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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.

Background: MicroRNA-125a (miR-125a) has been shown to function as tumor suppressive miRNA by pre-clinical in vitro studies. However, to the best of our knowledge, there is no study that investigated the clinical relevance of miR-125a in breast cancer patients. We hypothesized that miR-125a high expressing breast cancer associate with less aggressive cancer characteristics and with favorable survival outcome. Material and Methods: The clinicopathological and survival information associated with comprehensive transcriptomic data was analyzed in 2042 breast cancer patients from large publicly available databases, The Molecular Taxonomy of Breast Cancer International Consortium (METARBRIC) The Cancer Genome Atlas (TCGA), and GSE57897. The survival analysis, gene set enrichment analysis (GSEA) were conducted comparing miR-125a high expressing and low expressing tumors, divided by the median cutoff. The association between the miR-125a expression and tumor immune microenvironment was assessed by utilizing xCell. Results: The expression levels of miR-125a were lower in tumors compared with normal breast tissues in both TCGA and GSE57897 cohorts, which is in agreement with the notion that it is a tumor suppressive miRNA (p Citation Format: Yoshihisa Tokumaru, Manabu Futamura, Kohei Taniguchi, Masanori Oshi, Junichi Mase, Yoshimi Asano, Ryutaro Mori, Kazuaki Takabe, Kazuhiro Yoshida. microRNA-125a high expressing tumors enrich cell proliferation associated gene sets and associated with poor prognosis in estrogen receptor positive breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-10-04.

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 (IC(50)): 219.9 to 0.093 µM) and MDA-MB-231/5-FUR cells (IC(50): 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.

Background: Epithelial membrane protein 1 (EMP1) belongs to PMP22 gene family and is reported to be expressed low in numerous gastrointestinal cancers. However, little is known about its role in breast cancer. EMP1 functions to promote cell proliferation. In this study, we hypothesized that low EMP1 expressing breast cancer is associated with high proliferative characteristics and poor survival. Material and Methods: The clinicopathological data and transcriptome data of breast cancer patients from two independent large publicly available databases, The Cancer Genome Atlas (TCGA, n = 1090) and The Molecular Taxonomy of Breast Cancer International Consortium (METARBRIC, n = 1904), were utilized in the current study. Survival analyses; Overall survival (OS), Disease-specific survival (DSS) and Disease-free survival (DFS) were performed by comparing the high and low expression groups. CYT score, xCell, and other immunological factors were used to evaluate intratumoral immune cell composition. Also, gene set enrichment analysis (GSEA) was performed between EMP1 high and low expression groups. Results: We divided each cohort into EMP1 expression high and low groups by utilizing median cutoff. The expression levels of EMP1 were not associated with clinical stage in any subtypes. However, interestingly lower expression of EMP1 was significantly associated with more advanced grades in ER positive/HER2 negative (ER+/HER2) subtype in both TCGA and METABRIC cohorts (p< 0.001 and p< 0.001, respectively). Also, low EMP1 expressing tumors demonstrated higher MKI67 expression levels in ER+/HER2- subtype consistently in both TCGA (p< 0.001) and METABRIC cohorts (p< 0.001). Furthermore, GSEA demonstrated that low EMP1 expressing tumors enriched the gene sets associated with cell proliferation such as MYC Targets, E2F signaling, and G2M Checkpoint signaling, compared with low EMP1 expressing tumors in ER+/HER2- of both TCGA and METABRIC cohorts. On the contrary, high EMP1 expressing tumors enriched the immune related gene sets such as Coagulation, Inflammatory_Response, Complement, and IL-6_JAK_STAT3 Signaling in ER+/HER2- of both TCGA and METABRIC cohorts. To this end, we further hypothesized that high EMP1 tumors were associated with favorable tumor immune microenvironment (TIME) and analyzed TIME utilizing xCell. However, to our surprise high EMP1 expressing tumors were not associated with favorable TIME. Low EMP1 expressing tumors demonstrated worse DFS, DSS, and OS compared with high EMP1 expressing tumors in ER+/HER2- breast cancer patients (p=0.013, p=0.003, and p=0.006) which was not the case in the other subtypes in METABRIC cohort. Conclusion: Low EMP1 expressing tumors were associated with improved OS, DSS, DFS in ER-positive breast cancer patients. Also, low EMP1 expressing tumors were found to associate with advanced grades and enriched gene sets related to cell proliferation and cell cycle, which may explain the poor survival of patients with low EMP1 expressing ER+/HER2- breast cancer. Citation Format: Junko Ukai, Yoshihisa Tokumaru, Masanori Oshi, Yoshimi Niwa, Ryutaro Mori, Kazuaki Takabe, Manabu Futamura. EMP1 low expressing tumor is associated with cell proliferation and poor overall survival of ER-positive breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-28.

