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.

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.

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.

Consumption of Sugar-Sweetened Soft Drinks and Risk of Gastrointestinal Cancer: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: Previous observational studies have reported inconsistent findings on the association between consumption of sugar-sweetened soft drinks (SSSDs) and the risk of gastrointestinal (GI) cancer. This study investigated the associations between SSSD consumption and the risk of GI cancer using a systematic review and meta-analysis. METHODS: Observational epidemiological studies were searched from the PubMed and EMBASE databases until June 2021. We conducted a meta-analysis of all included studies and subgroup meta-analyses based on various factors. RESULTS: In a meta-analysis of 27 studies with nine case-control studies and 18 cohort studies, the consumption of SSSDs was modestly associated with an increased risk of GI cancer (odds ratio [OR]/relative risk [RR]: 1.08; 95% confidence interval [CI]: 1.01-1.16), with a significant positive dose-response relationship. In the subgroup meta-analysis by study design, there was a significant positive association between the consumption of SSSDs and GI cancer in cohort studies (RR: 1.11; 95% CI: 1.03-1.20; n = 18), but not in case-control studies. In the subgroup meta-analysis by type of cancer, consumption of SSSDs was significantly associated with an increased risk of colorectal cancer (OR/RR: 1.13; 95% CI: 1.07-1.19). CONCLUSIONS: This meta-analysis suggests that SSSD consumption significantly increases the risk of GI cancer, specifically colorectal cancer.

Trend Analysis and Prediction of Hepatobiliary Pancreatic Cancer Incidence and Mortality in Korea.

BACKGROUND: This study aimed to analyze the current trends and predict the epidemiologic features of hepatobiliary and pancreatic (HBP) cancers according to the Korea Central Cancer Registry to provide insights into health policy. METHODS: Incidence data from 1999 to 2017 and mortality data from 2002 to 2018 were obtained from the Korea National Cancer Incidence Database and Statistics Korea, respectively. The future incidence rate from 2018 to 2040 and mortality rate from 2019 to 2040 of each HBP cancer were predicted using an age-period-cohort model. All analyses, including incidence and mortality, were stratified by sex. RESULTS: From 1999 to 2017, the age-standardized incidence rate (ASIR) of HBP cancers per 100,000 population had changed (liver, 25.8 to 13.5; gallbladder [GB], 2.9 to 2.6; bile ducts, 5.1 to 5.9; ampulla of Vater [AoV], 0.9 to 0.9; and pancreatic, 5.6 to 7.3). The age-standardized mortality rate (ASMR) per 100,000 population from 2002 to 2018 of each cancer had declined, excluding pancreatic cancer (5.5 to 5.6). The predicted ASIR of pancreatic cancer per 100,000 population from 2018 to 2040 increased (7.5 to 8.2), but that of other cancers decreased. Furthermore, the predicted ASMR per 100,000 population from 2019 to 2040 decreased in all types of cancers: liver (6.5 to 3.2), GB (1.4 to 0.9), bile ducts (4.3 to 2.9), AoV (0.3 to 0.2), and pancreas (5.4 to 4.7). However, in terms of sex, the predicted ASMR of pancreatic cancer per 100,000 population in females increased (3.8 to 4.9). CONCLUSION: The annual incidence and mortality cases of HBP cancers are generally predicted to increase. Especially, pancreatic cancer has an increasing incidence and will be the leading cause of cancer-related death among HBP cancers.

Prognostic impact of tumor vascularity on CT in resectable intrahepatic cholangiocarcinoma.

BACKGROUND: We investigated the vascularity of intrahepatic cholangiocarcinoma (ICC) on computed tomography (CT) images and its association with ICC recurrence after surgery and prognosis after recurrence. METHODS: In this retrospective study, the data of patients who underwent resection with curative intent for ICC between March 2001 and July 2017 were reviewed. Clinicopathologic factors including tumor vascularity (hypovascular, rim-enhancement, and hypervascular) on CT that could affect recurrence-free survival (RFS) were assessed. The association between the vascularity of recurrent ICC and survival after recurrence was also analyzed. RESULTS: Overall, 147 patients were enrolled and followed up for a median of 36.1 months of which, 101 (68.7%) experienced ICC recurrence. Hypervascularity of ICC showed better RFS than other vascularities [rim-enhanced image hazard ratio (HR), 3.893; 95% confidence interval (CI), 1.700-8.915, p = 0.001; hypovascular image HR, 6.241; 95% CI, 2.670-14.586, p < 0.001]. The hypervascular recurrent ICC was also significantly associated with better survival after recurrence (log-rank test, p < 0.001). CONCLUSION: Hypervascular ICC was associated with a longer RFS and better prognosis after recurrence. The vascularity of ICC on CT may be a noninvasive, accessible, and useful prognostic index, and should be considered while planning treatment.

