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Chylous ascites is a rare form of ascites with high triglyceride content arising from the thoracoabdominal lymph nodes in the peritoneal cavity due to various benign or malignant etiologies, including pancreatic cancer. During cancer chemotherapy, the accumulation of ascites can lead to the deterioration of the patient’s general condition, making chemotherapy administration difficult, and resulting in a poor prognosis. We encountered a rare case of chylous ascites complicated by advanced pancreatic cancer. The patient presented with a discrepancy between the shrinkage of the pancreatic cancer and the accumulation of ascites. Therefore, we were able to promptly diagnose chylous ascites by performing biochemical tests. The patient was treated with octreotide, reportedly effective in treating chylous ascites, which rapidly improved the chylous ascites and general condition of the patient, allowing the patient to continue chemotherapy for pancreatic cancer. Therefore, physicians should consider the possibility of chylous ascites when clinically unexplained ascites are observed in patients with advanced cancer. The investigation and treatment of chylous ascites should be initiated as soon as possible.

Abstract Background Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer. Methods This multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma. Discussion GEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer. Trial registration This study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies.Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed.The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876–16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2− subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group.The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

Abstract Functional properties caused by TP53 mutations are involved in cancer development and progression. Although most of the mutations lose normal p53 functions, some of them, gain-of-function (GOF) mutations, exhibiting novel oncogenic functions. No reports have analyzed the impact of TP53 mutations on the gene expression profile of the p53 signaling pathway across cancer types. This study is a cross-cancer type analysis of the effects of TP53 mutations on gene expression. A hierarchical cluster analysis of the expression profile of the p53 signaling pathway classified 21 cancer types into two clusters (A1 and A2). Changes in the expression of cell cycle-related genes and MKI67 by TP53 mutations were greater in cluster A1 than in cluster A2. There was no distinct difference in the effects between GOF and non-GOF mutations on the gene expression profile of the p53 signaling pathway.

Abstract Background A paradigm shift has occurred in cancer chemotherapy from tumor‐specific treatment with cytotoxic agents to personalized medicine with molecular‐targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary‐sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions. Methods This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations. Results The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden‐high (TMB‐H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non‐small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%). Conclusion The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

BackgroundPembrolizumab-containing regimens are standards of care for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). The depth of response (DpR) predicts the survival of patients with several types of solid cancers; however, its association with the survival outcomes of patients with R/M HNSCC treated with pembrolizumab-containing regimens remains unclear.MethodsThis study included 66 patients with R/M HNSCC who received a pemblolizumab-containing regimen as a first-line therapy at Tohoku University Hospital, Sendai, Japan. The patients’ characteristics, combined positive score, baseline tumor size, tumor response, DpR, overall survival (OS), progression-free survival (PFS), PFS2, and adverse events were reviewed. The associations between DpR and survival outcomes were analyzed.ResultsThe 1 year-OS and 1 year-PFS rates of pembrolizumab-containing regimens were 69.4% and 24.4%, respectively. The response rate was 28.8%. The mean and median values of tumor change from baseline were 5.1% and −9.0%. In the correlation analysis, a significant negative correlation was observed between tumor change rate from baseline and survival outcomes (OS: r= −0.41, p=0.0017; PFS: r=−0.49, p

Summary: The BRCA1-interacting protein Obg-like ATPase 1 (OLA1) functions in centriole duplication. In this study, we show the role of the mitotic kinase Aurora A in the reduction of centrosomal OLA1. Aurora A binds to and polyubiquitinates OLA1, targeting it for proteasomal degradation. NIMA-related kinase 2 (NEK2) phosphorylates the T124 residue of OLA1, increases binding of OLA1 to Aurora A and OLA1 polyubiquitination by Aurora A, and reduces centrosomal OLA1 in G2 phase. The kinase activity of Aurora A suppresses OLA1 polyubiquitination. The decrease in centrosomal OLA1 caused by Aurora A-mediated polyubiquitination promotes the recruitment of pericentriolar material proteins in G2 phase. The E3 ligase activity of Aurora A is critical for centrosome amplification induced by its overexpression. The results suggest a dual function of Aurora A as an E3 ubiquitin ligase and a kinase in the regulation of centrosomal OLA1, which is essential for proper centrosome maturation in G2 phase.

