Malignant potential of neuroendocrine microtumor of the pancreas harboring high-grade transformation: lesson learned from a patient with von Hippel-Lindau syndrome

Pancreatic neuroendocrine microtumor (PNEMT) is a neuroendocrine tumor (NET) < 0.5 cm in diameter, and it is considered benign. We report a PNEMT with high-grade transformation (HGT). A man in his 60s with von Hippel-Lindau syndrome underwent surgical resection of a NET. A second sub-centimeter nodule with a nodule-in-nodule pattern was discovered. The 0.4 cm outer nodule contained clear columnar cells with round nuclei and indistinct nucleoli, while the 0.1 cm inner nodule had eosinophilic cells with an increased nuclear to cytoplasmic ratio, vesicular nuclei, and prominent nucleoli. Tumor cells in the outer and inner nodules were synaptophysin and chromogranin positive. Only the inner nodule was p53 positive, while the outer nodule was exclusively positive for carbonic anhydrase 9 and vimentin. The Ki-67 labeling indices for the outer and inner nodules were 2.1% (grade 1) and 44.3% (grade 3), respectively. This nodule was determined to be a PNEMT with HGT. Our findings suggest that a PNEMT may not always be benign and can undergo HGT.

Survival Benefit of Adjuvant Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma Who Underwent Surgery Following Neoadjuvant FOLFIRINOX / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The benefit of adjuvant chemotherapy following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant FOLFIRINOX is unclear. This study aimed to assess the survival benefit of adjuvant chemotherapy in this patient population. @*Materials and Methods@#This retrospective study included 218 patients with localized non-metastatic PDAC who received neoadjuvant FOLFIRINOX and underwent curative-intent surgery (R0 or R1) between January 2017 and December 2020. The association of adjuvant chemotherapy with disease-free survival (DFS) and overall survival (OS) was evaluated in overall patients and in the propensity score matched (PSM) cohort. Subgroup analysis was conducted according to the pathology-proven lymph node status. @*Results@#Adjuvant chemotherapy was administered to 149 patients (68.3%). In the overall cohort, the adjuvant chemotherapy group had significantly improved DFS and OS compared to the observation group (DFS: median, 13.8 months [95% confidence interval (CI), 11.0 to 19.1] vs. 8.2 months [95% CI, 6.5 to 12.0]; p < 0.001; and OS: median, 38.0 months [95% CI, 32.2 to not assessable] vs. 25.7 months [95% CI, 18.3 to not assessable]; p=0.005). In the PSM cohort of 57 matched pairs of patients, DFS and OS were better in the adjuvant chemotherapy group than in the observation group (p < 0.001 and p=0.038, respectively). In the multivariate analysis, adjuvant chemotherapy was a significant favorable prognostic factor (vs. observation; DFS: hazard ratio [HR], 0.51 [95% CI, 0.36 to 0.71; p < 0.001]; OS: HR, 0.45 [95% CI, 0.29 to 0.71; p < 0.001]). @*Conclusion@#Among PDAC patients who underwent surgery following neoadjuvant FOLFIRINOX, adjuvant chemotherapy may be associated with improved survival. Randomized studies should be conducted to validate this finding.

Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). @*Materials and Methods@#Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. @*Results@#Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. @*Conclusion@#Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.

