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Global longitudinal strain (GLS) is an echocardiographic measure to detect chemotherapy-related cardiovascular dysfunction. However, its limited availability and the needed expertise may restrict its generalization. Artificial intelligence (AI)-based GLS might overcome these challenges. Our aims are to explore the agreements between AI-based GLS and conventional GLS, and to assess whether the agreements were influenced by expertise levels, cardiac remodeling and cardiovascular diseases/risks. Echocardiographic images in the apical four-chamber view of left ventricle were retrospectively analyzed based on AI-based GLS in patients treated with chemotherapy, and correlation between AI-based GLS (Caas Qardia, Pie Medical Imaging) and conventional GLS (Vivid E9/VividE95, GE Healthcare) were assessed. The agreement between unexperienced physicians ("GLS beginner") and experienced echocardiographer were also assessed. Among 94 patients (mean age 69 ± 12 years, 73% female), mean left ventricular ejection fraction was 64 ± 6%, 14% of patients had left ventricular hypertrophy, and 21% had left atrial enlargement. Mean GLS was - 15.9 ± 3.4% and - 19.0 ± 3.7% for the AI and conventional method, respectively. There was a moderate correlation between these methods (rho = 0.74; p < 0.01), and bias was - 3.1% (95% limits of agreement: -8.1 to 2.0). The reproducibility between GLS beginner and an experienced echocardiographer was numerically better in the AI method than the conventional method (inter-observer agreement = 0.82 vs. 0.68). The agreements were consistent across abnormal cardiac structure and function categories (p-for-interaction > 0.10). In patients treated with chemotherapy. AI-based GLS was moderately correlated with conventional GLS and provided a numerically better reproducibility compared with conventional GLS, regardless of different levels of expertise., (© 2024. The Author(s).)

Background: Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer., Methods: We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case-control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software., Results: Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (n = 2), hypnotherapy (n = 2), and yoga therapy (n = 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.49-0.72, p < 0.00001; vomiting: RR = 0.54, 95% CI = 0.32-0.91, p = 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported., Conclusions: Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Venetoclax is an oral B-cell lymphoma-2 protein inhibitor. It is a key drug for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, venetoclax is administered at a fixed dose, irrespective of body surface area or weight. Furthermore, the plasma concentration of venetoclax varies widely between individuals and is influenced by diet. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help to optimize treatment in clinical practice. In this study, we aimed to develop a simple method to determine venetoclax concentrations in plasma. The analysis required the extraction of a 50-μL plasma sample and precipitation of proteins using acetonitrile extraction. Venetoclax and the internal standard (12.5-μg/mL ibrutinib) were separated by high-performance liquid chromatography (HPLC). The calibration curve was linear over the plasma venetoclax concentration range 0.25-10 μg/mL with a coefficient of determination (r2) of 0.9999. The coefficients of intra-day and inter-day validation were 0.8-4.1% and 1.3-3.3%, respectively. The assay accuracy was -2.8 to 1.6%, and the recovery was >97.2%. These results demonstrate a very simple, novel and sensitive HPLC-UV-based method for determining the concentration of plasma venetoclax, and confirm its applicability to the TDM of venetoclax in a clinical setting., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration-resistant prostate cancer (CRPC) progression. The neuromediator, gastrin-releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin-releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis-targeted (ARAT) agents., Methods: One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first-line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate-specific antigen (PSA) response and survival estimates., Results: In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: -34.5% vs. low ProGRP: -85.7% p = .033). PSA progression-free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA-PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA-PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003)., Conclusions: Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA- and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

A 46-year-old man was diagnosed with chronic myeloid leukemia (CML) in chronic phase. He was treated with imatinib, nilotinib, and dasatinib, but failed to achieve a complete cytogenetic response (CCyR). After tyrosine kinase inhibitor therapy, F317L BCR-ABL1 kinase domain mutation was detected. At age 66, the patient started ponatinib (PON) at 45 mg/day, and achieved CCyR within three months. Subsequently, PON was tapered to 15 mg once weekly due to arterial-occlusive events. PON was discontinued after a 3-year deep molecular response (≥ MR 4.5 ). However, the patient lost MR 4.0 within two months, and PON (15 mg once weekly) was restarted. He achieved MR 4.0 again within one month, and then a deeper molecular response (MR 5.0 ) after starting dialysis therapy at the same PON dose. The trough value of PON (15 mg once weekly) was 5.8 ng/ml, which suppressed F317L mutation in the CML clone. Currently, the patient is 77 years old and is sustaining MR 5.0 . Chronic renal failure may cause hyperabsorption and metabolic retardation in patients receiving PON. Initiation of hemodialysis may improve homeostasis resulting in enhanced anti-tumor immunity against CML.

