An outside individual option increases optimism and facilitates collaboration when groups form flexibly.

Voluntary participation is a central yet understudied aspect of collaboration. Here, we model collaboration as people's voluntary choices between joining an uncertain public goods provisioning in groups and pursuing a less profitable but certain individual option. First, we find that voluntariness in collaboration increases the likelihood of group success via two pathways, both contributing to form more optimistic groups: pessimistic defectors are filtered out from groups, and some individuals update their beliefs to become cooperative. Second, we reconcile these findings with existing literature that highlights the detrimental effects of an individual option. We argue that the impact of an outside individual option on collaboration depends on the "externality" of loners - the influence that those leaving the group still exert on group endeavors. Theoretically and experimentally, we show that if collaboration allows for flexible group formation, the negative externality of loners remains limited, and the presence of an individual option robustly aids collaborative success.

Association of Preoperative and Postoperative Plasma Syndecan-1 and Colorectal Cancer Outcome.

BACKGROUND/AIM: A three-dimensional network constructed using glycocalyx (GCX) extends throughout the cancer cell nest in human colorectal cancer (CRC). GCX was found to be closely related to cancer. We examined the prognostic correlation and potential of syndecan-1 (SDC1), a representative proteoglycan of GCX, as a biomarker. PATIENTS AND METHODS: We analyzed SDC1 in the transcriptomic profiles of a major publicly available CRC cohort from The Cancer Genome Atlas (TCGA) using a computational algorithm. We investigated serum SDC1 levels preoperatively and on postoperative day seven in 48 patients with stage I-III CRC who underwent surgery during July-December 2019 at Gifu University Hospital. RESULTS: For TCGA, no significant differences existed between the high and low SDC1 expression groups regarding disease-free, disease-specific, and overall survival for stage I-III, and only overall survival for stage IV was significantly different. In our study, among the 48 patients, 17 (no recurrence), 13 (1 recurrence), and 18 (10 recurrences) had stage I-III, respectively. Preoperative and postoperative day 7 SDC1 levels for patients with stage I-III were 10.7±2.3 and 9.9±3.1 ng/ml (p=0.40), 11.1±1.7 and 10.1±0.8 ng/ml (p=0.07), and 10.3±2.0 and 9.5±1.4 ng/ml (p=0.15), respectively. In stage II and III, patients were divided into two groups according to differences between preoperative and postoperative SDC1 levels (SDC1pre-pro). SDC1pre-pro ≤0 group significantly prolonged disease-free survival compared with SDC1pre-pro >0 group (p=0.048). CONCLUSION: Dynamic change in serum SDC1 levels serves as a prognostic biomarker for stage II and III colorectal cancer.

Application of an artificial intelligence-based system in the diagnosis of breast ultrasound images obtained using a smartphone.

BACKGROUND: Breast ultrasound (US) is useful for dense breasts, and the introduction of artificial intelligence (AI)-assisted diagnoses of breast US images should be considered. However, the implementation of AI-based technologies in clinical practice is problematic because of the costs of introducing such approaches to hospital information systems (HISs) and the security risk of connecting HIS to the Internet to access AI services. To solve these problems, we developed a system that applies AI to the analysis of breast US images captured using a smartphone. METHODS: Training data were prepared using 115 images of benign lesions and 201 images of malignant lesions acquired at the Division of Breast Surgery, Gifu University Hospital. YOLOv3 (object detection models) was used to detect lesions on US images. A graphical user interface (GUI) was developed to predict an AI server. A smartphone application was also developed for capturing US images displayed on the HIS monitor with its camera and displaying the prediction results received from the AI server. The sensitivity and specificity of the prediction performed on the AI server and via the smartphone were calculated using 60 images spared from the training. RESULTS: The established AI showed 100% sensitivity and 75% specificity for malignant lesions and took 0.2 s per prediction with the AI sever. Prediction using a smartphone required 2 s per prediction and showed 100% sensitivity and 97.5% specificity for malignant lesions. CONCLUSIONS: Good-quality predictions were obtained using the AI server. Moreover, the quality of the prediction via the smartphone was slightly better than that on the AI server, which can be safely and inexpensively introduced into HISs.