Adjuvant Chemotherapy for Resected Ampulla of Vater Carcinoma: Retrospective Analysis of 646 Patients / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This study evaluated the efficacy of adjuvant chemotherapy (AC) in patients with resected ampulla of Vater (AoV) carcinoma. @*Materials and Methods@#Data from 646 patients who underwent surgical resection at Asan Medical Center between 2000 and 2017 were retrospectively reviewed. @*Results@#The median age of the patients was 62 years, and 54.2% were male. Patients were classified into AC group (n=165, 25.5%) and no AC group (n=481, 74.5%). With a median follow-up duration of 88 months, in patients with stage I, II, III, median recurrence-free survival (RFS) was not reached, 44 months, and 15 months, respectively, and the median overall survival (OS) were not reached, 88 months and 35 months, respectively. Despite no statistical significance, RFS and OS were better in stage II patients with AC than in those without AC (median RFS, 151 months vs. 38 months; p=0.156 and median OS, 153 months vs. 74 months; p=0.299). In multivariate analysis for RFS and OS, TNM stage, R1 resection status, presence of lymphovascular invasion, and perineural invasion remained significant factors, whereas AC (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.54 to 1.00; p=0.052) was marginally related with RFS. After propensity score matching in only stage II/III patients, RFS and OS with AC were numerically longer than those without AC (HR, 0.80; 95% CI, 0.60 to 1.06; p=0.116 and HR, 0.77; 95% CI, 0.56 to 1.06; p=0.111). @*Conclusion@#AC with fluoropyrimidine did not improve survival of patients with resected AoV carcinoma. However, multivariate analysis with prognostic factors showed a marginally significant survival benefit with AC.

Adjuvant Chemotherapy for Resected Ampulla of Vater Carcinoma: Retrospective Analysis of 646 Patients / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This study evaluated the efficacy of adjuvant chemotherapy (AC) in patients with resected ampulla of Vater (AoV) carcinoma. @*Materials and Methods@#Data from 646 patients who underwent surgical resection at Asan Medical Center between 2000 and 2017 were retrospectively reviewed. @*Results@#The median age of the patients was 62 years, and 54.2% were male. Patients were classified into AC group (n=165, 25.5%) and no AC group (n=481, 74.5%). With a median follow-up duration of 88 months, in patients with stage I, II, III, median recurrence-free survival (RFS) was not reached, 44 months, and 15 months, respectively, and the median overall survival (OS) were not reached, 88 months and 35 months, respectively. Despite no statistical significance, RFS and OS were better in stage II patients with AC than in those without AC (median RFS, 151 months vs. 38 months; p=0.156 and median OS, 153 months vs. 74 months; p=0.299). In multivariate analysis for RFS and OS, TNM stage, R1 resection status, presence of lymphovascular invasion, and perineural invasion remained significant factors, whereas AC (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.54 to 1.00; p=0.052) was marginally related with RFS. After propensity score matching in only stage II/III patients, RFS and OS with AC were numerically longer than those without AC (HR, 0.80; 95% CI, 0.60 to 1.06; p=0.116 and HR, 0.77; 95% CI, 0.56 to 1.06; p=0.111). @*Conclusion@#AC with fluoropyrimidine did not improve survival of patients with resected AoV carcinoma. However, multivariate analysis with prognostic factors showed a marginally significant survival benefit with AC.

Development and External Validation of Survival Prediction Model for Pancreatic Cancer Using Two Nationwide Databases: Surveillance, Epidemiology and End Results (SEER) and Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP)

Background/Aims@#Several prediction models for evaluating the prognosis of nonmetastatic resected pancreatic ductal adenocarcinoma (PDAC) have been developed, and their performances were reported to be superior to that of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. We developed a prediction model to evaluate the prognosis of resected PDAC and externally validated it with data from a nationwide Korean database. @*Methods@#Data from the Surveillance, Epidemiology and End Results (SEER) database were utilized for model development, and data from the Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP) database were used for external validation. Potential candidate variables for model development were age, sex, histologic differentiation, tumor location, adjuvant chemotherapy, and the AJCC 8th staging system T and N stages. For external validation, the concordance index (C-index) and time-dependent area under the receiver operating characteristic curve (AUC) were evaluated. @*Results@#Between 2004 and 2016, data from 9,624 patients were utilized for model development, and data from 3,282 patients were used for external validation. In the multivariate Cox proportional hazard model, age, sex, tumor location, T and N stages, histologic differentiation, and adjuvant chemotherapy were independent prognostic factors for resected PDAC. After an exhaustive search and 10-fold cross validation, the best model was finally developed, which included all prognostic variables. The C-index, 1-year, 2-year, 3-year, and 5-year time-dependent AUCs were 0.628, 0.650, 0.665, 0.675, and 0.686, respectively. @*Conclusions@#The survival prediction model for resected PDAC could provide quantitative survival probabilities with reliable performance. External validation studies with other nationwide databases are needed to evaluate the performance of this model.

