Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

New Function Annotation of PROSER2 in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to the absence of diagnostic markers and molecular targets. Here, we took an unconventional approach to identify new molecular targets for pancreatic cancer. We chose uncharacterized protein evidence level 1 without function annotation from extensive proteomic research on pancreatic cancer and focused on proline and serine-rich 2 (PROSER2), which ranked high in the cell membrane and cytoplasm. In our study using cell lines and patient-derived orthotopic xenograft cells, PROSER2 exhibited a higher expression in cells derived from primary tumors than in those from metastatic tissues. PROSER2 was localized in the cell membrane and cytosol by immunocytochemistry. PROSER2 overexpression significantly reduced the metastatic ability of cancer cells, whereas its suppression had the opposite effect. Proteomic analysis revealed that PROSER2 interacts with STK25 and PDCD10, and their binding was confirmed by immunoprecipitation and immunocytochemistry. STK25 knockdown enhanced metastasis by decreasing p-AMPK levels, whereas PROSER2-overexpressing cells increased the level of p-AMPK, indicating that PROSER2 suppresses invasion via the AMPK pathway by interacting with STK25. This is the first demonstration of the novel role of PROSER2 in antagonizing tumor progression via the STK25-AMPK pathway in PDAC. LC-MS/MS data are available at MassIVE (MSV000092953) and ProteomeXchange (PXD045646).

Conditional Relative Survival of Exocrine Pancreatic Cancer: A Population-Based Study.

BACKGROUND: Adjusted prognostic information is important for treatment decisions, especially in elderly patients or survivors of exocrine pancreatic cancer (EPC). This study aims to investigate conditional relative survival (CS) rates and conditional probabilities of death in patients with EPC. METHODS: Data of 77,975 individuals diagnosed with EPC between 1999 and 2019 were obtained from the Korea Central Cancer Registry. CS was analyzed across strata including histology groups (ductal adenocarcinoma excluding cystic or mucinous [group I, PDAC] and ductal adenocarcinoma specified as mucinous or cystic adenocarcinoma [group II]), and age. RESULTS: For PDAC, the overall 5-year relative survival (RS) rate at diagnosis, 3-year CS of 2-year survivors, and 5-year CS of 5-year survivors were 8.5%, 50.1%, and 77.6%, respectively. Overall conditional probabilities of death were 85.2% (≥ 80 years), 73.5% (70-79 years), and 62.0% (60-69 years) in year 1 after diagnosis. Among patients with localized or regional stage who underwent surgery, conditional probabilities of death of ≥ 80, 70-79, and 60-69 years were 37.7%, 32.5%, and 22.6% in the first year, and 26.6%, 27.2%, and 26.0% in year 2 after diagnosis. CONCLUSIONS: Half of patients with EPC who survived for 2 years survived for an additional 3 years. However, 5-year PDAC survivors require follow-up as more than 20% do not survive for a further 5 years. Elderly patients should not be excluded from active treatment for localized or regional-stage PDAC, as the CS of elderly patients who are fit enough to undergo surgery is not inferior to that of younger patients.

Purple Corn Extract Improves Dry Eye Symptoms in Models Induced by Desiccating Stress and Extraorbital Lacrimal Gland Excision.

Dry eye disease (DED) occurs when there are not enough tears, and the associated symptoms-burns, itching, and a gritty feeling in the eye-can cause great discomfort. The purpose of this study was to evaluate the therapeutic effect of purple corn extract (PCE) on DED. Pretreatment with PCE prevented desiccation-stress-induced cell damage in human retinal pigment epithelial cells and primary human corneal epithelial cells. Furthermore, PCE reduced the mRNA expression of inflammatory mediators in the induction of desiccation stress. The therapeutic effects of PCE on DED were evaluated in an animal model with induced unilateral excision of the exorbital lacrimal gland. The administration of PCE was effective at recovering tear production, corneal surface irregularity, and conjunctival goblet cell density, as well as at reducing apoptotic cell death in the outer layer of the corneal epithelium. Collectively, PCE improved dry eye symptoms, and, therefore, it could be a potential agent to ameliorate and/or treat DED.