Doublet or Triplet Antiemetic Prophylaxis for Nausea and Vomiting Induced by Trastuzumab Deruxtecan: an Open-Label, Randomized, and Multicenter Exploratory Phase 2 Study.

Background: Trastuzumab deruxtecan is classified as an anticancer agent that poses a moderate emetic risk in the international guidelines for antiemetic therapy. The guidelines recommend emesis prophylaxis using a two-drug combination therapy comprising a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). However, the high incidence of nausea and vomiting associated with trastuzumab deruxtecan is problematic. The National Comprehensive Cancer Network guideline version 1.2023 classified trastuzumab deruxtecan as having a high risk of emesis and changed its recommendation to a triplet regimen including a neurokinin-1 receptor antagonist (NK1RA). However, the emetogenic potential of trastuzumab-deruxtecan and the optimal antiemetic prophylaxis are controversial. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment comprising 5-HT3RA and DEX with or without a NK1RA in preventing trastuzumab deruxtecan-induced nausea and vomiting. Methods: We conducted an open-label and randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer who were scheduled to receive trastuzumab deruxtecan were enrolled in this study. The patients were randomly assigned to receive granisetron and DEX (arm GD) or granisetron, DEX, and aprepitant (fosaprepitant; arm GDA). The primary endpoint was complete response (CR; no emesis or no rescue therapy) during the overall phase (120 h after the start of trastuzumab deruxtecan). Results: Between September 2020 and March 2023, 40 patients were randomly assigned to the GD (n = 19) or GDA (n = 21) arm. In the GDA arm, one patient who did not complete the use of the rescue medication listed in the diary was excluded from the efficacy analysis, which included the use of rescue medication. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA arms, respectively (odds ratio 0.1334; 95% confidence interval [CI]: 0.0232-0.7672; P = 0.0190), with a difference of 33.2%. No grade 3 or 4 toxicity related to antiemetic therapy was observed. Conclusions: Patients receiving trastuzumab deruxtecan require triple therapy, including mandatory NK1RA administration.

Neoadjuvant chemotherapy using nanoparticle albumin-bound paclitaxel plus trastuzumab and pertuzumab followed by epirubicin and cyclophosphamide for operable HER2-positive primary breast cancer: a multicenter phase II clinical trial (PerSeUS-BC04).

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) is a promising antibody partner for anti-human epidermal growth factor receptor 2 (HER2). We performed neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer (BC) using nab-PTX plus trastuzumab (T-mab) and pertuzumab (P-mab), followed by epirubicin and cyclophosphamide (EC). METHODS: In this multicenter phase II clinical trial (January 2019-July 2020), patients with stage I (T1c)-IIIB HER2-positive primary BC were treated with four cycles of nab-PTX plus T-mab and P-mab, followed by four cycles of EC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints were clinical response rate (RR), adverse events (AE), and tumor-infiltrating lymphocytes (TILs) in biopsy samples. RESULTS: In total, 43 patients were enrolled (mean age, 54 years). Twenty-two patients had HER2, and 21 patients had luminal/HER2-subtypes. The overall pCR rate was 53.5% (23/43, 95% CI: 42.6-64.1%, p = 0.184), whilst the pCR for HER2 was 68.2% (15/22, 95% CI: 45.1-86.1) and 38.1% for luminal/HER2 (8/21, 95% CI: 18.1-61.6%). The RR was 100% [clinical (c) CR:25, partial response (PR): 18]. AEs (≥ G3) included neutropenia (23.3%), leukopenia (7.0%), liver dysfunction (7.0%), and peripheral neuropathy (4.7%) when nab-PTX was administered. EC administration resulted in leukopenia (34.2%), neutropenia (31.6%), and febrile neutropenia (15.8%). The TILs in preoperative biopsy samples were significantly higher in pCR compared to non-pCR samples. CONCLUSION: Nab-PTX plus T-mab and P-mab induced a high pCR rate in HER2-positive BC, particularly in the HER2-subtype. Given that AEs are acceptable, this regimen is safe and acceptable as NAC for HER2-positive BC.