Randomized controlled study comparing the analgesic effects of intravenous patient-controlled analgesia and patient-controlled epidural analgesia after open major surgery for pancreatobiliary cancer.

BACKGROUND: This randomized clinical trial was performed to compare pain scales between intravenous patient-controlled analgesia (IV-PCA) and patient-controlled epidural analgesia (PCEA) in patients undergoing open surgical resection of major pancreatobiliary malignancies. METHODS: One hundred ten patients were randomly assigned to the PCEA or IV-PCA group. We compared the numeric rating scale pain score during ambulation on postoperative day (PD) 2 and at rest (at 06:00, 12:00, and 18:00) from PD 1 to 7, the serum level of troponin I on PD 1, and the incidence of postoperative complications between the two groups. RESULTS: There were no significant differences in the pain scores during ambulation on PD 2, at rest up to PD 7, serum troponin I level, and postoperative complication rates. The incidences of nausea (20.4% vs. 6.3%; p = 0.039) and drowsiness (20.4% vs. 0%; p = 0.001) were higher in the IV-PCA group and the rate of dysuria (0% vs. 14.6%; p = 0.004) was higher in the PCEA group. CONCLUSION: PCEA showed no superiority over IV-PCA in terms of postoperative pain relief or morbidity after major open surgery for pancreatobiliary malignancies. The method of analgesia should be considered based the characteristics of the patient, surgeon, anesthesiologist, and institute.

Comparison of oncologic outcomes between open and laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma using data from the KOTUS-BP national database: overcoming selection bias and the necessity of definite indications.

BACKGROUND: Despite the lack of high-level evidence, laparoscopic distal pancreatectomy (LDP) is frequently performed in patients with pancreatic ductal adenocarcinoma (PDAC) owing to advancements in surgical techniques. The aim of this study was to investigate the long-term oncologic outcomes of LDP in patients with PDAC via propensity score matching (PSM) analysis using data from a large-scale national database. METHODS: A total of 1202 patients who were treated for PDAC via distal pancreatectomy across 16 hospitals were included in the Korean Tumor Registry System-Biliary Pancreas. The 5-year overall (5YOSR) and disease-free (5YDFSR) survival rates were compared between LDP and open DP (ODP). RESULTS: ODP and LDP were performed in 846 and 356 patients, respectively. The ODP group included more aggressive surgeries with higher pathologic stage, R0 resection rate, and number of retrieved lymph nodes. After PSM, the 5YOSRs for ODP and LDP were 37.3% and 41.4% (p = 0.150), while the 5YDFSRs were 23.4% and 27.2% (p = 0.332), respectively. Prognostic factors for 5YOSR included R status, T stage, N stage, differentiation, and lymphovascular invasion. CONCLUSION: LDP was performed in a selected group of patients with PDAC. Within this group, long-term oncologic outcomes were comparable to those observed following ODP.

Effects of Pancreatic Enzyme Replacement Therapy on Body Weight and Nutritional Assessments After Pancreatoduodenectomy in a Randomized Trial.

BACKGROUND & AIMS: We studied the effects of pancreatic enzyme replacement therapy (PERT) on body weight, nutritional status, and quality of life (QoL) in patients with pancreatic exocrine insufficiency after pancreatoduodenectomy. METHODS: We performed a randomized, double-blind trial of 304 patients who underwent pancreatoduodenectomy at 7 tertiary referral hospitals in South Korea. Patients with fecal levels of elastase of 200 µg/g or less, before and after surgery, were assigned randomly to groups that received PERT (a single capsule of 40,000 IU pancreatin, Norzyme (40,000 IU, Pankreatan; Nordmark Arzneimittel GmbH & Co, Uetersen, Germany), 3 times each day during meals for 3 months; n = 151) or placebo (n = 153). Protocol completion was defined as taking more than two thirds of the total dose without taking other digestive enzymes; the protocol was completed by 71 patients in the PERT group and 93 patients in the placebo group. Patients underwent a physical examination, oral glucose tolerance tests, and blood tests at baseline and at month 3 of the study period. The primary end point was change in body weight. Secondary end points were changes in bowel habits, nutritional parameters, and QoL. RESULTS: In the per-protocol analysis, 3 months after the study began, patients in the PERT group gained a mean of 1.09 kg in weight and patients in the placebo group lost a mean of 2.28 kg (difference between groups, 3.37 kg; P < .001). However, no difference in body weight was observed between groups in the intent-to-treat analysis. Three months after the study began, the mean serum levels of prealbumin increased by 10.9 mg/dL in the PERT group and increased by 7.8 mg/dL in the placebo group (P = .002). Poor compliance to PERT was a significant risk factor for weight loss (P < .001). There was no significant difference in QoL scores between groups. CONCLUSIONS: In the intent-to-treat analysis of data from a randomized trial, we found no significant effect of PERT on mean body weights of patients with pancreatic exocrine insufficiency after pancreatoduodenectomy. However, with active education and monitoring, PERT could increase body weight and nutritional parameters. ClinicalTrials.gov no: NCT02127021.