An 18-year-old Japanese man was diagnosed with an undifferentiated sarcoma of the spermatic cord, with multiple distant metastases to the lungs and bones. The patient received doxorubicin-based standard chemotherapy. Although the chemotherapy was effective, it induced severe adverse events, which led to treatment discontinuation. A comprehensive genomic profiling test using resected tumor tissue revealed the BRAF V600E mutation. Based on the result, the patient received combination therapy with dabrafenib and trametinib. The combination therapy achieved a good response with few adverse events. However, 6.5 months later, pleural metastases and meningeal dissemination had emerged. A liquid comprehensive genomic profiling test was performed after the progression to identify the resistance mechanism, which resulted in the detection of no actionable gene alterations other than BRAF V600E. This report shows that the BRAF V600E mutation may be a promising therapeutic target and that resistance to the targeted therapy could also occur in soft tissue sarcoma. The significance of BRAF mutations across different types of cancer should be validated, and it is necessary to apply targeted therapies and develop methods to overcome resistance based on the optimal use of comprehensive genomic profiling tests.

Background: The TP53 signature that predicts the mutation status of TP53 has been shown to be a prognostic factor and predictor of neoadjuvant chemotherapy (NAC) response. Objectives: The current study sought to investigate the utility of the TP53 signature for predicting pathological complete response (pCR) and its prognostic significance among patients with residual disease (RD). Design: The study followed a retrospective cohort study design. Methods: Patients with T1-3/N0-1 from a cohort of those with HER2-negative breast cancer who received NAC were selected. Ability to predict pCR was evaluated using odds ratio, positive and negative predictive values, sensitivity, and specificity. Prognostic factors in the RD group were explored using the Cox proportional hazards model with distant recurrence-free survival (DRFS). Four independent cohorts were used for validation. Results: A total of 333 eligible patients were classified into the TP53 mutant signature (n = 154) and wild-type signature (n = 179). Among the molecular and pathological factors, the TP53 signature had the highest predictive power for pCR. In 4 independent cohorts (n = 151, 85, 104, and 67, respectively), pCR rate in TP53 mutant signature group was significantly higher than that in the wild-type group. Univariate and multivariate analyses on DRFS in the RD group identified the TP53 signature and nodal status as independent prognostic factors, with the former having a better hazard ratio than the latter. After comparing DRFS between 3 groups (pCR, RD/ TP53 wild-type signature, and RD/ TP53 mutant signature groups), the RD/ TP53 mutant signature group showed significantly worse prognosis compared with others. The RD/ TP53 wild-type signature group did not exhibit inferior DRFS compared with the pCR group. Conclusion: Our results showed that the TP53 mutant signature can predict pCR and that combining pathological response and TP53 mutant signature allows for the identification of subgroups with truly poor prognosis.

Background Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response.Methods We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody.Results Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8+ effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8+ T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8+ T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment.Conclusions SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.