The mechanism underlying resistance to 5-fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells.

Fluoro-deoxyuridine monophosphate (FdUMP) is an active metabolite of 5-fluorouracil (5-FU) synthesized through two hypothesized pathways: The orotate phosphoribosyl transferase-ribonucleotide reductase (OPRT-RR) pathway and the thymidine phosphorylase-thymidine kinase (TP-TK) pathway. In the present study, the mechanism underlying 5-FU resistance was investigated, focusing on changes in 5-FU metabolism using MCF-7, 5-FU-resistant MCF-7/5-FUR, MDA-MB-231 and 5-FU-resistant MDA-MB-231/5-FUR breast cancer cells. The amount of FdUMP present following treatment with 5-FU was determined by the density of the upper band of thymidylate synthase detected by western blotting, and its changes were investigated. MCF-7/5-FUR cells exhibited 5-FU resistance (36.6-fold), and showed decreased OPRT (-69.3%) and TK (-42.6%) levels. MDA-MB-231/5-FUR cells also exhibited 5-FU resistance (15.8-fold), and showed decreased TP (-79.0%) and increased TK (+184%) levels. MCF-7/5-FUR and MDA-MB-231/5-FUR cells both showed decreased synthesis of FdUMP by 91 and 86%, respectively. In MCF-7 and MCF-7/5-FUR cells, the synthesis of FdUMP was decreased when 5-FU was combined with an RR inhibitor, indicating that FdUMP was synthesized through the OPRT-RR pathway. The synthesis of FdUMP was decreased when 5-FU was combined with a TP inhibitor in MDA-MB-231 cells and combined with an RR inhibitor in MDA-MB-231/5-FUR cells, indicating that the synthesis pathway of FdUMP was changed from the TP-TK pathway to the OPRT-RR pathway on acquiring resistance to 5-FU. Notably, the synthesis of FdUMP was increased and the resistance to 5-FU was reversed in MCF-7/5-FUR cells (half maximal inhibitory concentration (IC50): 219.9 to 0.093 µM) and MDA-MB-231/5-FUR cells (IC50: 157.3 to 31.0 µM) when 5-FU was combined with a TP inhibitor. In conclusion, the metabolism of 5-FU and the mechanism underlying the resistance to 5-FU differed among cell lines, and inhibition of TP reversed resistance to 5-FU, thus suggesting that the combination of 5-FU and a TP inhibitor may be considered a promising cancer therapy.

Evaluation of histopathological heterogeneity of colorectal cancer liver metastasis sites after preoperative chemotherapy.

Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. The present study analyzed the association between histopathological changes in the primary site and liver metastases. The present study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine (Gifu, Japan) between January 2006 and August 2015. The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. The present study evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. The group that underwent hepatectomy after chemotherapy (n=25) was compared with the group that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (P=0.04). In conclusion, chemotherapy appeared to change histopathological heterogeneity. The present study suggested that the histopathological change of intratumoral heterogeneity is reflected by the response to chemotherapy.

Impact of Gemcitabine Plus S1 Neoadjuvant Chemotherapy on Borderline Resectable Perihilar Cholangiocarcinoma.