Surgery for elderly patients with resectable pancreatic cancer, a comparison with non-surgical treatments: a retrospective study outcomes of resectable pancreatic cancer.

BACKGROUND: We designed a retrospective study to compare prognostic outcomes based on whether or not surgical resection was performed in elderly patients aged(≥75 years) with resectable pancreatic cancer. METHODS: We retrospectively analyzed 49 patients with resectable pancreatic cancer (surgery group, resection was performed for 38 cases; no surgery group, resection was not performed for 11 cases) diagnosed from January 2003 to December 2014 at the National Cancer Center, Korea. RESULTS: There was no significant difference in demographics between the two groups. The surgery group showed significantly better overall survival after diagnosis than the no surgery group (2-year survival rate, 40.7% vs. 0%; log-rank test, p = 0.015). Multivariate analysis revealed that not having undergone surgical resection [hazard ratio (HR) 2.412, P = 0.022] and a high Charlson comorbidity index (HR 5.252, P = 0.014) were independent prognostic factors for poor overall survival in elderly patients with early stage pancreatic cancer. CONCLUSIONS: In the present study, surgical resection resulted in better prognosis than non-surgical resection for elderly patients with resectable pancreatic cancer. Except for patients with a high Charlson comorbidity index, an aggressive surgical approach seems to be beneficial for elderly patients with resectable pancreatic cancer.

Cytopathological results of initial endoscopic ultrasound-guided fine needle aspiration for primary mass and prognosis in pancreatic cancer patients.

OBJECTIVES: Clinical outcomes remain unclear in patients suspected of having pancreatic cancer with indeterminate endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) results. This work aimed to investigate the prognosis of pancreatic cancer patients with indeterminate findings at initial EUS-FNA. METHODS: Findings in all patients who underwent EUS-FNA for suspected pancreatic cancer between 2008 and 2015 at the National Cancer Center, Korea, were retrospectively reviewed. A final diagnosis of pancreatic ductal adenocarcinoma was based on pathology reports. RESULTS: Of the 144 patients evaluated, 113 (78%) were diagnosed as being positive/suspicious for malignancy on cytological evaluation and 31 (22%) as having atypia/negative/non-diagnostic findings at initial EUS-FNA but subsequently diagnosed with pancreatic ductal adenocarcinoma. Tumour size, clinical stage and treatment modalities did not differ significantly between these two groups. Median overall survival was significantly shorter in patients diagnosed (11.3 ± 0.74 months; 95% confidence interval [CI], 9.4-12.8 months) than non-diagnosed (16.9 ± 2.34 months; 95% CI, 12.0-17.4 months) on initial EUS-FNA (P = .024). Multivariate Cox regression analysis showed that a non-diagnosis on initial EUS-FNA was independently associated with better overall survival (hazard ratio, 0.58; 95% CI, 0.38-0.88; P = .011). CONCLUSIONS: Non-diagnostic results on initial EUS-FNA of a primary mass may be associated with better prognosis in patients with pancreatic cancer.