Background: Epithelial-mesenchymal transition (EMT) is a well-known multistep process of cancer cell invasion and metastasis, as well as treatment resistance. Our group has been reporting the predictive role of scores generated using Gene Set Variation Analysis (GSVA) of Hallmark pathways in breast cancer. In this study, we hypothesized that EMT score high breast cancer is aggressive and is associated with poor clinical outcome. Material and Methods: The clinicopathological data and transcriptome data of breast cancer patients from three independent large publicly available databases, The Cancer Genome Atlas (TCGA, n = 1077), The Molecular Taxonomy of Breast Cancer International Consortium (METARBRIC, n = 1904), and GSE96058 (n=3069) were utilized. Survival analyses; Overall survival (OS), Disease-specific survival (DSS) and Disease-free survival (DFS) were performed by comparing the high and low score groups. Tumor immune microenvironment was analyzed utilizing the values reported by Thorsson et al. Also, single sample Gene Set Enrichment analysis (ssGSEA) was performed between EMT high and low expression groups utilizing singe cell sequence cohorts. Results: EMT score was generated by Gene Set Variation Analysis of a Hallmark gene set and we divided each cohort into EMT score high and low groups by utilizing median as the cutoff. To our surprise, EMT score of the primary tumor was not associated with metastasis (N and M categories of cancer staging), Nottingham histological grade, nor MKI67 expression levels consistently in TCGA, METABRIC, and GSE96058. EMT score high tumors were not associated with worse DFS, DSS, OS in TCGA and METABRIC and OS in GSE96058. Analyses using xCell demonstrated that EMT score high tumors were associated with high infiltration of stromal cells such as adipocyte (p< 0.001, p< 0.001 and p< 0.001, respectively) and fibroblasts (p< 0.001, p< 0.001 and p< 0.001, respectively) in all three cohorts, TCGA, METABRIC, and GSE96058. Also, myeloid cells such as macrophages (p< 0.001, p< 0.001 and p< 0.001, respectively) and dendritic cells (p< 0.001, p< 0.001 and p< 0.001, respectively) were highly infiltrated with EMT score high tumors. Result of ssGSEA of single cell sequence cohorts revealed that cancer associated fibroblasts demonstrated highest EMT scores compared with the other cell types such as cancer cells, T-cells, B-cells, or myeloid cells. In other words, EMT score of a bulk tumor may reflect the signature from fibroblasts rather than cancer cells. Conclusion: We found that cancer associated fibroblasts rather than cancer cells are the major source of the transcriptomic signatures of EMT in the bulk tumor, which cautions us to be careful with the interpretation of the results of EMT signature from a bulk tumor. Citation Format: Yoshihisa Tokumaru, Rongrong Wu, Junko Ukai, Masanori Oshi, Yoshimi Niwa, Ryutaro Mori, Kazuaki Takabe, Manabu Futamura. Transcriptomic signature score of Epithelial-Mesenchymal Transition (EMT) of a bulk tumor may not reflect that of cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-03.