Exocrine pancreatic cancer as a second primary malignancy: A population-based study.

Backgrounds/Aims: Although cancer survivors are at higher risk of developing second primary malignancies, cancer surveillance strategies for them have not yet been established. This study aimed to identify first primary cancers that had high risks of developing second primary exocrine pancreatic cancer (EPC). Methods: Data on individuals diagnosed with primary cancers between 1993 and 2017 were obtained from the Korea Central Cancer Registry. The standardized incidence ratios (SIRs) of second primary EPCs were analyzed according to the primary tumor sites and follow-up periods. Results: Among the 3,205,840 eligible individuals, 4,836 (0.15%) had second primary EPCs, which accounted for 5.8% of the total EPC patients in Korea. Between 1 and 5 years after the diagnosis of first primary cancers, SIRs of second primary EPCs were increased in patients whose first primary cancers were in the bile duct (males 2.99; females 5.03) in both sexes, and in the small intestine (3.43), gallbladder (3.21), and breast (1.26) in females. Among those who survived 5 or more years after the diagnosis of first primary cancers, SIRs of second primary EPCs were elevated in patients whose first primary cancers were in the bile duct (males 2.61; females 2.33), gallbladder (males 2.29; females 2.22), and kidney (males 1.39; females 1.73) in both sexes, and ovary (1.66) and breast (1.38) in females. Conclusions: Survivors of first primary bile duct, gallbladder, kidney, ovary, and female breast cancer should be closely monitored for the occurrence of second primary EPCs, even after 5 years of follow-up.

Efficacy of ferric carboxymaltose in iron deficiency anemia patients scheduled for pancreaticoduodenectomy.

Purpose: Perioperative transfusion is reported to be an independent risk factor not only for postoperative complications but also for early recurrence of periampullary carcinoma after pancreaticoduodenectomy (PD). The purpose of this study was to evaluate the safety and efficacy of ferric carboxymaltose (FCM) in reducing the need for perioperative transfusion in iron deficiency anemia patients scheduled for PD. Methods: Twenty-two male patients (hemoglobin [Hb] 7 to <13 g/dL) and 18 female patients (Hb 7 to <12 g/dL) were enrolled in the study group and administered FCM 1-3 weeks before PD. The perioperative transfusion rate was the primary endpoint; morbidity, length of postoperative hospital stay, change in hematological parameters after FCM injection, and adverse effects of FCM were also investigated. Results: The perioperative transfusion rate of the study group was 22.5% (9 of 40). Hb level was significantly higher on the day of the operation compared to baseline (P < 0.001). Levels of Hb, transferrin saturation, and ferritin were higher at the follow-up compared to baseline (P = 0.008, P = 0.033, and P < 0.001, respectively). Conclusions: FCM administration was associated with a reduced need for perioperative transfusion and can safely stabilize hematological parameters.

Development and applications of enzymatic modified starch with high water solubility providing a continuous supply of glucose.

Amylopectin clusters (APCs) are produced by cyclodextrin glucanotransferase (EC 2.4.1.19). Their solubility rate in aqueous solution was found to be 16.7 %. The weight-average molecular weight of APCs is ∼105 Da, as determined by multiangle laser light scattering analysis. Side chain length analysis indicated that the relative proportions of side chains with a degree of polymerization in the ranges of 2-8 and 25-50 decreased and increased, respectively, during preparation of APCs. In the exercise experiment, the blood glucose level of rats was higher in the APC-treated group than in the groups treated with commercial carbohydrate supplement (CCD) and glucose. In the forced swimming test, the swimming time in the APC and CCD groups increased by 22.6 % and 31.1 %, respectively, compared with the glucose administration group. The insulin levels were also similar between the APC and CCD groups. However, the glycogen levels in the liver and muscles of mice were significantly higher in the APC group than control group. These results suggest that APCs could potentially enhance endurance when added to sports drinks.