Prognostic Implications of Multiplex Detection of KRAS Mutations in Cell-Free DNA from Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Cell-free DNA (cfDNA) is known to provide potential biomarkers for predicting clinical outcome, but its value in pancreatic ductal adenocarcinoma (PDAC) has not been fully evaluated. The aim of this study was to evaluate the clinical applicability of quantitative analysis of multiplex KRAS mutations in cell-free DNA from patients with PDAC. METHODS: A total of 106 patients with PDAC were enrolled in this prospective study. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). RESULTS: KRAS mutations were detected in 96.1% of tissue samples. Eighty patients (80.5%) harbored KRAS mutations in cfDNA, with a median KRAS mutation concentration of 0.165 copies/µL and a median fractional abundance of 0.415%. Multivariable analyses demonstrated that the KRAS mutation concentration [hazard ratio (HR), 2.08; 95% CI, 1.20-3.63] and KRAS fraction (HR, 1.73; 95% CI, 1.02-2.95) were significant factors for progression-free survival. KRAS mutation concentration (HR, 1.97; 95% CI, 1.05-3.67) also had prognostic implications for overall survival. Subgroup analyses showed that KRAS mutation concentration and fractional abundance significantly affected progression-free survival in resectable PDAC (P = 0.016). Moreover, when combined with the cancer biomarker CA19-9, the KRAS mutation concentration in cfDNA showed additive benefits for the prediction of overall survival. CONCLUSIONS: This study demonstrates that multiplex detection of KRAS mutations in plasma cfDNA is clinically relevant, providing a potential candidate biomarker for prognosis of PDAC.

Nutritional Status of Patients with Cancer: A Prospective Cohort Study of 1,588 Hospitalized Patients.

BACKGROUND: We aimed to assess the nutritional status of cancer patients according to site or treatment type. METHODS: We prospectively evaluated the nutritional status of 1,588 patients based on cancer site and treatment type using the Patient-Generated Subjective Global Assessment tool. We also investigated length of stay (LOS), complication rates after surgery and quality of life (QoL). RESULTS: The patients with esophageal, pancreaticobiliary, and lung cancer had higher malnutrition rates than those with stomach, liver, and colon cancer (52.9%, 47.6%, and 42.8% vs. 29.1%, 24.7%, and 15.9%, respectively; P < 0.05). Patients undergoing chemoradiotherapy (CRT) or supportive care had higher malnutrition rates than those undergoing surgery (35.2% or 68.6% vs. 12.3%; P < 0.05). Among patients undergoing surgery, malnourished patients had longer LOS and tended to have more complications than well-nourished patients (P < 0.05 and P = 0.146, respectively). Malnourished patients had also poorer QoL than well-nourished patients (P < 0.05). CONCLUSION: Malnutrition complicated more in patients with esophageal, pancreaticobiliary, or lung cancer than in those with stomach, liver, or colon cancer. Patients undergoing CRT or supportive care are more likely to be malnourished than those undergoing surgery. Malnutrition may increase LOS and impair QoL.

Risk prediction of post-hepatectomy liver failure in patients with perihilar cholangiocarcinoma.

BACKGROUND AND AIM: In most patients with perihilar cholangiocarcinoma (PHCC), major hepatectomy and extrahepatic bile duct resection are needed for surgical radicality, and a high risk of hepatic insufficiency exists. This study aims to develop a prediction model for post-hepatectomy liver failure (PHLF) in patients with PHCC. METHODS: A total of 143 patients who underwent major liver resection and extrahepatic bile duct resection for PHCC between October 2001 and December 2013 were included. Clinically relevant PHLF was defined as liver failure corresponding to grade B or C of the International Study Group of Liver Surgery criteria. Multivariate logistic regression was used to develop the PHLF risk model. Model performance was evaluated internally using the area under the curve analysis (discrimination) after 1000 bootstrap resampling and the Hosmer-Lemeshow goodness-of-fit test (calibration). RESULTS: Post-hepatectomy liver failure occurred in 43.4% of patients (n = 62). In multivariate analysis, PHLF was significantly associated with future liver remnant ratio (odds ratio [OR] per 10% = 0.68, 95% confidence interval [CI] 0.51-0.88), intraoperative blood loss (OR per 1 L = 1.82, 95% CI 1.11-3.17), and preoperative prothrombin time > 1.20 (OR = 3.22, 95% CI 1.15-9.97). The PHLF risk score model showed good discrimination (area under the curve = 0.708, 95% CI 0.623-0.793) and calibration (P = 0.227). CONCLUSIONS: The risk model proposed in this study accurately predicted PHLF in patients with PHCC. This offers surgeons a practical guide to quantitative risk assessment of hepatic insufficiency and aids decision-making in surgical treatment and perioperative management.

Kocher maneuver to facilitate cytoreduction within the foramen of Winslow.