BACKGROUND: Surgical resection is the only curative strategy for perihilar cholangiocarcinoma (PHC), but recurrence rates are high even after purported curative resection. This study aimed to evaluate the efficacy and safety of gemcitabine/S-1 (GS) combination chemotherapy in the neoadjuvant setting. METHODS: In an open-label, single-arm, phase 2 study, neoadjuvant chemotherapy (NAC) with GS, repeated every 21 days, was administered for three cycles to patients with histologic or cytologically confirmed borderline resectable (BR) PHC who were eligible for inclusion in the study. In this study, BR PHC was defined as positive for lymph node metastasis and for cancerous vascular invasion or Bismuth type 4 on preoperative imaging. The primary end point consisted of the 3- and 5-year survival rates. The secondary end points were feasibility, resection rate, and pathologic effect. RESULTS: The study enrolled 60 patients between January 2011 and December 2016. With respect to toxicity, the major adverse effect was neutropenia, which reached grade 3 or 4 in 53.3% of cases. The overall disease control rate was 91.3%. The median survival time for the entire cohort was 30.3 months. For all the patients, the estimated 3-year survival rate was 44.1%, and the 5-year survival rate was 30.0%. Resection with curative intent was performed for 43 (71%) of the 60 patients. For 81% of the resected patients, R0 resection was performed, and Clavien-Dindo grade 3 complications or a higher morbidity rate was seen in 41% of the patients. The median survival time was 50.1 months for the resected and 14.8 months for the unresected patients. For the resected patients, the estimated 3-year survival rate was 55.8%, and the estimated 5-year survival rate was 36.4%. CONCLUSIONS: Gemcitabine/S-1 combination NAC has promising efficacy and good tolerability for patients with BR PHC.

The Role of Adjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma Patients with Pathological Positive Lymph Nodes After Neoadjuvant Chemotherapy Followed by Esophagectomy: a Single Institute Retrospective Analysis.

The need for adjuvant therapy after radical resection for patients with stage II-III thoracic esophageal squamous cell carcinoma (TESCC) who have undergone neoadjuvant chemotherapy (NAC) has not been determined. Since recurrence can occur after radical resection and since the prognosis is still poor, it is necessary to consider additional treatment strategies, including adjuvant chemotherapy. We retrospectively investigated the significance of adjuvant therapy after NAC followed by radical resection for TESCC. Between 2008 and 2018, 115 patients with clinical stage II-III underwent radical subtotal esophagectomy after neoadjuvant therapy. Among them, 62 were analyzed, excluding patients with T4 tumors and patients who had undergone R plus resection or who were receiving preoperative chemoradiotherapy. We compared patients who received adjuvant chemotherapy with those who only received observation; we examined overall survival (OS) and recurrence rates. Twenty-nine patients (46.7%) had lymph node metastasis, 12 of whom received adjuvant chemotherapy (41.3%). The recurrence rates for patients with and without lymph node metastasis were 55.1 % and 15.1%, respectively (p = 0.0022). Among patients with lymph node metastasis, there was no significant difference in the recurrence rate (p = 0.9270) or OS (p = 0.5416) based on the administration of adjuvant chemotherapy. However, in 15 patients with two or more positive lymph nodes, adjuvant chemotherapy increased OS (p = 0.0404). Adjuvant chemotherapy was associated with improved OS in clinical stage II-III TESCC patients with two or more pathological positive lymph nodes after NAC followed by radical surgery. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13193-021-01419-0.

Mechanism of acquired 5FU resistance and strategy for overcoming 5FU resistance focusing on 5FU metabolism in colon cancer cell lines.

Fluorouracil (5FU) is converted to its active metabolite fluoro­deoxyuridine monophosphate (FdUMP) through the orotate phosphoribosyl transferase (OPRT)­ribonucleotide reductase (RR) pathway and thymidine phosphatase (TP)­thymidine kinase (TK) pathway and inhibits thymidylate synthase (TS), leading to inhibition of thymidine monophosphate (dTMP) synthesis through a de novo pathway. We investigated the mechanism of 5FU resistance and strategies to overcome it by focusing on 5FU metabolism. Colon cancer cell lines SW48 and LS174T and 5FU­resistant cell lines SW48/5FUR and LS174T/5FUR were used. FdUMP amount was measured by western blotting. The FdUMP synthetic pathway was investigated by combining TP inhibitor (tipiracil hydrochloride; TPI) or RR inhibitor (hydroxyurea; HU) with 5FU. Drug cytotoxicity was observed by crystal violet staining assay. FdUMP was synthesized through the OPRT­RR pathway in SW48 cells but was scarcely synthesized through either the OPRT­RR or TP­TK pathway in SW48/5FUR cells. FdUMP amount in SW48/5FUR cells was reduced by 87% vs. SW48 cells. Expression levels of OPRT and TP were lower in SW48/5FUR when compared with these levels in the SW48 cells, indicating decreased synthesis of FdUMP­led 5FU resistance. These results indicated that fluoro­deoxyuridine (FdU) rather than 5FU promotes FdUMP synthesis and overcomes 5FU resistance. Contrastingly, FdUMP was synthesized through the OPRT­RR and TP­TK pathways in LS174T cells but mainly through the TP­TK pathway in LS174T/5FUR cells. FdUMP amount was similar in LS174T/5FUR vs. the LS174T cells. OPRT and RR expression was lower and TK expression was higher in LS174T/5FUR vs. the LS174T cells, indicating that dTMP synthesis increased through the salvage pathway, thus leading to 5FU resistance. LS174T/5FUR cells also showed cross­resistance to FdU and TS inhibitor, suggesting that nucleoside analogs such as trifluoro­thymidine should be used to overcome 5FU resistance in these cells. 5FU metabolism and mechanisms of 5FU resistance are different in each cell line. Both synthesized FdUMP amount and FdUMP sensitivity should be considered in 5FU­resistant cells.