15-Year Experience of Distal Pancreatectomy with Celiac Axis Resection (DP-CAR) for Pancreatic Cancer-A Korean Nationwide Investigation.

BACKGROUND: As systemic treatment for pancreatic cancer advances, distal pancreatectomy with celiac axis resection (DP-CAR) has been considered a curative-intent surgical option for advanced pancreatic cancer. This study aimed to review the surgical and oncologic outcomes of patients undergoing DP-CAR based on Korean nationwide data. METHODS: We collected the data of patients who underwent DP-CAR for pancreatic cancer between 2007 and 2021 at seven major hospitals in Korea. The clinicopathological characteristics, postoperative complications, and data on the survival of the patients were retrospectively reviewed. Logistic regression analysis was performed to identify risk factors for postoperative complications and survival. RESULTS: A total of 75 patients, consisting mainly of borderline resectable (n = 32) or locally advanced (n = 30) pancreatic cancer, were included in the analysis. Forty-two (56.0%) patients underwent neoadjuvant treatment (NAT). Twenty (26.7%) patients experienced Clavien-Dindo grade ≥ 3 complications, including four patients with ischemic gastropathy, two with hepatic ischemia, and two procedure-related mortalities. Neoadjuvant chemotherapy increased the risk of postoperative complications (p = 0.028). The median recurrence-free and overall survival were 7 and 19 months, with a 5-year survival rate of 13% and 24%, respectively. In the NAT group, a decrease in CA 19-9 and the post-NAT maximum standardized uptake value (SUVmax) in positron emission tomography were associated with survival after surgical resection. CONCLUSIONS: Despite the possibility of major complications, DP-CAR could be a feasible option for achieving curative resection with fair survival outcomes in patients with borderline resectable or locally advanced pancreatic cancer. Further studies investigating the safety of the procedure and identifying proper surgical candidates with potential survival gains are necessary.

Exploring Connections between Oral Microbiota, Short-Chain Fatty Acids, and Specific Cancer Types: A Study of Oral Cancer, Head and Neck Cancer, Pancreatic Cancer, and Gastric Cancer.

The association between oral microbiota and cancer development has been a topic of intense research in recent years, with compelling evidence suggesting that the oral microbiome may play a significant role in cancer initiation and progression. However, the causal connections between the two remain a subject of debate, and the underlying mechanisms are not fully understood. In this case-control study, we aimed to identify common oral microbiota associated with several cancer types and investigate the potential mechanisms that may trigger immune responses and initiate cancer upon cytokine secretion. Saliva and blood samples were collected from 309 adult cancer patients and 745 healthy controls to analyze the oral microbiome and the mechanisms involved in cancer initiation. Machine learning techniques revealed that six bacterial genera were associated with cancer. The abundance of Leuconostoc, Streptococcus, Abiotrophia, and Prevotella was reduced in the cancer group, while abundance of Haemophilus and Neisseria enhanced. G protein-coupled receptor kinase, H+-transporting ATPase, and futalosine hydrolase were found significantly enriched in the cancer group. Total short-chain fatty acid (SCFAs) concentrations and free fatty acid receptor 2 (FFAR2) expression levels were greater in the control group when compared with the cancer group, while serum tumor necrosis factor alpha induced protein 8 (TNFAIP8), interleukin-6 (IL6), and signal transducer and activator of transcription 3 (STAT3) levels were higher in the cancer group when compared with the control group. These results suggested that the alterations in the composition of oral microbiota can contribute to a reduction in SCFAs and FFAR2 expression that may initiate an inflammatory response through the upregulation of TNFAIP8 and the IL-6/STAT3 pathway, which could ultimately increase the risk of cancer onset.