Objective The relationship between the prognosis and magnitude of a decrease in tumor blood flow according to estimated tumor differentiation remains unclear. This study investigated the relationship between reductions in the rate of mean computed tomography (CT) attenuation values and the clinical prognosis. Methods We evaluated 63 consecutive patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). The oncological aggressiveness of the tumors was estimated using classification by dynamic CT enhancement patterns. The utility of changes in mean CT attenuation values of intra-hepatic targets during treatment to estimate the prognosis was investigated by calculating the progression-free survival (PFS) and post-progression survival (PPS). A multivariate analysis was used to identify potential confounders for the survival after progression during lenvatinib therapy. Results The rate of decrease in the mean CT attenuation value gradually increased according to the degree of deterioration in estimated tumor differentiation, and the rate of a decrease in attenuation ≥40% showed a tendency to increase (p=0.064). This trend was reflected by a better objective response in oncological aggressiveness heterogeneous enhancement patterns (Type-3 and Type-4) than a homogeneous enhancement pattern (Type-2) (83% vs. 56% of modified Response Evaluation Criteria in Solid Tumors). This resulted in a similar PFS between the groups (p=0.773), whereas the PPS was significantly worse when the rate of decrease in the attenuation value was ≥40% (p=0.012). A multivariate analysis confirmed that a rate of decease in attenuation value ≥40% was a poor prognostic factor for the PPS (hazard ratio, 2.993; 95% confidence interval, 1.196-7.490; p=0.019). Conclusion A rate of decrease in attenuation ≥40% may reflect a good response of a highly malignant tumor to lenvatinib. Therefore, this value may have utility as a surrogate marker for estimating the oncological aggressiveness of tumors and their associated prognosis.

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP -deleted cancers. Here, we report the discovery of development candidate MRTX1719 . MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP -deleted cells compared to MTAP -wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP -deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2 H )-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719 .

Cisplatin (CDDP) is a well-known anticancer agent, and CDDP-induced nephrotoxicity (CIN) is one of the most serious adverse effects. Previously, we revealed that while celecoxib reduces CIN, diclofenac does not appear to enhance it. Furthermore, we reported that diclofenac additively enhances the cytotoxic effect of CDDP on CDDP-resistant A549 cells (A549/DDP cells) and their spheroids. In addition, celecoxib reduces the cytotoxic effect of CDDP on A549/DDP cells while demonstrating an anticancer effect; however, it enhanced the effect of CDDP cytotoxicity on spheroids. Therefore, we evaluated the effects of diclofenac or celecoxib on CIN and the antitumor effect of CDDP in a xenograft mouse model transplanted with A549/DDP cells. Although CDDP did not decrease tumor size and tumor weight, these parameters were significantly reduced following co-administration with diclofenac when compared with the control group. Conversely, celecoxib marginally suppressed the antitumor effect of CDDP. Moreover, CDDP increased the mRNA levels of kidney injury molecule 1 (Kim-1), a renal disorder marker, in the kidneys of xenograft mice; treatment with celecoxib and diclofenac did not impact Kim-1 mRNA levels increased by CDDP. In conclusion, diclofenac potentiated the antitumor effect of CDDP without enhancing CIN., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Purpose: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial., Methods: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated., Results: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%)., Conclusions: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS., (© 2021. Springer Nature Singapore Pte Ltd.)

Certain non-steroidal anti-inflammatory drugs (NSAIDs) are known to have anticancer effects. However, it is unclear whether all NSAIDs have anticancer effects, and thus far, very few studies have compared the antitumor effects among multiple NSAIDs. Therefore, we aimed to identify NSAIDs that enhance the anticancer effect of cisplatin (CDDP); the effects of 17 NSAIDs in lung cancer cells and their spheroids as cancer stem cells (CSCs) were evaluated. Some of the NSAIDs showed cytotoxic effects against A549 and SBC-3 cells and their CDDP-resistant cell lines (A549/DDP and SBC-3/DDP cells, respectively). In addition, co-addition of CDDP and celecoxib, which showed cytotoxic effects, increased the resistance to CDDP by increasing SLC7A11, which is one of the CDDP resistance mechanisms, in A549/DDP and SBC-3/DDP cells. On the other hand, celecoxib also showed antitumor effects on the spheroids of A549/DDP and SBC-3/DDP cells, and enhanced the antitumor effect of CDDP while increasing the mRNA levels of SLC7A11. Moreover, diclofenac was also cytotoxic and enhanced the cytotoxic effect of CDDP in cancer cells and CSCs. In conclusion, some NSAIDs including celecoxib and diclofenac may enhance the therapeutic efficacy of CDDP., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Japan. Prognosis is poor, and until recently sorafenib was the only treatment option available for patients with unresectable disease. Lenvatinib is the first therapy to demonstrate noninferiority to sorafenib. An analysis was conducted using clinical data from Japanese patients in the phase III REFLECT trial to assess the cost-effectiveness of lenvatinib versus sorafenib for first-line treatment of unresectable HCC in Japan., Methods: A partitioned survival model was implemented adopting the perspective of the Japanese healthcare system, with costs and outcomes modeled over a lifetime horizon and using a discount rate of 2%, as per Japanese guidelines. Population data from the Japanese subpopulation of REFLECT were used to extrapolate outcomes, and costs and resource use were based on Japanese sources. The Japanese tariff was applied to EQ-5D data collected during the REFLECT clinical trial to obtain utility values reflecting the preferences of the Japanese population., Results: Compared with sorafenib, lenvatinib is dominant because it is associated with a reduction in incremental costs of ¥156 799 and incremental quality-adjusted life-years of 0.31. These results were robust to changes in key assumptions, and probabilistic outcomes aligned with deterministic outcomes., Conclusion: Given the use of Japan-specific data in the cost-effectiveness model, it is expected that the use of lenvatinib as a first-line treatment in Japan will be associated with cost savings and improved clinical outcomes versus sorafenib for patients with unresectable HCC., (Copyright © 2020. Published by Elsevier Inc.)