Incidental Gallbladder Cancer on Cholecystectomy: Strategy for Re-resection of Presumed Benign Diseases from a Retrospective Multicenter Study by the Yokohama Clinical Oncology Group.

BACKGROUND/AIM: Current expert consensus recommends re-resection for incidental gallbladder cancer (IGBC) of pT1b-3. This study examined whether this consensus was reasonably applicable to patients with IGBC in one Japanese region. PATIENTS AND METHODS: This was a multicenter, retrospective analysis of cholecystectomies for presumed benign diseases between January 2000 and December 2009. RESULTS: IGBC was diagnosed in 70 (1.0%) out of 6,775 patients undergoing cholecystectomy. Five-year disease-specific cumulative survival was 100% in 19 patients with pT1a, 80.0% in five with pT1b, 49.5% in 33 with pT2, and 23.1% in 13 with pT3. Re-resection was not performed for the 24 patients with pT1a/1b disease, whereas 24 out of 46 patients with pT2/3 underwent re-resection. Regardless of re-resection, independent factors associated with a poor prognosis on multivariate analysis were grade 2 or poorer disease and bile spillage at prior cholecystectomy. In the 24 patients with pT2/3 re-resection, 11 patients without either of these two factors had significantly better 5-year disease-specific cumulative survival than the 13 patients with one or two independent factors associated with a poor prognosis (72.7% vs. 30.8%, p=0.009). CONCLUSION: This Japanese regional study suggests that indication of re-resection for IGBC should not be determined by pT-factor alone and that much more attention should be paid to pathological and intraoperative findings at prior cholecystectomy.

MYC Up-regulation Is a Useful Biomarker for Preoperative Neoadjuvant Chemotherapy Combined With Anti-EGFR in Liver Metastasis from Colorectal Cancer.

BACKGROUND/AIM: At present, there are no biomarkers to predict the effects of molecular targeted drugs in patients with CRC with liver metastasis. Thus, we performed this study to explore potential biomarkers for these patients. MATERIALS AND METHODS: We obtained cancer tissue specimens from liver metastasis-bearing CRC patients who received the following preoperative neoadjuvant chemotherapies with molecular targeted drugs: i) no therapy (n=3), ii) 5-FU+oxaliplatin+anti-EGFR (n=3), iii) and 5-FU+oxaliplatin+anti-VEGF (n=3). RESULTS: We investigated the RNA expression of 84 genes related to cancer drug resistance using an RT-PCR array. The MYC gene was the only gene that was significantly up-regulated in CRC tissue specimens from anti-EGFR group in comparison to the anti-VEGF group. CONCLUSION: MYC up-regulation in the primary CRC tissues may be a potentially useful biomarker for selecting anti-EGFR combination therapy in neoadjuvant chemotherapy for CRC with liver metastasis.

MIEAP, a p53-downstream gene, is associated with suppression of breast cancer cell proliferation and better survival.