Heukharang lettuce (Lactuca sativa L.) leaf extract displays sleep-promoting effects through GABAA receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Although lettuce is traditionally known to have hypnotic and sedative effects, to date, only a few studies have documented its sleep-promoting effects and elucidated the related mechanisms. AIM OF THE STUDY: We aimed to investigate the sleep-promoting activity of Heukharang lettuce leaf extract (HLE) with increased lactucin content, known as a sleep-promoting substance in lettuce, in animal models. MATERIALS AND METHODS: To evaluate the effect of HLE on sleep behavior, analysis of electroencephalogram (EEG), gene expression of brain receptors, and activation mechanisms using antagonists were investigated in rodent models. RESULTS: High-performance liquid chromatography analysis showed that HLE contained lactucin (0.78 mg/g of extract) and quercetin-3-glucuronide (1.3 mg/g of extract). In the pentobarbital-induced sleep model, the group administered 150 mg/kg of HLE showed a 47.3% increase in sleep duration time as compared to the normal group (NOR). The EEG analysis showed that the HLE significantly increased non-rapid eye movement (NREM), where delta waves were improved by 59.5% when compared to the NOR, resulting in increased sleep time. In the caffeine-induced arousal model, HLE significantly decreased the awake time increased by caffeine administration (35.5%) and showed a similar level to NOR. In addition, HLE increased the gene and protein expression of gamma-aminobutyric acid receptor type A (GABAA), GABA type B, and 5-hydroxytryptamine (serotonin) receptor 1A. In particular, in comparison to the NOR, the group administered 150 mg/kg HLE showed an increase in expression levels of GABAA and protein by 2.3 and 2.5 times, respectively. When the expression levels were checked using GABAA receptor antagonists, HLE showed similar levels to NOR, as the sleep duration was reduced by flumazenil (45.1%), a benzodiazepine antagonist. CONCLUSIONS: HLE increased NREM sleep and significantly improved sleep behavior due to its action on the GABAA receptors. The collective findings suggest that HLE can be used as a novel sleep-enhancing agent in the pharmaceutical and food industries.

Prevalence and Risk Factors of Germline Pathogenic Variants in Pancreatic Ductal Adenocarcinoma.

PURPOSE: The genetic attribution for pancreatic ductal adenocarcinoma (PDAC) has been reported as 5%-10%. However, the incidence of germline pathogenic variants (PVs) in Korean PDAC patients has not been thoroughly investigated. Therefore, we studied to identify the risk factors and prevalence of PV for future treatment strategies in PDAC. MATERIALS AND METHODS: Total of 300 (155 male) patients with a median age of 65 years (range, 33 to 90 years) were enrolled in National Cancer Center in Korea. Cancer predisposition genes, clinicopathologic characteristics, and family history of cancer were analyzed. RESULTS: PVs were detected in 20 patients (6.7%, median age 65) in ATM (n=7, 31.8%), BRCA1 (n=3, 13.6%), BRCA2 (n=3), and RAD51D (n=3). Each one patient showed TP53, PALB2, PMS2, RAD50, MSH3, and SPINK1 PV. Among them, two likely PVs were in ATM and RAD51D, respectively. Family history of various types of cancer including pancreatic cancer (n=4) were found in 12 patients. Three patients with ATM PVs and a patient with three germline PVs (BRCA2, MSH3, and RAD51D) had first-degree relatives with pancreatic cancer. Familial pancreatic cancer history and PVs detection had a significant association (4/20, 20% vs. 16/264, 5.7%; p=0.035). CONCLUSION: Our study demonstrated that germline PVs in ATM, BRCA1, BRCA2, and RAD51D are most frequent in Korean PDAC patients and it is comparable to those of different ethnic groups. Although this study did not show guidelines for germline predisposition gene testing in patients with PDAC in Korea, it would be emphasized the need for germline testing for all PDAC patients.

Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. METHODS: Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naïve tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. RESULTS: Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (aldehyde dehydrogenase 1 family member A1 [ALDH1A1] inhibitor) exhibited synergism with nanoparticle albumin-bound-paclitaxel in the organoid model for the stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in the stem-like and metabolism subtypes. The poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis not only reproduced the 3 subtypes but also showed heterogeneity in iCC. CONCLUSIONS: This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.

Features of T1 pancreatic cancer and validation of the eighth edition AJCC staging system definition using a Korean-Japanese joint cohort and the SEER database.