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.

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.

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.

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.

Approximately 24 cases of cytokeratin-positive interstitial reticulum cell tumors have been reported in English literature. In this paper, we report a case of cytokeratin-positive interstitial reticulum cell tumor that was localized in the parafollicular region of the axillary lymph node and was an incidental finding in a patient with breast cancer. A 50 year-old woman underwent a mastectomy and lymph node dissection following a preoperative diagnosis of bilateral breast cancer. Histopathological examination revealed that the patient had non-invasive and invasive ductal carcinoma in the right and left mammary glands. Although we could not detect breast cancer metastasis in the lymph nodes, one of eight right axillary lymph nodes harbored an 11 × 8 mm discohesive sheet of large polygonal epithelioid tumor cells in the parafollicular area. Tumor cells were immunoreactive for AE1/AE3, CAM5.2, CK18 and l-caldesmon and negative for CD1a, CD21, CD23, CD31, CD68, and S‑100 protein markers. Based on these findings, the lesion was diagnosed as a cytokeratin-positive interstitial reticulum cell tumor of the lymph node. Notably, this early-stage cytokeratin-positive interstitial reticulum cell tumor demonstrated focal nuclear YAP/TAZ proto-oncogene products, which were recently identified as critical for differentiation, maturation, and function of fibroblastic reticular cells. To the best of our knowledge, this is the first report to describe nuclear YAP/TAZ immunoreactivity in cytokeratin-positive interstitial reticulum cell tumors.

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.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.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%.Gemcitabine/S-1 combination NAC has promising efficacy and good tolerability for patients with BR PHC.

Introduction The World Health Organization (WHO) proposed an integrated classification for intraductal papillary neoplasm of the bile duct (IPNB) in 2010. However, IPNB reportedly shows considerable geographic variation. This Japanese single-institution study examined outcomes of surgery for IPNB and the prognostic impact of immunohistochemical mucin expression patterns. Materials and methods Patients with IPNB were identified from 413 patients who underwent curative-intent surgery for biliary tract (excluding gallbladder) neoplasms from 1992 to 2016 by retrospective macro- and microscopic reevaluation of resected specimens. Their clinicopathological variables were analyzed. Results Twenty-two (5%) 2010 WHO classification-based patients with IPNB were identified. The other 391 patients had common-type cholangiocarcinoma. The histopathological grade was low/intermediate in 2 patients (9%), high in 8 (36%), and invasive carcinoma (ICa) in 12 (55%). The 10-year overall survival rate was 100% in 10 patients with low–high grade IPNB and 69% in 12 patients with ICa. These rates were significantly (p = 0.018) or marginally (p = 0.089) better than that (38%) of 391 other-cholangiocarcinoma patients. In the 12 patients with ICa, R0 or R1 resection, MUC5AC, and MUC6 expression significantly affected survival. Notably, all seven patients with ICa exhibiting MUC5AC expression survived throughout the study period, while four of five patients with ICa who did not exhibit MUC5AC expression died of recurrence (with vs. without MUC5AC: 10-year overall survival, 100% vs. 60%, respectively; p = 0.018). Conclusion Our 24-year, single institution's experience suggests that Japanese patients with IPNB favorably respond to surgery, even with ICa. MUC5AC and MUC6 expression may be predictive of favorable outcomes.