Abstract Liphagal, isolated from the marine sponge Aka coralliphaga, exhibits phosphatidylinositol 3‐kinase alpha (PI3Kα) inhibitory activity and cytotoxic effects in human cancer cells. Siphonodictyal B, the biogenetic precursor of liphagal, also has PI3K inhibitory activity. However, its cytotoxic or antitumor activities have not been evaluated. In this study, we demonstrated that siphonodictyal B inhibits several kinases such as CDK4/6, CDK7, and PIM2 in addition to PI3K in vitro and that siphonodictyal B exhibits more potent cytotoxic effects than liphagal against human colon cancer cell lines. Furthermore, treatment with siphonodictyal B resulted in increased PARP cleavage, a larger sub‐G1 fraction, and a larger annexin V‐positive cell population, all of which are indicative of apoptosis induction. As a mechanism of apoptosis induction, we found that siphonodictyal B activates the p38 MAPK pathway, leading the upregulation of proapoptotic factors. Moreover, siphonodictyal B increased ROS levels, thus promoting p38 MAPK pathway activation. NAC, an ROS scavenger, almost completely reversed both the cytotoxic and p38 MAPK pathway‐activating effects of siphonodictyal B. These results indicate that the p38 MAPK pathway might be involved downstream of ROS signaling as part of the mechanism of siphonodictyal B‐induced apoptosis. Finally, siphonodictyal B displayed antitumor effects in a human colon cancer xenograft mouse model and increased p38 phosphorylation in tumor tissue. These results suggest that siphonodictyal B could serve as the basis of a novel anticancer drug.

Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying many MLH1 variants in Lynch syndrome. Combined with analyses of conservation, the thermodynamic stability predictions separate disease-linked from benign MLH1 variants, and therefore hold potential for Lynch syndrome diagnostics.

Abstract Background The aim of this study was to identify miRNAs specifically dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer. Methods Candidate dysregulated miRNAs were selected in genome-wide miRNA expression array analysis using a screening set composed of 15 BRAF-mutated and 15 non-KRAS/BRAF-mutated colorectal cancers. The miRNA expressions were validated in another set of patients. The functional roles of the miRNAs were analyzed by cell growth and invasion assays. The association between miRNA expression status and the clinical outcome of patients treated with various chemotherapies was analyzed. Results Within the top five of the miRNAs screened, we validated miRNA-31 (miR-31) and miR-135b as up-regulated, while miR-193a-3p was down-regulated in BRAF-mutated cancer. Moreover, miR-193a-3p inhibited cell growth, and invasion of colorectal cancer cells. Low miR-193a-3p expression was associated with shorter progression-free survival in patients who received anti-EGFR therapy. Conclusions Our results disclose a novel tumor suppressive role of miR-193a-3p in colorectal cancer. These results could lead to novel therapeutic strategies for colorectal cancer, particularly in BRAF-mutated colorectal cancer.

Background: Bone is a metastatic site for various types of cancer. Cancer patients in whom bone metastases progress often have skeletal-related events (SREs). Denosumab and zoledronic acid are both bone-modifying agents that prevent the occurrence of SREs. Denosumab has been shown to be superior to zoledronic acid in delaying SREs in various types of cancer, such as breast cancer, lung cancer, and multiple myeloma. However, it is still uncertain whether denosumab is superior to zoledronic acid in delaying the time to SREs in other types of cancers, including gastrointestinal cancer, pancreas-biliary system cancer, and other rare cancers. Patients and methods: This retrospective study was conducted based on medical records from 2009 to 2015. Eligible patients who had been diagnosed with bone metastases from gastrointestinal cancer, pancreas-biliary system cancer, and rare cancers were included. Patients were assigned to a denosumab group, zoledronic acid group, or group without bone-modifying agent treatment (no-treatment group). Results: The study included 168 patients. The times to SREs in the denosumab, zoledronic acid, and no-treatment groups were 186 days [95% confidence interval (CI), 96–323 days], 79 days (95% CI, 45–118 days), and 31 days (95% CI, 13–76 days), respectively. Although, a few patients had grade 3 or 4 adverse events in the denosumab and zoledronic acid groups, the bone-modifying agent treatment was not terminated. Conclusion: From the perspective of the efficacy and safety of denosumab for delaying the time to SREs, denosumab should be used to prevent SREs in patients with bone metastases from gastrointestinal cancer, pancreas-biliary system cancer, and other rare cancers.