BACKGROUND/PURPOSE: Little is known about the features of T1 pancreatic ductal adenocarcinoma (PDAC) and its definition in the eighth edition of the American Joint Committee on Cancer (AJCC) staging system needs validation. The aims were to analyze the clinicopathologic features of T1 PDAC and investigate the validity of its definition. METHOD: Data from 1506 patients with confirmed T1 PDAC between 2000 and 2019 were collected and analyzed. The results were validated using 3092 T1 PDAC patients from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The median survival duration of patients was 50 months, and the 5-year survival rate was 45.1%. R0 resection was unachievable in 10.0% of patients, the nodal metastasis rate was 40.0%, and recurrence occurred in 55.2%. The current T1 subcategorization was not feasible for PDAC, tumors with extrapancreatic extension (72.8%) had worse outcomes than those without extrapancreatic extension (median survival 107 vs. 39 months, p < .001). Extrapancreatic extension was an independent prognostic factor whereas the current T1 subcategorization was not. The results of this study were reproducible with data from the SEER database. CONCLUSION: Despite its small size, T1 PDAC displayed aggressive behavior warranting active local and systemic treatment. The subcategorization by the eighth edition of the AJCC staging system was not adequate for PDAC, and better subcategorization methods need to be explored. In addition, the role of extrapancreatic extension in the staging system should be reconsidered.

Validation of quantitative prognostic prediction using ADV score for resection of hepatocellular carcinoma: A Korea-Japan collaborative study with 9200 patients.

BACKGROUND: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation. METHODS: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020. RESULTS: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p < .001). Disease-free survival (DFS), overall survival (OS), and post-recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p < .001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥ .577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K-adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates. CONCLUSIONS: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence.

Synergistic effects of concurrent photodynamic therapy with indocyanine green and chemotherapy in hepatocellular carcinoma cell lines and mouse models.

BACKGROUND: Photodynamic therapy (PDT) using an 808 nm laser irradiation with indocyanine green (ICG) has shown tumoricidal effects in a hepatocellular (HCC) orthotopic xenograft model. Recently, combining PDT with concurrent chemotherapy has shown synergistic outcomes and a better therapeutic effect for cancer treatment. In the present study, we utilized a combination of chemotherapy drugs and PDT using ICG in vitro and in vivo in a patient-derived orthotopic xenograft (PDoX) model. METHOD: We independently performed PDT and chemotherapy with sorafenib or doxorubicin in the Huh-7 and Hep3b cell lines by increasing the sorafenib or doxorubicin concentration and increasing the total energy of 808 nm light. Subsequently, we combined the two treatments to confirm the effects on cell viability. The combination index (CI) was evaluated in vitro, and thereafter, in the HCC PDoX mouse model, 808 nm laser irradiation with intravenously injected ICG and chemotherapy using doxorubicin were performed for twelve days. RESULT: The viability of the Huh-7 and Hep3B cell lines decreased rapidly as the concentration of sorafenib or doxorubicin increased and as the total energy of 808 nm light increased. The cell viability of the Huh-7 and Hep3b cell lines with combined PDT and chemotherapy was less than that with PDT or chemotherapy alone. The CI was <1 in the sorafenib- or doxorubicin-treated Huh-7 and Hep3b cell lines. In the HCC PDoX mouse model, tumor size was markedly decreased, and complete remission achieved compared to that of the single chemotherapy or PDT and control groups. CONCLUSION: The synergistic effect of concurrent PDT and chemotherapy in the HCC cell line and PDoX model was confirmed with no definite adverse effect. Concurrent PDT and chemotherapy could be applied in further preclinical studies.

Proposal of nomograms to predict clinical outcomes in patients with ampulla of Vater cancer based on the Korea-Japan collaborative study.