A potential site for incomplete cytoreduction in patients with peritoneal metastases is the foramen of Winslow, especially the posterior aspect of the hepatoduodenal ligament. The Kocher maneuver can be used to rotate the duodenum, head of pancreas, and portal structures 180°. In so doing, the foramen of Winslow is clearly exposed for peritonectomy. Residual tumor at this site is a prominent cause of unnecessary treatment failure in the management of patients with mucinous appendiceal neoplasms.

Outcomes for Patients with Recurrent Intrahepatic Cholangiocarcinoma After Surgery.

BACKGROUND: This study aimed to analyze the postoperative outcomes for patients with recurrent intrahepatic cholangiocarcinoma (ICC) and to determine the prognostic factors. In addition, this study investigated the effects of various treatment methods for patients with recurrent ICC. METHODS: This retrospective study analyzed the postoperative outcomes and prognostic factors of recurrent ICC that occurred for 81 of 128 patients who underwent hepatic resection for ICC between April 2001 and April 2013. In addition, the outcomes for a number of treatment methods were assessed for patients with recurrent ICC. RESULTS: After resection, the 128 patients with ICC had survival rates of 73 % at 1 year, 52 % at 3 years, and 43 % at 5 years. Recurrent ICC developed in 81 patients (56 men and 25 women) with a median age of 63 years. The median time from initial resection to recurrence was 9 months (range, 0-124 months), and the median survival time after recurrence was 8 months (range, 0-108 months). After recurrence, the overall survival rates were 47 % at 1 year, 23 % at 3 years, and 15 % at 5 years. Multivariate analysis showed disease-free survival time shorter than 1 year and bile duct invasion to be significant prognostic factors. Among the treatment methods, local management such as surgery, transarterial chemoembolization, and radiofrequency ablation were effective in select cases with localized intrahepatic and extrahepatic recurrence. CONCLUSION: Active local treatment (i.e., surgery, transarterial chemoembolization [TACE], and radiofrequency ablation [RFA]) may improve survival for patients with localized ICC recurrence.

Dynamic and unique nucleolar microenvironment revealed by fluorescence correlation spectroscopy.

Organization and functions of the nucleolus is maintained by mobilities and interactions of nucleolar factors. Because the nucleolus is a densely packed structure, molecular crowding effects determined by the molecular concentrations and mobilities in the nucleolus should also be important for regulating nucleolar organization and functions. However, such molecular property of nucleolar organization is not fully understood. To understand the biophysical property of nucleolar organization, the diffusional behaviors of inert green fluorescent protein (GFP) oligomers with or without nuclear localization signals (NLSs) were analyzed under various conditions by fluorescence correlation spectroscopy. Our result demonstrates that the mobility of GFPs inside the nucleolus and the nucleoplasm can be represented by single free diffusion under normal conditions, even though the mobility in the nucleolus is considerably slower than that in the chromatin region. Moreover, the free diffusion of GFPs is found to be significantly size- and NLS-dependent only in the nucleolus. Interestingly, the mobility in the nucleolus is highly sensitive to ATP depletion, as well as actinomycin D (ActD) treatment. In contrast, the ultra-structure of the nucleolus was not significantly changed by ATP depletion but was changed by ActD treatment. These results suggest that the nucleolus behaves similarly to an open aqueous-phase medium with an increased molecular crowding effect that depends on both energy and transcription.

Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial.

BACKGROUND: Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. OBJECTIVES: This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. METHODS: Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6-9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. RESULTS: The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P = 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p = 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p = 0.744). CONCLUSIONS: PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT01587534.

ERα regulates chromosome alignment and spindle dynamics during mitosis.

Estrogen receptors are activated by the hormone estrogen and they control cell growth by altering gene expression as a transcription factor. So far two estrogen receptors have been found: ERα and ERß. Estrogen receptors are also implicated in the development and progression of breast cancer. Here, we found that ERα localized on the spindle and spindle poles at the metaphase during mitosis. Depletion of ERα generated unaligned chromosomes in metaphase cells and lagging chromosomes in anaphase cells in a transcription-independent manner. Furthermore, the levels of ß-tubulin and γ-tubulin were reduced in ERα-depleted cells. Consistent with this, polymerization of microtubules in ERα-depleted cells and turnover rate of α/ß-tubulin were decreased than in control cells. We suggest that ERα regulates chromosome alignment and spindle dynamics by stabilizing microtubules during mitosis.

Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer.

OBJECTIVE: Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. METHODS: We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. RESULTS: After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. CONCLUSIONS: Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC.