Analysis of Recent Improvement of Survival Outcomes in Patients with Pancreatic Cancer Who Underwent Upfront Surgery.

Background/Aims: : Recently, patients with pancreatic cancer (PC) who underwent resection have exhibited improved survival outcomes, but comprehensive analysis is limited. We analyzed the trends of contributing factors. Methods: : Data of patients with resected PC were retrospectively collected from the Korean Health Insurance Review and Assessment Service (HIRA) database and separately at our institution. Cox regression analysis was conducted with the data from our institution a survival prediction score was calculated using the ß coefficients. Results: : Comparison between the periods 2013-2015 (n=3,255) and 2016-2018 (n=3,698) revealed a difference in the median overall survival (25.9 months vs not reached, p<0.001) when analyzed with the HIRA database which was similar to our single-center data (2013-2015 [n=119] vs 2016-2018 [n=148], 20.9 months vs 32.2 months, p=0.003). Multivariable analyses revealed six factors significantly associated with better OS, and the scores were as follows: age >70 years, 1; elevated carbohydrate antigen 19-9 at diagnosis, 1; R1 resection, 1; stage N1 and N2, 1 and 3, respectively; no adjuvant treatment, 2; FOLFIRINOX or gemcitabine plus nab-paclitaxel after recurrence, 4; and other chemotherapy or supportive care only after recurrence, 5. The rate of R0 resection (69.7% vs 80.4%), use of adjuvant treatment (63.0% vs 74.3%), and utilization of FOLFIRINOX or gemcitabine plus nab-paclitaxel (25.2% vs 47.3%) as palliative chemotherapeutic regimen, all increased between the two time periods, resulting in decreased total survival prediction score (mean: 7.32 vs 6.18, p=0.004). Conclusions: : Strict selection of surgical candidates, more use of adjuvant treatment, and adoption of the latest combination regimens for palliative chemotherapy after recurrence were identified as factors of recent improvement.

Real-world dose reduction of standard and modified FOLFIRINOX in metastatic pancreatic cancer: a systematic review, evidence-mapping, and meta-analysis.

Background: FOLFIRINOX, used in metastatic pancreatic cancer (MPC), is highly efficacious but also toxic. Various dose modifications for FOLFIRINOX have been introduced to reduce toxicity. However, these studies lack a unified pattern for 'planned' dose modification, and the 'actually administered' dose varied more. Objective: To map a 10-year trend for 'planned' and 'actual' doses of FOLFIRINOX and investigate the clinical outcomes according to dose modification. Data sources and methods: A comprehensive systematic literature search was conducted from January 2011 to September 2021. All studies for FOLFIRINOX as first-line treatment in MPC were considered. Selected studies were firstly classified according to prospective versus retrospective research, secondly standard versus modified FOLFIRINOX, and thirdly 'planned' versus 'actual' dose. For evidence-mapping for the trend of dose modification, we developed a web-based interactive bubble-plot program (www.RDI-map.com). Objective response rate (ORR) and hematologic toxicity were set as endpoints for the comparison of clinical outcomes according to dose modification. Results: A total of 37 studies were identified for evidence-mapping (11 prospective and 26 retrospective studies). There were 12 different types of 'planned' dose modification in FOLFIRINOX ranging 75-100% oxaliplatin, 75-100% irinotecan, 0-100% 5-fluorouracil (5-FU) bolus, and 75-133% 5-FU continuous injection. The 'actual' dose further decreased to 54-96%, 61-88%, 0-92%, and 63-98%, respectively. For the standard versus modified FOLFIRINOX, the ORR was 28.2% (95% CI: 22.5-33.9%) and 33.8% (95% CI: 30.3-37.3%), respectively (p = 0.100), and the incidence of febrile neutropenia was 11.6% (95% CI: 0-16.0%) and 5.5% (95% CI: 0-8.9%), respectively (p = 0.030). Conclusions: RDI-map.com enables multifactorial evidence-mapping for practical FOLFIRINOX dose reduction. The pattern of dose modification was not consistent across studies, and there was a significant gap between the 'planned' and 'actual' doses. Modified FOLFIRINOX showed similar efficacy to the standard regimen with reduced incidence of febrile neutropenia.

Efficacy improvement in searching MEDLINE database using a novel PubMed visual analytic system: EEEvis.

PubMed is the most extensively used database and search engine in the biomedical and healthcare fields. However, users could experience several difficulties in acquiring their target papers facing massive numbers of search results, especially in their unfamiliar fields. Therefore, we developed a novel user interface for PubMed and conducted three steps of study: step A, a preliminary user survey with 76 medical experts regarding the current usability for the biomedical literature search task at PubMed; step B is implementing EEEvis, a novel interactive visual analytic system for the search task; step C, a randomized user study comparing PubMed and EEEvis. First, we conducted a Google survey of 76 medical experts regarding the unmet needs of PubMed and the user requirements for a novel search interface. According to the data of preliminary Google survey, we implemented a novel interactive visual analytic system for biomedical literature search. This EEEvis provides enhanced literature data analysis functions including (1) an overview of the bibliographic features including publication date, citation count, and impact factors, (2) an overview of the co-authorship network, and (3) interactive sorting, filtering, and highlighting. In the randomized user study of 24 medical experts, the search speed of EEEvis was not inferior to PubMed in the time to reach the first article (median difference 3 sec, 95% CI -2.1 to 8.5, P = 0.535) nor in the search completion time (median difference 8 sec, 95% CI -4.7 to 19.1, P = 0.771). However, 22 participants (91.7%) responded that they are willing to use EEEvis as their first choice for a biomedical literature search task, and 21 participants (87.5%) answered the bibliographic sorting and filtering functionalities of EEEvis as a major advantage. EEEvis could be a supplementary interface for PubMed that can enhance the user experience in the search for biomedical literature.

Impact of histopathological type on the prognosis of ampullary carcinoma: A systematic review and meta-analysis.

Histologically, ampullary carcinomas (ACs) can be classified into intestinal (INT-AC) and pancreatobiliary (PB-AC) subtypes. However, the prognostic implications of these subtypes remain unclear. This study aimed to evaluate the impact of the histopathologic phenotype of ACs on survival following pancreaticoduodenectomy. We searched PubMed, Embase, and Medline for studies published in English from 1994 to 2021. A meta-analysis was performed using Review Manager 5.3. The primary endpoint was overall survival (OS). We identified 3,890 articles; of these, 37 articles involving 3,455 participants (1,659 INT-ACs and 1,796 PB-ACs) were included. Patients in the PB-ACs group had significantly shorter OS than those in the INT-ACs group (hazard ratio [HR]: 1.79, 95% confidence interval [95% CI]: 1.51-2.13, p < 0.001, I2 = 61%). A similar tendency was observed in the immunohistochemistry staining group (HR: 1.76, 95% CI: 1.33-2.33, p < 0.001, I2 = 67%), which included 24 studies and 1,638 patients, and the non-immunohistochemistry group (HR: 1.84, 95% CI: 1.53-2.22, p = 0.04, I2 = 46%), which included 13 studies and 1,817 patients. Subgroup analysis revealed that patients with PB-AC had higher frequencies of advanced (III, IV) and pT3-4 stage AC, lymph node metastasis, poorly differentiated tumor, positive surgical margins, lymphovascular invasion, and perineural invasion, than those with INT-AC. Patients with PB-AC had a significantly shorter OS than those with INT-AC due to a higher aggressiveness. Because the histopathologic subtype is a major prognostic factor in patients with resected AC, routine histopathologic classification should be considered even in clinical settings without immunohistochemistry.