BACKGROUND: In this study, we aimed to develop and validate a nomogram to predict overall survival (OS) and recurrence-free survival (RFS) in patients who underwent curative resection of ampulla of Vater (AOV) cancer. This is the first study for nomograms in AOV cancer patients using retrospective data based on an international multicenter study. METHODS: A total of 2007 patients with AOV adenocarcinoma who received operative therapy between 2002 January and 2015 December in Korea and Japan were retrospectively assessed to develop a prediction model. Nomograms for 5-year OS and 3-year RFS were constructed by dividing the patients who received and who did not receive adjuvant therapy after surgery, respectively. Significant risk factors were identified by univariate and multivariate Cox analyses. Performance assessment of the four prediction models was conducted by the Harrell's concordance index (C-index) and calibration curves using bootstrapping. RESULTS: A total of 2007 and 1873 patients were collected for nomogram construction to predict 5-year OS and 3-year RFS. We developed four types of nomograms, including models for 5-year OS and 3-year RFS in patients who did not receive postoperative adjuvant therapy, and 5-year OS and 3-year RFS in patients who received postoperative adjuvant therapy. The C-indices of these nomograms were 0.795 (95% confidence interval [CI]: 0.766-0.823), 0.712 (95% CI: 0.674-0.750), 0.804 (95% CI: 0.7778-0.829), and 0.703 (95% CI: 0.669-0.737), respectively. CONCLUSIONS: This predictive model could help clinicians to choose optimal treatment and precisely predict prognosis in AOV cancer patients.

Capecitabine and temozolomide for metastatic intermediate to high-grade pancreatic neuroendocrine neoplasm: a single center experience.

BACKGROUND/AIMS: The combination of capecitabine and temozolomide (CAPTEM) is one of the treatment options for metastatic pancreatic neuroendocrine neoplasms (pNENs). This study aims to evaluate the efficacy of CAPTEM in patients with metastatic intermediate to high-grade pancreatic neuroendocrine tumor (pNET) or carcinoma (pNEC). METHODS: This study was conducted retrospectively in a single center. Patients were treated for intermediate to high-grade tumor with 750 mg/m² of capecitabine twice daily from day 1 to 14 and 200 mg/m² of temozolomide once daily from day 10 to 14, repeating twice in a cycle of 28 days. The primary outcomes were durations of overall survival (OS) and progression-free survival (PFS). The secondary outcomes consisted of objective response rate and disease control rate. RESULTS: A total of 12 patients (grade 2 NET in six, grade 3 NET in three, NEC in three patients) who received CAPTEM were included in this study. Patients received a median of five cycles (range, 2 to 46) of CAPTEM. The median dose combined 1,150 mg of capecitabine and 300 mg of temozolomide. The median OS and PFS were 41.2 months (range, 3.2 to 167) and 39.7 months (range, 2.1 to 100), respectively. Patients with NET had longer OS and PFS compared to those of patients with NEC (p = 0.002 and p = 0.028). High Ki-67 proliferative index (> 50%) was significantly associated with poor survival outcomes. CONCLUSION: CAPTEM showed favorable survival outcomes in patients with metastatic intermediate to high-grade pNENs. Our study supports that CAPTEM may be an effective treatment option for metastatic pNENs.

Do jejunal veins matter during pancreaticoduodenectomy?

When planning pancreaticoduodenectomy for pancreatic head cancer, the prevalence of anatomical variation of the proximal jejunal vein (PJV), the associated short-term surgical outcomes, and the level of PJV convergence to the superior mesenteric vein must be carefully analyzed from both technical and oncological points of view. The prevalence of the first jejunal trunk (FJT) and PJV located ventral to the superior mesenteric artery is 58%-88% and 13%-37%, respectively. Patients with the FJT had a larger amount of intraoperative bleeding and a higher proportion of patients requiring transfusions compared to those without a common trunk. The risk of transfusion was higher in patients with ventral PJV compared to those with dorsal PJV. Although less frequent, sacrificing the FJT can result in fatal venous congestion of the jejunum. Therefore, a well-planned approach for pancreaticoduodenectomy, based on preoperative evaluation of anatomical variation in the PJV, may help reduce intraoperative bleeding and postoperative morbidity. Additionally, the importance of invasion into the PJVs should be revisited in terms of resectability and oncological clearance.