The concept of “borderline resectable” was recently introduced to the field of surgery for pancreatic cancer, and surgical outcomes for this disease with extremely dismal prognosis have improved since the introduction of this concept. However, no such concept has yet been introduced to the field of surgery for hilar cholangiocarcinoma (HCca). To determine a definition and criteria for “borderline resectable” in the field of surgery for HCca. Retrospective analysis of 88 patients undergoing curative-intent surgery for HCca at our institution between May 1992 and December 2008 to clarify independent prognostic factors. Survival outcomes were obtained for these 88 patients, with a 5-year overall survival rate of 31.8%. Independent factors predictive of cancer death were determined by multivariate analysis to be the presence of regional lymph node metastasis (LNM) and pathological confirmed vascular invasion (VI). Cumulative survival rates of 23 patients with both LNM and VI who underwent surgery were significantly worse than those of the remaining 65 surgically treated patients and similar to those of 26 patients who were considered to have unresectable disease and treated with non-surgical multidisciplinary treatment during the same study period. Outcomes of surgery for cases of HCca showing regional LNM and VI were no better than those of non-surgical treatment for unresectable disease. Coexistence of these two factors indicates oncologically dismal condition and thus such cases should be considered “borderline resectable.” Treatments additional to surgery are required for “borderline resectable” cases to obtain better outcomes.

Mitochondria‐eating protein (Mieap), encoded by a p53‐target gene, plays an important role in mitochondrial quality control (MQC). Mieap has been reported to have a critical role in tumor suppression in colorectal cancer. Here, we investigated its role as a tumor suppressor in breast cancer. The enforced expression of exogenous Mieap in breast cancer cells induced caspase‐dependent apoptosis, with activation of both caspase‐3/7 and caspase‐9. Immunohistochemistry revealed endogenous Mieap in the cytoplasm in 24/75 (32%) invasive ductal carcinomas (IDC), 15/27 (55.6%) cases of ductal carcinoma in situ (DCIS) and 16/18 (88.9%) fibroadenomas (FA) (IDC vs DCIS; P = 0.0389, DCIS vs FA; P = 0.0234, IDC vs FA; P

Fluorouracil (5FU) is converted to its active metabolite fluoro-deoxyuridine 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 5FU-resistant 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 OPRT-RR pathway in SW48 cells but was scarcely synthesized through either the OPRT-RR or TP-TK 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 FdUMP-led 5FU resistance. These results indicated that fluoro-deoxyuridine (FdU) rather than 5FU promotes FdUMP synthesis and overcomes 5FU resistance. Contrastingly, FdUMP was synthesized through the OPRT-RR and TP-TK pathways in LS174T cells but mainly through the TP-TK 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 cross-resistance to FdU and TS inhibitor, suggesting that nucleoside analogs such as trifluoro-thymidine 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 5FU-resistant cells.

Background: 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. This study analyzed the correlation between histopathological changes in the primary site and liver metastases. Patients and Methods: This study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine from January 2006 to August 2015. Results: 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. We 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. We compared the group which underwent hepatectomy after chemotherapy (n=25) with 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). Conclusion: Chemotherapy appears to change histopathological heterogeneity.Our study suggests that the change of intratumoral heterogeneity reflect by the response of chemotherapy.

Background: Bone-only metastatic breast cancer is believed to be non-life-threatening, and mild therapy is frequently selected to avoid adverse events of drug therapy. However, the prognoses of such patients are not well studied. Methods: Patients who received drug therapies for metastatic breast cancer between 2004 and 2016 at our institution were divided into the “Bone-only metastasis”, “non-visceral”, and “visceral” groups based on the mode of the first metastasis, and the efficacy of the first-line therapy and survival of these patients were compared. Results: There were 131 eligible patients, and the bone-only metastasis, non-visceral, and visceral groups included 26, 25, and 80 patients, respectively. The median survival time (MST) of the overall survival (OS) in each group was 35.1, 34.9, and 37.4 months, respectively (p=0.71). The clinical benefit rates of first-line therapy in the bone-only metastasis, non-visceral, and visceral groups were 66.7%, 45%, and 69.3%, respectively, and the MST of the time to treatment failure (TTF) in each group was 6.3, 5.5, and 5.8 months, respectively, showing that the efficacy of first-line therapy did not significantly differ among the groups. In the bone-only metastasis group, patients with

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.

