectively; P < 0.001). In high SMI patients, the rate of postoperative infectious complications was significantly lower in those who received immunonutrition than in those who did not receive immunonutrition (31.9 vs. 46.1%, respectively; OR, 1.82; P = 0.045). Further, similar findings were exhibited in low SMI patients (26.3 vs. 83.6%, respectively; OR, 14.31; P < 0.001), even though OR was markedly higher in low vs. high SMI patients. CONCLUSION: There is a stronger association with reduced infectious complications in patients who have low SMI and receive immunonutrition (UMIN-CTR Identifier: UMIN000035775.).

Sphingosine-1-phosphate Receptor-1 Promotes Vascular Invasion and EMT in Hepatocellular Carcinoma.

BACKGROUND: It remains unknown whether epithelial-mesenchymal transition (EMT)-mediated vascular invasion and cancer stemness are associated with sphingosine-1-phosphate receptor-1 (S1PR1) expression in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the correlation between S1PR1 expression and prognosis of patients with primary HCC and to define the potential of S1PR as a therapeutic target. MATERIALS AND METHODS: We investigated 108 patients who underwent primary surgical resection for HCC treatment. Expression of S1PR1 and EMT markers was analyzed to predict prognosis of patients with HCC. Furthermore, three-dimensional organotypic culture, anoikis assay, and cell invasion were performed to validate the association of S1PR1 with EMT and cancer stemness. RESULTS: Among patients with HCC, the high S1PR1 expression group had significantly shorter overall survival than the low expression group. Moreover, high S1PR1 expression was significantly associated with shorter recurrence-free survival, increased risk of portal and hepatic vein invasion, and intrahepatic metastasis. Multivariate analyses revealed that S1PR1 overexpression was an independent prognostic factor in patients with HCC. S1PR1 overexpression positively correlated with vimentin and MMP-9 expression and negatively correlated with E-cadherin. In addition, S1PR1 overexpression induced EMT and enhanced tumor invasion and cancer stemness. CONCLUSIONS: S1PR1 overexpression, via EMT-induced vascular invasion and increased cancer stem cell properties, establishes a metastatic niche, enhances the capacity of hematogenous metastasis, and associates with poor outcomes in patients with HCC. Hence, S1PR1 may serve as a therapeutic target for patients with HCC with vascular invasion.

Clinical practice guidelines for the management of biliary tract cancers 2019: The 3rd English edition.

BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014. METHODS: In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as Grade 1 (strong) or Grade 2 (weak) according to the concepts of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: The 31 CQs covered the six topics: (a) prophylactic treatment, (b) diagnosis, (c) biliary drainage, (d) surgical treatment, (e) chemotherapy, and (f) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded. CONCLUSIONS: This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.