Combination therapy with gemcitabine and docetaxel has been reported to be a good therapeutic strategy for patients with soft tissue sarcoma. The aim of the present study was to analyze the efficacy and toxicity of gemcitabine with docetaxel in Japanese patients with advanced bone and soft tissue sarcoma.We retrospectively analyzed the effect of gemcitabine and docetaxel therapy on overall response, progression-free survival, overall survival, and toxicity in 42 patients with bone or soft tissue sarcoma who had received the therapy between October 2006 and September 2015, at Tohoku University Hospital.The median age was 55 years; 23 patients were men, and 19 were women. Eight had bone sarcoma and 34 had soft tissue sarcoma. Forty patients (95%) had previously been treated with one or more chemotherapeutic regimens. The overall response rate was 6.9% and the disease control rate was 55%. The median progression-free survival was 2.3 months and the median overall survival was 14.3 months. Grade 3 or more neutropenia and febrile neutropenia were observed in 74% and 4.8% of all patients, respectively.The response rate was lower and myelosuppression was more frequently observed than in other previous reports. On the other hand, most of toxicities were enough manageable. In addition, some patients had long survival with a good response. Our study supports the notion that gemcitabine and docetaxel therapy is a good therapeutic option for treating patients with advanced soft tissue sarcoma as well as bone sarcoma, also in Asian populations.

Some elderly cancer patients, even with good Eastern Cooperative Oncology Group performance status (ECOG-PS), have poor survival outcomes and cannot tolerate standard therapy. Few studies have detailed the associations between the G8 screening tool, ECOG-PS, and overall survival (OS) in such patients.Cancer patients, aged 70 years or older, were assessed for G8 and classified into three groups according to their G8 score: 14 as the high score group. We retrospectively analyzed the association between G8 score and OS in all patients and for each ECOG-PS-categorized group.Out of 264 enrolled patients, most patients (87%) with solid tumor were categorized as TNM stage IV. ECOG-PS was 0 or 1 in 215 patients and ≥2 in 48; there was missing data for one patient. Among all patients, the low score group with a median OS of 7.7 months survived significantly less than both the high score group with a median OS of 25.6 months [Hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.96-6.63; p < 0.0001] and the intermediate score group with a median of 15.6 months (HR 1.83; 95% CI, 1.28-2.65; p < 0.001). In the multivariate analysis, TNM stage and G8 score were independent prognostic factors for OS. When patients with an ECOG-PS of 0 or 1 were analyzed, patients with a lower G8 score showed significantly shorter OS than patients with a higher score when any two groups were compared.This novel classification of the G8 score contributes to prompt identification of patients with poor prognosis and improved the prognostic value of ECOG-PS. Using G8 with ECOG-PS may be helpful in deciding treatment for elderly patients with advanced cancer.

The requirement of central venous (CV) port implantation is increasing with the increase in the number of cancer patients and advancement in chemotherapy. In our division, medical oncologists have implanted all CV ports to save time and consultation costs to other departments. Recently, upper arm implantation has become the first choice as a safe and comfortable method in our unit. Here we report our experience and discuss the procedure and its potential advantages.All CV port implantations (n = 599) performed in our unit from January 2006 to December 2011 were analyzed. Procedural success and complication rates between subclavian and upper arm groups were compared.Both groups had similar patient characteristics. Upper arm CV port and subclavian implantations were equivalently successful and safe. Although we only retrospectively analyzed data from a single center, the upper arm group had a significantly lower overall postprocedural complication rate than the subclavian group. No pneumothorax risk, less risk of arterial puncture by ultrasound, feasibility of stopping potential arterial bleeding, and prevention of accidental arterial cannulation by targeting the characteristic solitary basilic vein were the identified advantages of upper arm CV port implantation. In addition to the aforementioned advantages, there is no risk of "pinch-off syndrome," possibly less patient fear of manipulation, no scars on the neck and chest, easier accessibility, and compatibility with the "peripherally inserted central catheter" technique.Upper arm implantation may benefit clinicians and patients with respect to safety and comfort. We also introduce our methods for upper arm CV port implantation with the videos.