Prediction model using clinical factors for radiation exposure during endoscopic retrograde cholangiopancreatography.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) requires radiation. This study aimed to assess the clinical factors influencing radiation exposure and devise a scoring model for predicting high-dose radiation exposure. METHODS: Endoscopic retrograde cholangiopancreatography cases recorded between 2016 and 2019 in a single tertiary teaching hospital were retrospectively reviewed. A scoring model was created by bootstrap method in a derivation cohort (2016-2018) and was assessed in a validation cohort (2019). RESULTS: Out of 4223 ERCPs, 2983 and 1240 cases were included in the derivation and validation cohorts, respectively. In the derivation cohort, 746 cases (top 25%) comprised the high-dose exposure group, and 2237 cases (bottom 75%) comprised the low-dose exposure group. Nine clinical parameters associated with high-dose exposure were male, pancreatic sphincterotomy, balloon dilatation, biliary or pancreatic drainage, procedures with contrast dye, endoscopist, in-hospital ERCP, and spot image. Stone removal was included by bootstrap analysis. As presented in a nomogram, the weight score of each variable was as follows: male, 1; pancreatic sphincterotomy, 3; balloon dilatation, 7; stone removal, 3; biliary or pancreatic drainage, 5; procedures with contrast dye, 1; endoscopist B, 4; endoscopist C, 5; in-hospital procedure, 3; and spot image, 3. A total score ≥ 15 suggested a high-dose radiation exposure. The sensitivity and specificity of the model for high-dose exposure were 0.562 and 0.813, respectively. In the validation cohort, the model showed reasonable predictability. CONCLUSIONS: Various factors were associated with radiation exposure. The simple scoring system in this study could guide endoscopists in predicting the risk of high-dose radiation exposure.

Real-World Outcomes of Gemcitabine, Cisplatin, and Nab-Paclitaxel Chemotherapy Regimen for Advanced Biliary Tract Cancer: A Propensity Score-Matched Analysis.

Background/Aims: Advanced biliary tract cancer (BTC) is associated with poor survival. A recent phase II study of triplet combination chemotherapy, including gemcitabine, cisplatin, and nanoparticle albumin-bound (nab)-paclitaxel, has shown promising results. This study aimed to compare the efficacy of triplet and standard doublet chemotherapy in a real-world setting. Methods: Patients with advanced BTC treated with triplet and doublet chemotherapy regimens were recruited. The propensity-score nearest neighbor matching method with a ratio of one-to-one was used to create a matched cohort for comparison. Progression-free survival (PFS), overall survival (OS), and safety profiles were examined in both groups. Results: A total of 68 patients (n=34 per group) were included in the matched cohort, and their baseline characteristics were well balanced. Survival outcomes in the triplet chemotherapy group were not better than those in the doublet chemotherapy group, with a median PFS of 7.5 months (95% confidence interval [CI], 4.1 to 10.9) versus 7.2 months (95% CI, 5.6 to 8.9) (hazard ratio [HR], 0.93; 95% CI, 0.53 to 1.62; p=0.793) and a median OS of 13.7 months (95% CI, 8.8 to 18.7) versus 12.2 months (95% CI, 8.4 to 16.0) (HR 0.73; 95% CI, 0.38 to 1.41; p=0.354), respectively. In addition, the treatment-related severe adverse events, such as neutropenia, were more common in the triplet chemotherapy group. Conclusions: Gemcitabine, cisplatin, and nab-paclitaxel did not improve the PFS or OS compared to that achieved by standard chemotherapy in patients with advanced BTC. The benefits of triplet chemotherapy in advanced BTC require examination in large randomized controlled trials.

Induction FOLFIRINOX followed by stereotactic body radiation therapy in locally advanced pancreatic cancer.