Mitochondria-eating protein (MIEAP; also known as SPATA18), a p53-downstream gene, is involved in mitochondrial quality control (MQC). Enforced MIEAP expression induces caspase-dependent cell death in vitro, and impairment of the p53/MIEAP-regulated MQC pathway is frequently observed in breast cancer (BC), resulting in poor disease-free survival (DFS). To investigate the clinical significance of MIEAP in BC, we identified 2,980 patients from two global, large-scale primary BC cohorts: the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=1,904) and the Cancer Genome Atlas (TCGA; n=1,076). We divided patients in each cohort into high and low groups based on median gene expression levels and analyzed the association between MIEAP expression and clinical outcomes. Compared with normal tumors, MIEAP expression was significantly downregulated in all patients with p53-mutant BC regardless of subtype. MIEAP expression was negatively correlated with KI67 expression. Gene set enrichment analysis demonstrated that cell cycle- and proliferation-associated gene sets were significantly enriched in MIEAP-low tumors compared to MIEAP-high tumors. Patients with MIEAP-high luminal subtype were associated with significantly longer DFS than those with MIEAP-low luminal tumors in both cohorts, whereas significantly longer overall survival was observed only in the METABRIC cohort, which has roughly double the number of samples. These results indicated that the mechanistic role of MIEAP is clinically relevant in the two independent cohorts. This is the first study to use large cohorts to demonstrate the association between MIEAP expression and survival in patients with luminal subtype BC.

Ascending colon cancer with synchronous right external iliac lymph node metastasis.

A 75-year-old woman was diagnosed with anemia during hospitalization for the treatment of right superior ophthalmic arteriovenous fistula. Colonoscopy revealed an entire circumference of type 2 tumor in the ascending colon. Computed tomography showed ascending colon wall thickening, a tumor with a maximum diameter of 32 mm on the right external iliac artery and multiple low-density nodules in the spleen. We performed right hemicolectomy with D3 lymph node dissection, splenectomy and right external iliac lymph node dissection. Histopathological finding revealed moderately-differentiated adenocarcinoma in ascending colon and right external iliac lymph node. The lesion of spleen was diagnosed as splenic lymphangioma. The patient was discharged on postoperative day 18. Additional treatments, including chemotherapy, were not performed, and no recurrences were seen up to 66 months after surgery. We herein report an uncommon event of ascending colon cancer with synchronous right external iliac lymph node metastasis, which was successfully treated by surgical resection, made feasible when the distant lymph node metastasis is localized.

Predictive Ability of Preoperative PT-INR and Postoperative MCP1 for Post-hepatectomy Liver Failure.

BACKGROUND: We sought a diagnostic tool using perioperative variables that might predict post-hepatectomy liver failure (PHLF). PATIENTS AND METHODS: In 68 patients undergoing major hepatectomy, data on inflammatory markers and coagulation factors were prospectively collected and were compared between patients with International Study Group of Liver Surgery definition grade B/C PHLF (LF group) and those without LF (non-LF group). RESULTS: Preoperatively, the LF group (n=9; 13.2%) had a lower platelet count and a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity and a higher prothrombin time-International Normalized Ratio (PT-INR) than the non-LF group. On postoperative day 1, the LF group had significantly higher serum interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2), and IL10 levels than the non-LF group. The logistic regression model that included preoperative PT-INR and CCL2 on postoperative day 1 predicted grade B/C PHLF with 100% sensitivity and 89.8% specificity. CONCLUSION: Our findings suggest that the combination of preoperative PT-INR and CCL2 on postoperative day 1 can predict PHLF earlier and precisely after major hepatectomy.

Prophylactic drain management after pancreaticoduodenectomy without focusing on the drain fluid amylase level: A prospective validation study regarding criteria for early drain removal that do not include the drain fluid amylase level.

BACKGROUND/PURPOSE: Early drain removal (EDR) based on drain fluid amylase level (DFA) after pancreaticoduodenectomy excluded 15%-40% patients from EDR because of inappropriate DFA. METHODS: Of 198 pancreatoduodenectomy cases, we used the first 105 cases as an exploration cohort to construct the optimal criteria for EDR on postoperative day (POD)4 that were applied to the subsequent 93 cases used as the validation cohort. After that, we examined another 142 patients to further assess the efficacy of the new EDR criteria. RESULTS: Of the four independent predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) ([1] soft pancreas, [2] positive drain fluid culture on POD1, and [3] serum C-reactive protein [CRP] ≥13 mg/dL on POD4) in the exploration cohort, EDR was applied to cases in the validation cohort meeting the [2] and/or [3], enabling 96% (89/93) applicability of EDR. Outcomes were improved in the validation cohort compared to the exploration cohort; CR-POPF: 8.6% vs 25.7%, P = .005; Dindo-Clavien grade ≥ 3 complications: 23.7% vs 41.9%, P = .007; and median hospital stay (day): 21 vs 27, P = .005. The subsequent 142 patients showed 92% (131/142) applicability of EDR and 5.6% (8/142) incidence of CR-POPF. CONCLUSIONS: Our new criteria for EDR, without DFA, enabled ≥ 90% applicability of EDR and reduced CR-POPF.

Low Incidence of High-Grade Pancreatic Intraepithelial Neoplasia Lesions in a Crmp4 Gene-Deficient Mouse Model of Pancreatic Cancer.

Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRASG12D; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRASG12D; Pdx1-Cre; Crmp4-/- (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN.

Efficacy of prolonged elemental diet therapy after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: A pilot prospective randomized trial (UMIN000004108).

BACKGROUNDS AND AIMS: This randomized clinical trial examined efficacy of prolonged elemental diet (ED) therapy after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC), which often causes postoperative malnutrition leading to worsened short- and long-term outcomes. METHODS: Thirty-nine patients with PDAC receiving PD was randomly assigned to prolonged ED group (PEDG) and control group (CG). Fat-free ED (Elental®, EA Pharma CO., Ltd., Tokyo, Japan) via tube jejunostomy was initiated on postoperative day 1 and increased to maintain with 600 kcal/day in addition to oral intake. ED was discontinued if sufficient oral intake was achieved in CG but continued during 3 postoperative months in PEDG. Primary outcome was complication necessitating readmission. Secondary outcomes were nutritional parameters, relative dose intensity (RDI) in cases of adjuvant chemotherapy, and survival outcomes. RESULTS: Twenty patients were assigned to CG and 19 to PEDG. Cumulative post-discharge readmission rate was significantly lower in PEDG than in CG (PEDG vs CG; 12.6% vs 43.7% at 12-post-discharge-month; p = 0.018). Total calorie and ED-derived protein intakes were significantly larger in PEDG than in CG up to 3-postoperative-month but thereafter similar among groups. Lymphocyte counts were significantly increased and neutrophil-to-lymphocyte-ratio (NLR) was significantly reduced in PEDG than in CG at 2-, 3-, and 6-postoperative-month. However, other outcome measures did not differ among groups. CONCLUSION: This trial failed to show survival benefit of prolonged ED therapy but demonstrated its favorable effect on increased lymphocyte counts, reduced NLR, and prevention of complications necessitating readmission, those which may lead to survival benefit with some modifications.

Combination chemotherapy with TAS-102 plus bevacizumab in salvage-line treatment of metastatic colorectal cancer: A single-center, retrospective study examining the prognostic value of the modified Glasgow Prognostic Score in salvage-line therapy of metastatic colorectal cancer.

The combination regimen of TAS-102, a novel oral nucleoside antitumor agent containing trifluridine and tipiracil hydrochloride, with bevacizumab (C-TASK FORCE), a selective monoclonal antibody inhibitor of vascular endothelial growth factor-A, as salvage-line therapy for metastatic colorectal cancer (mCRC) was established based on its high clinical effectiveness. The aim of the present study was to evaluate the prognostic accuracy of the modified Glasgow Prognostic Score (mGPS) in patients receiving TAS-102 plus bevacizumab. The study included 17 patients (12 men and 5 women, mean age 60.4±13.4 years) with unresectable mCRC who were confirmed to have wild-type or mutant RAS genes. The patients received salvage-line treatment with TAS-102 plus bevacizumab at the Surgical Oncology Department of Gifu University School of Medicine between March 2016 and August 2018. The study population was heavily pretreated; the majority of the patients (71%) had received ≥4 prior regimens and, in addition to fluoropyrimidine, irinotecan and oxaliplatin, all had received bevacizumab (100%) and either cetuximab or panitumumab (47%). The RAS status was wild-type in 9 (53%) and mutant in 8 (47%) patients. The primary tumor locations included the right-sided colon in 5 patients (29%; cecum in 2 and transverse colon in 3 cases) and left-sided colorectum in 12 patients [71%; sigmoid colon in 4, rectosigmoid (Rs) in 4, and rectum above/below the peritoneal reflection (Ra/b) in 4 cases]. Metastatic sites included the liver in 15 (88%), lung in 13 (76%), lymph nodes in 7 (41%), and peritoneal dissemination in 5 (24%) patients. The number of metastatic sites was 1 in 3 (18%) and >2 in 14 (82%) patients. Their first staging imaging scans (after 2 cycles of therapy) were available for review in all 17 patients. At first evaluation, 5 (29%) patients had progressive disease (PD), 12 (71%) had stable disease, and none had a partial response to TAS-102 plus bevacizumab. The median overall survival (OS) of 14.1 months and progression-free survival (PFS) of 6.8 months were comparable to the 11.2 and 5.6 months, respectively, in the C-TASK FORCE study. Upon considering three groups, namely mGPS 0, mGPS 1 and mGPS 2, the median PFS times were significantly different (mGPS 0 vs. mGPS 2, P=0.02; and mGPS 1 vs. mGPS 2, P=0.06). The median PFS times in the mGPS 0, 1 and 2 groups were 12.1, 4.8 and 2.3 months, respectively. Median OS was also significantly different (mGPS 0 vs. mGPS 2, P=0.01; and mGPS 1 vs. mGPS 2, P=0.04). The median OS times in the mGPS 0, 1 and 2 groups were 14.0, not reached, and 2 months, respectively. The present study demonstrated the efficacy and safety of the TAS-102 plus bevacizumab combination as salvage-line treatment. This combination therapy (the TAS-102 plus bevacizumab) has obtained valid results with PFS OS as well as C-TASK.FORCE study. The results of the present study also confirmed the prognostic accuracy of mGPS in salvage-line treatment of patients with mCRC.

MiR-194-5p in Pancreatic Ductal Adenocarcinoma Peritoneal Washings is Associated with Peritoneal Recurrence and Overall Survival in Peritoneal Cytology-Negative Patients.

BACKGROUND: Peritoneal dissemination is one of the major recurrence patterns in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with poor prognosis. Here, we assessed the diagnostic potential of microRNA (miRNA) profiles in peritoneal washings for prediction of peritoneal dissemination in PDAC. PATIENTS AND METHODS: From January 2016 to July 2017, peritoneal washings were obtained prospectively from 59 patients with PDAC undergoing surgery the Yokohama City University Hospital. MiRNA expression was evaluated by Agilent human miRNA microarray and quantitative reverse-transcription polymerase chain reaction. RESULTS: Microarray analysis identified upregulated and downregulated miRNAs in peritoneal washings of patients with peritoneal dissemination. We validated four miRNAs (miR-141-3p, miR-194-3p, miR-194-5p, and miR-200c-3p) with high expression in peritoneal washings. The cumulative incidence rate of peritoneal recurrence in peritoneal cytology-negative patients in the miR-194-5p high group was significantly higher than that in the miR-194-5p low group (p = 0.002). Univariate and multivariate analyses revealed that high miR-194-5p was associated with overall survival (OS). CONCLUSIONS: High expression of miR-194-5p in peritoneal washings is associated with peritoneal recurrence and poor OS in patients with peritoneal cytology-negative PDAC.