BackgroundCervical esophageal adenocarcinoma has a low incidence rate and its treatment involves various strategies. We report a patient with locally advanced cervical to upper esophageal adenocarcinoma, able to undergo induction chemotherapy and radical surgery. We report our case as a valuable clinical experience.Case presentationThe patient complained of throat stuffiness. We found a poorly differentiated adenocarcinoma between the cervical esophagus and the upper thoracic esophagus. The primary lesion had infiltrated into the tracheal membrane and had metastatized into the cervical lymph nodes. The initial diagnosis was T4bN1M0 stage IVA. The lower edge of the tumor was close to the tracheal bifurcation, making it difficult to create a longitudinal tracheal foramen during surgery. Therefore, when biweekly-DCF therapy was performed as induction chemotherapy, the tumor shrank sufficiently. Furthermore, tumor infiltration into the tracheal membrane decreased, allowing us to perform total laryngopharyngoesophagectomy with three-field lymph node dissection and reconstruction using free jejunal grafts and subtotal stomach via a posterior mediastinum route and a permanent tracheal foramen as a radical surgery. The pathological diagnosis was T2/MP, N1, and the effect of chemotherapy was grade 2. The patient is followed-up regularly.ConclusionsCervical esophageal adenocarcinoma was rare, but technically reliable and safe oncologic surgery was possible after induction chemotherapy.

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.

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.

Background 5FU can be converted to its active metabolite fluoro-deoxyuridine monophosphate (FdUMP) through two pathways: the orotate phosphoribosyl transferase–ribonucleotide reductase (OPRT–RR) pathway and the thymidine phosphorylase–thymidine kinase (TP–TK) pathway. We investigated the mechanism underlying 5FU-resistance, focusing on the changes in the 5FU metabolisms. Methods MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU or fluoro-deoxyuridine (FdU) in combination with hydroxyurea (HU) or tipiracil (TPI). The amount of FdUMP was determined by the density of the upper band of thymidylate synthase on Western blotting. Results The MKN45/F2R cells exhibited 5FU resistance (37.1-fold) and showed decreased OPRT and increased TP levels. In both cells, the FdUMP after treatment with 5FU was decreased when RR was inhibited by HU but not when TP was inhibited by TPI. A metabolome analysis revealed the loss of intracellular deoxyribose 1-phosphate (dR1P) in both cells, indicating that FdUMP was synthesized from 5FU only through the OPRT–RR pathway because of the loss of dR1P. After the knockdown of TK, the FdUMP after treatment with FdU was decreased in MKN45 cells. However, it was not changed in MKN45/F2R cells. Furthermore, TP inhibition caused an increase in FdUMP after treatment with 5FU or FdU and reversed the 5FU resistance in MKN45/F2R cells, indicating that FdUMP was reduced through the TP–TK pathway in MKN45/F2R cells. Conclusions In MKN45/F2R cells, the reduction of FdUMP through the TP–TK pathway caused 5FU resistance, and the inhibition of TP reversed the resistance to 5FU, suggesting that the combination of 5FU and TPI is a promising cancer therapy.

Purpose To assess the predictive ability of the maximum chemiluminescence intensity (CImax) for severe neutropenia (SN) during neoadjuvant chemo(radio)therapy [NAC(RT)] in patients with advanced pancreatic or biliary tract cancer. Methods Clinicopathological variables and blood test data before NAC(RT) were evaluated in 64 patients with advanced pancreatic or biliary tract cancer who received gemcitabine plus tegafur/gimeracil/oteracil as NAC(RT). Results Thirty-nine patients (60.9%) developed Grade 3–4 SN. The median time between commencing NAC(RT) and the onset of SN was 15 (range 10–36) days. SN occurred during the NAC period, not the RT period. The CImax, neutrophil count, serum interleukin-6 level, C-reactive protein level, complement C3 titer, serum complement titer, and 50.0% hemolytic unit of complement before NAC(RT) were significantly lower in patients with SN than in those without SN (P