Enhanced recovery after surgery: operation-related factors

The enhanced recovery after surgery (ERAS) program, which has been recently introduced in the field of perioperative care, represents a multimodal strategy to attenuate the loss, and improve the restoration, of functional capacity after surgery. This program aims to reduce morbidity and enhance recovery by reducing surgical stress, optimizing pain control, and facilitating early resumption of an oral diet and early mobilization. Considering this perspective, protocols for enhanced recovery should include comprehensive and evidence-based guidelines for best perioperative care. Appropriate protocol implementation may reduce complication rates and enhance functional recovery and thereby reduce the duration of hospitalization.Current Concepts: In major abdominal surgeries, the recommended ERAS protocols involve common items such as preoperative counseling, preoperative optimization, prehabilitation, preoperative nutrition, fasting and carbohydrate loading, bowel preparation, thromboprophylaxis, antimicrobial prophylaxis, surgical access, drainage, nasogastric intubation, urinary drainage, early mobilization and prevention of postoperative ileus, postoperative glycemic control, and postoperative nutritional care. These items have been briefly reviewed with the relevant evidence.Discussion and Conclusion: ERAS is a comprehensive and evidence-based guideline for optimal perioperative care. Although a number of ERAS items still require high-level evidence through well-designed randomized controlled trials, the ERAS guidelines can serve as adequate recommendations for our practice. Thus, these items can be introduced and adopted with evidence. In addition, it is important to remove items that are not supported by evidence from routine procedures.

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3- CD4+ T Cells in Biliary Tract Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. @*Materials and Methods@#A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. @*Results@#The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS. @*Conclusion@#The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.

Lymph node size and its association with nodal metastasis in ductal adenocarcinoma of the pancreas

Background@#Although lymph node metastasis is a poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC), our understanding of lymph node size in association with PDAC is limited. Increased nodal size in preoperative imaging has been used to detect node metastasis. We evaluated whether lymph node size can be used as a surrogate preoperative marker of lymph node metastasis. @*Methods@#We assessed nodal size and compared it to the nodal metastatic status of 200 patients with surgically resected PDAC. The size of all lymph nodes and metastatic nodal foci were measured along the long and short axis, and the relationships between nodal size and metastatic status were compared at six cutoff points. @*Results@#A total of 4,525 lymph nodes were examined, 9.1% of which were metastatic. The mean size of the metastatic nodes (long axis, 6.9±5.0 mm; short axis, 4.3±3.1 mm) was significantly larger than that of the non-metastatic nodes (long axis, 5.0±4.0 mm; short axis, 3.0±2.0 mm; all p<.001). Using a 10 mm cutoff, the sensitivity, specificity, positive predictive value, overall accuracy, and area under curve was 24.8%, 88.0%, 17.1%, 82.3%, and 0.60 for the long axis and 7.0%, 99.0%, 40.3%, 90.6%, and 0.61 for the short axis, respectively. @*Conclusions@#The metastatic nodes are larger than the non-metastatic nodes in PDAC patients. However, the difference in nodal size was too small to be identified with preoperative imaging. The performance of preoperative radiologic imaging to predict lymph nodal metastasis was not good. Therefore, nodal size cannot be used a surrogate preoperative marker of lymph node metastasis.

Prognostic factors predicting survival rate over 10 years of patients with intrahepatic cholangiocarcinoma after hepatic resection

PURPOSE@#Hepatic resection is considered as the optimal treatment for intrahepatic cholangiocarcinoma (IHCC); however, the survival rate after resection is low and the analysis of long-term (≥10 years) survivors is rare. This study aims to analyze the clinicopathological factors affecting the long-term survival of patients with IHCC.@*METHODS@#Between January 2003 and December 2012, a single-institution cohort of 429 patients who underwent hepatic resection for IHCC were reviewed retrospectively. Surgical results, recurrence, and survival rates were investigated, and multivariate analyses were performed to identify prognostic factors.@*RESULTS@#The overall 1- , 3- , 5- and 10-year survival rates of patients were 76.5%, 44.1%, 33.3%, and 25.1%, respectively. Multivariate analysis showed that the serum CA 19-9 level (≥38 U/mL) (P < 0.001), lymph node (LN) metastasis (P = 0.001), and lymphovascular invasion (LVI) (P = 0.012) were independent factors associated with overall survival. In particular, CA 19-9 level and histologic type were determined to be independent factors affecting survival for more than 10 years.@*CONCLUSION@#CA 19-9 (≥38 U/mL), LN metastasis, and LVI were identified as independent risk factors for survival after resection of IHCC. CA 19-9 (<38 U/mL) and histologic type were independent factors predicting survival for more than 10 years.

Predictors of early recurrence following a curative resection in patients with a carcinoma of the ampulla of Vater

Purpose@#Ampulla of Vater (AoV) carcinoma has a relatively good prognosis. The 5-year recurrence rate for AoV is still around 40%–50% however, and most recurrences occur in the early period. The aim of this study was to identify predictors of an early recurrence in AoV patients following a curative resection. @*Methods@#The clinicopathological data for 501 consecutive patients that underwent a resection for AoV in our institute between January 2000 and December 2015 were retrospectively reviewed. The characteristics of any recurrences and early recurrence patients were analyzed accordingly. Early recurrence was defined as occurring within one year of resection. @*Results@#There were 170 diagnosed recurrences in our study population, 57.1% of whom were men, with a mean age of 60.1 years (range, 30–94 years). Almost all of the study patients underwent a pancreaticoduodenectomy, and 9% underwent minimally invasive surgery. Of the 170 recurrent cases, 107 were diagnosed with an early recurrence and had 1-, 3-, and 5-year overall survival rates of 77.7%, 18.4%, 10.5%, respectively. The factors that significantly influenced early recurrences, determined by multivariate analysis, lymphovascular invasion (LVI), lymph node ratio (LNR), and poor differentiation were found to be independent determinants of a recurrence within 1 year. @*Conclusion@#An early recurrence in AoV patients is ultimately lethal even though this cancer has a good prognosis. LVI, LNR, and poor differentiation are powerful predictors of an early recurrence in AoV. Hence, intensive surveillance and new therapeutic strategies should be considered for AoV patients with these predictors following a curative resection.

Efficacy and Safety of Pembrolizumab in Patients with RefractoryAdvanced Biliary Tract Cancer: Tumor Proportion Score as a PotentialBiomarker for Response / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit,and novel therapies need to be investigated. @*Materials and Methods@#In this prospective cohort study, programmed death ligand-1 (PD-L1)–positive BTC patientswho progressed on first-line gemcitabine plus cisplatin were enrolled. Pembrolizumab 200mg was administered intravenously every 3 weeks. @*Results@#Between May 2018 and February 2019, 40 patients were enrolled. Pembrolizumab wasgiven as second-line (47.5%) or  third-line therapy (52.5%). The objective response ratewas 10% and 12.5% by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 andimmune-modified RECIST (imRECIST) and median duration of response was 6.3 months.Among patients with progressive disease as best response, one patient (1/20, 5.0%)achieved complete response subsequently. The median progression-free survival (PFS) andoverall survival (OS) were 1.5 months (95% confidence interval [CI], 0.0 to 3.0) and 4.3months (95% CI, 3.5 to 5.1), respectively, and objective response per imRECIST was significantlyassociated with PFS (p < 0.001) and OS (p=0.001). Tumor proportion score  50%was significantly associated with higher response rates including the response after pseudoprogression(vs. < 50%; 37.5% vs. 6.5%; p=0.049). @*Conclusion@#Pembrolizumab showed modest anti-tumor activity in heavily pretreated PD-L1–positiveBTC patients. In patients who showed objective response, durable response could beachieved.

Validation of the 8th Edition of the American Joint Committee onCancer Staging System for Gallbladder Cancer and Implications forthe Follow-up of Patients without Node Dissection / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The 8th edition of gallbladder cancer staging in the American Joint Committee on Cancer(AJCC) staging system changed the T and N categories. @*Materials and Methods@#In order to validate the new staging system, a total of 348 surgically resected gallbladdercancers were grouped based on the 8th edition of the T and N categories and comparedwith patients’ survival. @*Results@#Significant differences were noted between T1b-T2a (p=0.003) and T2b-T3 (p < 0.001)tumors, but not between Tis-T1a, T1a-T1b, and T2a-T2b tumors. However, significant survivaldifferences were observed both by the overall and pair-wise (T1-T2, T2-T3) comparisons(all, p < 0.001) without dividing T1/T2 subcategories. When cases with ! 6 examined lymphnodes were evaluated, significant survival differences were observed among the entire comparison(p < 0.001) and pair-wise comparisons of N0-N1 (p=0.001) and N1-N2 (p=0.039)lesions. When cases without nodal dissection (NX) were additionally compared, significantsurvival differences were observed between patients with N0-NX (p=0.001) and NX-N1(p < 0.001) lesions. @*Conclusion@#The T category in the 8th edition of the AJCC staging system did not completely stratify theprognosis of patients with gallbladder cancer. Modification by eliminating T subcategoriescan better stratify the prognosis. In contrast, the N category clearly determines patients’survival with ! 6 examined lymph nodes. The survival time in patients of gallbladder cancerswithout nodal dissection is between N0 and N1 cases. Therefore, close postoperative followedup is recommended for those patients.

Prognostic Predictability of American Joint Committee on Cancer 8th Staging System for Perihilar Cholangiocarcinoma: Limited Improvement Compared with the 7th Staging System / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This study was conducted to evaluate the prognostic values of the 7th and 8th American Joint Committee on Cancer (AJCC) staging systems for patients with resected perihilar cholangiocarcinoma (PHCC). @*Materials and Methods@#A total of 348 patients who underwent major hepatectomy for PHCC between 2008 and 2015 were identified from a single center. Overall survival (OS) was estimated using the Kaplan-Meier method and compared across stage groups with the log-rank test. The concordance index was used to evaluate the prognostic predictability of the 8th AJCC staging system compared with that of the 7th. @*Results@#In the 8th edition, the stratification of each group of T classification improved compared to that in the 7th, as the survival rate of T4 decreased (T2, 31.2%; T3, 13.9%; T4, 15.1%; T1- T2, p=0.260; T2-T3, p=0.001; T3-T4, p=0.996). Both editions showed significant survival differences between each N category, except between N1 and N2 (p=0.063) in 7th edition. Differences of point estimates between the 8th and 7th T and N classification and overall stages were +0.028, +0.006, and +0.039, respectively (T, p=0.005; N, p=0.115; overall stage, p=0.005). In multivariable analysis, posthepatectomy liver failure, T category, N category, distant metastasis, histologic differentiation, intraoperative transfusion, and resection margin status were associated with OS. @*Conclusion@#The prognostic predictability of 8th AJCC staging for PHCC improved slightly, with statistical significance, compared to the 7th edition, but its overall performance is still unsatisfactory.

Prognosis of Pancreatic Cancer Patients with Synchronous or Metachronous Malignancies from Other Organs Is Better than Those with Pancreatic Cancer Only / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Pancreatic cancer associated double primary tumors are rare and their clinicopathologic characteristics are not well elucidated. MATERIALS AND METHODS: Clinicopathologic factors of 1,352 primary pancreatic cancers with or without associated double primary tumors were evaluated. RESULTS: Of resected primary pancreatic cancers, 113 (8.4%) had associated double primary tumors, including 26 stomach, 25 colorectal, 18 lung, and 13 thyroid cancers. The median interval between the diagnoses of pancreatic cancer and associated double primary tumors was 0.5 months. Overall survival (OS) of pancreatic cancer patients with associated double primary tumors was longer than those with pancreatic cancer only (median, 23.1 months vs. 17.0 months; p=0.002). Patients whose pancreatic cancers were resected before the diagnosis of metachronous tumors had a better OS than patients whose pancreatic cancer resected after the diagnosis of metachronous tumors (48.9 months and 13.5 months, p=0.001) or those whose pancreatic cancers were resected synchronously with non-pancreas tumors (19.1 months, p=0.043). The OS of pancreatic cancer patients with stomach (33.9 months, p=0.032) and thyroid (117.8 months, p=0.049) cancers was significantly better than those with pancreas cancer only (17.0 months). CONCLUSION: About 8% of resected pancreatic cancers had associated double primary tumors, and those from the colorectum, stomach, lung, and thyroid were common. Patients whose pancreatic cancer was resected before the diagnosis of metachronous tumors had better OS than those resected after the diagnosis of metachronous tumors or those resected synchronously.

Transduodenal ampullectomy for ampullary tumors - single center experience of consecutive 26 patients

PURPOSE: Transduodenal ampullectomy (TDA) has been reported in a limited number of cases and in a small number of case series. The aim of this study was to analyze perioperative and long-term oncological outcomes of patients with ampullary tumors who underwent TDA in a single large-volume center. METHODS: Through a retrospective review of data from 2004 to 2016, we identified 26 patients who underwent TDA at Asan Medical Center. RESULTS: Eleven of 26 patients underwent TDA for T1 and carcinoma in situ (high-grade dysplasia) cancer; these patients are still alive without recurrence. A major in-hospital complication (3.8%) occurred in 1 case, but there was no case of 90-day mortality. In addition, none of the patients was diagnosed as having newly developed diabetes mellitus after TDA. No significant differences were found between open and laparoscopic-TDA in terms of operation time, painkiller use, and hospital stay. CONCLUSION: TDA is a feasible and effective surgical procedure for the treatment of selected patients with ampullary tumors. It is an alternative treatment option in cases of ampullary tumors not amenable to endoscopic papillectomy or pancreaticoduodenectomy.

Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients. METHODS: To validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival. RESULTS: PR expression was gradually decreased from normal islets (49/49 cases, 100%) to neuroendocrine microadenoma (14/21, 66.6%) to PanNETs (60/277, 21.3%; p < .001). PanNETs with loss of PR expression were associated with increased tumor size (p < .001), World Health Organization grade (p = .001), pT classification (p < .001), perineural invasion (p = .028), lymph node metastasis (p = .004), activation of alternative lengthening of telomeres (p = .005), other peptide hormonal expression (p < .001) and ATRX/DAXX expression (p = .015). PanNET patients with loss of PR expression (5-year survival rate, 64.1%) had significantly poorer recurrence-free survival outcomes than those with intact PR expression (90%) by univariate (p = .012) but not multivariate analyses. Similarly, PanNET patients with PR expression loss (5-year survival rate, 76%) had significantly poorer overall survival by univariate (p = .015) but not multivariate analyses. CONCLUSIONS: Loss of PR expression was noted in neuroendocrine microadenomas and was observed in the majority of PanNETs. This was associated with increased grade, tumor size, and advanced pT and pN classification; and was correlated with decreased patient survival time by univariate but not multivariate analyses. Loss of PR expression can provide additional information on shorter disease-free survival in PanNET patients.

Branch duct intraductal papillary mucinous neoplasm of the pancreas: single-center experience with 324 patients who underwent surgical resection

BACKGROUNDS/AIMS: International treatment guidelines for branch duct intraductal papillary mucinous neoplasm (BD-IPMN) of the pancreas have been proposed, for features associated with malignancy and invasiveness. We investigated the clinicopathological characteristics that are predictive of malignancy or invasiveness and disease recurrence. METHODS: A review of 324 patients with resected and pathologically confirmed BD-IPMN, between March 1997 and December 2013, was conducted. RESULTS: There were 144 (44.4%) low grade dysplasia (LGD), 138 (42.6%) intermediate grade dysplasia (IMGD), 17 (5.3%) high grade dysplasia (HGD), and 25 (7.7%) invasive carcinoma (invIPMC) cases. The 5-year survival rates were 98.1% for LGD, 95.3% for IMGD, 100% for HGD, and 71.8% for invIPMC. Through a univariate analysis, the male sex was associated with malignancy, and CA19-9 was related to both malignant and invasive IPMN. The high risk or worrisome features of the international guidelines were associated with both malignant and invasive IPMN: the total bilirubin of the head/uncinate lesion, tumor size, mural nodule, and the size of the main pancreatic duct (MPD). Through a multivariate analysis, the male sex, elevated CA19-9, mural nodule, and dilated MPD diameter were independently correlated with the malignant IPMN. The elevated CA19-9 and dilated MPD diameter were also correlated with invasive carcinoma. The patient age and the initial pathological diagnosis were strongly associated with disease recurrence following surgical resection. CONCLUSIONS: The high risk or worrisome features in the current treatment guidelines for BD-IPMN are confined to the morphological characteristics of the disease. Patient factors and biological features should also be considered in order to develop optimal therapeutic or surveillance strategies.

Laparoscopic treatment of hepatic cysts located in the posterosuperior segments of the liver

PURPOSE: Laparoscopy is considered the treatment of choice for hepatic cysts, especially those located in anterolateral segments (AL; segments II, III, IVb, V, and VI) because of the ease of laparoscopic access. Here, we evaluated the feasibility and safety of laparoscopic treatment of hepatic cysts in posterosuperior segments (PS; segments I, IVa, VII, and VIII). METHODS: We retrospectively analyzed clinical data for 34 patients who underwent laparoscopic treatment of hepatic cysts between September 2004 and December 2012. Patients were divided into two groups depending on whether the main largest cyst was located in AL (n = 20) or PS (n = 14). Laparoscopic cyst unroofing was performed in 29 patients with symptomatic simple cysts. Laparoscopic resection was performed in 5 patients with suspected cystic neoplasms. RESULTS: There were no deaths or major complications. The mean operation time was 110 minutes and the mean hospital stay was 4.4 days. The mean cyst size was not significantly different (P = 0.511) but the frequency of multiple cysts was significantly greater in group PS (P = 0.003). The predominant type of resection was unroofing in both groups (P = 0.251). The mean blood loss (P = 0.747), mean hospital stay (P = 0.812), mean operation time (P = 0.669), morbidity rate (P = 0.488), and relapse rate (P = 0.448) were not significantly different. Relapse occurred in one patient who underwent reunroofing 17 months later. The median follow-up is 62 months. CONCLUSION: Laparoscopy is a safe procedure for hepatic cysts located in posterosuperior segments.

Patterns of failure and prognostic factors in resected extrahepatic bile duct cancer: implication for adjuvant radiotherapy

PURPOSE: To find the applicability of adjuvant radiotherapy for extrahepatic bile duct cancer (EBDC), we analyzed the pattern of failure and evaluate prognostic factors of locoregional failure after curative resection without adjuvant treatment. MATERIALS AND METHODS: In 97 patients with resected EBDC, the location of tumor was classified as proximal (n = 26) and distal (n = 71), using the junction of the cystic duct and common hepatic duct as the dividing point. Locoregional failure sites were categorized as follows: the hepatoduodenal ligament and tumor bed, the celiac artery and superior mesenteric artery, and other sites. RESULTS: The median follow-up time was 29 months for surviving patients. Three-year locoregional progression-free survival, progression-free survival, and overall survival rates were 50%, 42%, and 52%, respectively. Regarding initial failures, 79% and 81% were locoregional failures in proximal and distal EBDC patients, respectively. The most common site was the hepatoduodenal ligament and tumor bed. In the multivariate analysis, perineural invasion was associated with poor locoregional progression-free survival (p = 0.023) and progression-free survival (p = 0.012); and elevated postoperative CA19-9 (> or =37 U/mL) did with poor locoregional progression-free survival (p = 0.002), progression-free survival (p < 0.001) and overall survival (p < 0.001). CONCLUSION: Both proximal and distal EBDC showed remarkable proportion of locoregional failure. Perineural invasion and elevated postoperative CA19-9 were risk factors of locoregional failure. In these patients with high risk of locoregional failure, adjuvant radiotherapy could be considered to improve locoregional control.