Incidence, mortality and survival of gallbladder, extrahepatic bile duct, and pancreatic cancer using Korea central cancer registry database: 1999-2019.

Backgrounds/Aims: In Korea, pancreatic cancer and "gallbladder and extrahepatic bile duct cancer" were ranked the 8th and 9th most frequent cancers in 2019 and the 4th and 6th most common causes of cancer deaths in 2020, respectively. Methods: This review provides national cancer statistics and secular trends of 207,521 patients with gallbladder (n = 44,178), extrahepatic bile duct (n = 61,856), and pancreatic cancer (n = 101,487) between 1999 and 2019 in Korea. Results: The crude incidence rate in both sexes increased in the gallbladder (2.8 to 5.4 per 100,000), extrahepatic bile duct (3.6 to 9.0), and pancreatic cancer (5.5 to 15.8). The age-standardized incidence rate in both sexes significantly increased in the extrahepatic bile duct (3.7 to 4.1) and pancreatic (5.6 to 7.6) cancers but decreased in gallbladder cancer (2.9 to 2.4). The overall 5-year relative survival rate increased in the gallbladder (21.8% to 30.6%), extrahepatic bile duct (23.1% to 27.5%), and pancreatic (8.5% to 13.3%) cancers. Between 2006 and 2019, the proportion of localized or regional stages remained stable. The proportion of surgical treatment within the first 4 months after diagnosis was relatively higher in the gallbladder (42.2%) and extrahepatic bile duct (45.9%) cancers than in pancreatic cancer (22.2%). Conclusions: The crude incidence and mortality rates of the gallbladder, extrahepatic bile duct, and pancreatic cancer are steadily increasing in Korea, and the prognosis remains poor. Early detection, active application of surgical treatment, and minimization of the proportion of untreated patients are required to improve the survival rates of these cancers.

Effect of preoperative nutritional support in malnourished patients with pancreatobiliary cancer: a quasi-experimental study.

BACKGROUND: In malnourished patients, postoperative morbidity, hospitalization period, and medical expenses are reportedly to be high. We evaluated the clinical impact of a preoperative nutritional support program (PNSP) among malnourished cancer patients. METHODS: For this quasi-experimental study, we enrolled 90 patients who underwent major pancreatobiliary cancer surgery. Malnutrition was defined as at least one of the following: (1) Patient-Generated Subjective Global Assessment (PG-SGA) grade B or C; (2) > 10% weight loss within 6 months; (3) body mass index <18.5 kg/m2; and (4) serum albumin level < 3.0 g/dL. Forty-five malnourished patients allocated to the PNSP group received in-hospital PNSP for a median of 6 (4-35) days. In the PNSP group, the nutrition support team calculated the patients' daily nutritional requirements based on their nutritional status and previous day's intake. The supplementation targets were as follows: total calorie intake, 30-35 kcal/kg/day; protein intake, 1.2-1.5 g/kg/day; and lipid intake, 1-1.5 g/kg/day. Patients who did not meet the diagnostic criteria for malnutrition were allocated to the well-nourished group and underwent surgery without receiving the PNSP (n = 45). We compared the perioperative nutritional indices (as measured using PG-SGA), postoperative outcome, and quality of life (QOL) according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0. RESULTS: In the PNSP group, the proportion of patients with serum prealbumin <16 mg/dL decreased significantly after PNSP (29.5% vs. 8.9%, p = 0.013). Moreover, patients with PG-SGA grade A had a statistically significant increase (2.2% vs. 50%, p < 0.001). The overall and major complication rates were higher in the PNSP group than in the well-nourished group without significance (51.1%, 33.3%; 42.2%, 26.7%, respectively). However, the overall and major complication rates were similar between the subgroup with PG-SGA improvement after PNSP and the well-nourished group (40.9% vs. 42.2%, p = 0.958; 27.3% vs. 26.7%, p = 0.525, respectively). QOL indicators in the PNSP group were comparable with those in the well-nourished group after PNSP. CONCLUSION: PNSP may improve perioperative nutritional status and clinical outcomes among malnourished patients with pancreatobiliary cancer.