Introduction: FOLFIRINOX (the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is the preferred systemic regimen for locally advanced pancreatic cancer (LAPC). Furthermore, stereotactic body radiation therapy (SBRT) is a promising treatment option for achieving local control in these patients. However, clinical outcomes in patients with LAPC treated using FOLFIRINOX followed by SBRT have not been clarified. Therefore, we aimed to evaluate clinical outcomes of induction FOLFIRINOX treatment followed by SBRT in patients with LAPC. Methods: To this end, we retrospectively reviewed the medical records of patients with LAPC treated with induction FOLFIRINOX followed by SBRT in a single tertiary hospital. We evaluated overall survival (OS), progression-free survival (PFS), resection rate, SBRT-related adverse events, and prognostic factors affecting survival. Results: Fifty patients were treated with induction FOLFIRINOX for a median of 8 cycles (range: 3-28), which was followed by SBRT. The median OS and PFS were 26.4 (95% confidence interval [CI]: 22.4-30.3) and 16.7 months (95% CI: 13.0-20.3), respectively. Nine patients underwent conversion surgery (eight achieved R0) and showed better OS than those who did not (not reached vs. 24.1 months, p = 0.022). During a follow-up period of 23.6 months, three cases of grade 3 gastrointestinal bleeding at the pseudoaneurysm site were noted, which were managed successfully. Analysis of the factors affecting clinical outcomes revealed that a high radiation dose (≥ 35 Gy) resulted in a higher rate of conversion surgery (25% [8/32] vs. 5.6% [1/18], respectively) and was an independent favorable prognostic factor for OS in the adjusted analysis (hazard ratio: 2.024, 95% CI: 1.042-3.930, p = 0.037). Conclusion: Our findings suggest that induction FOLFIRINOX followed by SBRT in patients with LAPC results in better survival with manageable toxicities. A high total SBRT dose was associated with a high rate of conversion surgery and could afford better survival.

Clinical Impact of Unexpected Para-Aortic Lymph Node Metastasis in Surgery for Resectable Pancreatic Cancer.

Radiologically identified para-aortic lymph node (PALN) metastasis is contraindicated for pancreatic cancer (PC) surgery. There is no clinical consensus for unexpected intraoperative PALN enlargement. To analyze the prognostic role of unexpected PALN enlargement in resectable PC, we retrospectively reviewed data of 1953 PC patients in a single tertiary center. Patients with unexpected intraoperative PALN enlargement (group A1, negative pathology, n = 59; group A2, positive pathology, n = 13) showed median overall survival (OS) of 24.6 (95% CI: 15.2-33.2) and 13.0 (95% CI: 4.9-19.7) months, respectively. Patients with radiological PALN metastasis without other metastases (group B, n = 91) showed median OS of 8.6 months (95% CI: 7.4-11.6). Compared with group A1, groups A2 and B had hazard ratios (HRs) of 2.79 (95% CI, 1.4-5.7) and 2.67 (95% CI: 1.8-4.0), respectively. Compared with group A2, group B had HR of 0.96 (95% CI: 0.5-1.9). Multivariable analysis also showed positive PALN as a negative prognostic factor (HR 2.57, 95% CI: 1.2-5.3), whereas positive regional lymph node did not (HR 1.32 95% CI: 0.8-2.3). Thus, unexpected malignant PALN has a negative prognostic impact comparable to radiological PALN metastasis. This results suggests prompt pathologic evaluation for unexpected PALN enlargements is needed and on-site modification of surgical strategy would be considered.

Primary Granulocyte Colony-Stimulating Factor Prophylaxis in Metastatic Pancreatic Cancer Patients Treated with FOLFIRINOX as the First-Line Treatment.

Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) has been proven efficacious in metastatic pancreatic cancer (MPC), physicians hesitate to administer it due to its hematologic toxicities. We investigated the usefulness of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. We reviewed electronic medical records of MPC patients with good performance status who were administered FOLFIRINOX as the first-line treatment from 2011 to 2017. The patients were divided into primary G-CSF prophylaxis users (group A) and non-users or therapeutic/secondary users (group B). Cumulative relative dose (cRDI), adverse effects (AEs), and overall survival (OS) were compared. A total of 165 patients (group A (57) vs. group B (108)) were investigated. Intergroup differences in baseline characteristics were not significant, although the cRDI and the number of treatment cycles were both higher in group A than in group B (cRDI: 80.6% vs. 73.9%, p = 0.007; 9 vs. 6 cycles, p = 0.004). Primary G-CSF prophylaxis reduced the risk of neutropenia (55.6% to 31.6%, p = 0.003) and febrile neutropenia (18.5% to 1.8%, p = 0.002) and improved OS (8.8 to 14.7 months; hazard ratio [HR]: 1.766, 95% CI: 1.257-2.481, p = 0.001). When administering FOLFIRINOX for MPC, primary G-CSF prophylaxis could be rationalized to reduced AEs and improve survival; more prospective studies are needed.