Background: The sensitivity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in hepatocellular carcinoma (HCC) is low; however, clinical evidence demonstrating its prognostic value in patients with HCC has recently been reported. This study aimed to assess the value of 18F-FDG-PET/CT as a tool for evaluating the response of HCC to lenvatinib treatment., Methods: We evaluated 11 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18F-FDG-PET/CT from April 2018 to December 2019. The tumor-to-normal liver ratio (TLR) of the target tumor was measured before and during the course of lenvatinib treatment with 18F-FDG-PET/CT (pre and post analysis, respectively), with a TLR ≥2 classified as PET-positive HCC. At the time of each evaluation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the modified RECIST (mRECIST), and the tumor marker alfa-fetoprotein (AFP)., Results: Of 11 patients, 3 (27%) and 8 (73%) had an objective response to lenvatinib treatment at the time of post-analysis by RECIST 1.1 and mRECIST, respectively. There were 3 (27%) and 7 (64%) patients with PET-positive HCC at the time of pre- and post-analysis, respectively. There was a significant correlation between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019). Based on these results, we were able to perform liver resection on 4 patients with PET-positive HCC as conversion therapy. Three samples from these patients showed poorly differentiated tumors., Conclusion: 18F-FDG-PET/CT has potential as an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality may provide useful information for considering prognosis and subsequent therapy., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Background and Aim: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of overall prognosis in patients with hepatocellular carcinoma treated with lenvatinib., Methods: Forty-eight consecutive patients who received lenvatinib treatment were reviewed. The oncological aggressiveness of tumors estimated using 18F-FDG-PET/CT was investigated by the analysis of progression-free survival (PFS), post-progression survival (PPS), and overall survival (OS). Multivariate analysis was used to identify potential confounders for OS during lenvatinib therapy., Results: Using the Modified Response Evaluation Criteria in Solid Tumors, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with a better objective response to lenvatinib than a TLR <2 (78 vs. 62%), resulting in a similar PFS (p = 0.751). Because of a significantly worse PPS, OS with a TLR ≥2 was poor compared to a TLR < 2 (p = 0.012). Multivariate analysis confirmed that a TLR ≥ 2 was associated with poor OS (hazard ratio, 2.709; 95% CI, 1.140-6.436; p = 0.024). Analysis of 24 patients who received a repeat 18F-FDG-PET/CT showed that daily changes expressed as ΔTLR × 103/day over the treatment course tended to be different among the types of subsequent treatment. A R0 resection and lenvatinib-TACE sequential therapy provided good disease control (median, -4.593 and -0.024, respectively) compared with other treatments (median, 5.278) (p = 0.075)., Conclusion: Lenvatinib has acceptable disease control regardless of estimated tumor differentiation. A high TLR (≥2) is a poor prognostic factor of OS following lenvatinib treatment, while ΔTLR × 103/day provides useful information of disease control status., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, will be used in combination first-line therapies against metastatic renal cell carcinoma (mRCC), but its effects as a first-line monotherapy are unclear. Thus, we aimed to elucidate pretreatment clinical factors that predict the prognosis of patients with mRCC receiving first-line axitinib therapy. We enrolled 63 patients with mRCC treated with axitinib as first-line therapy between Nov. 2003 and Jul. 2018. Progression-free survival (PFS) and overall survival (OS) were assessed using the Wald χ 2 statistic in Cox proportional hazards regression. Median patient age was 67 (range: 25-85) years. Seven (11.1%) patients were classified as being at favorable risk, 33 (52.4%) at intermediate risk, and 23 (36.5%) at poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification system. Median follow-up duration after axitinib initiation was 14 (range: 1-72) months. Median PFS and OS were 18 months and 65 months, respectively. Cox regression analyses of clinical predictors revealed that high C-reactive protein (CRP) levels were significantly correlated with shorter PFS [hazard ratio (HR), 1.63; 95% confidence interval (CI) 1.7-4.0)], whereas spindle cells and poor IMDC risk scores were related to worse OS (HR, 2.87 and 2.88, respectively; 95% CI 1.4-11.0 and 1.1-8.5, respectively). Thus, patients with mRCC and spindle histology or poor IMDC risk scores had worse OS, and those with high CRP levels had shorter PFS in first-line axitinib treatment. Other therapies might be more suitable for initial management of such patients.

Cisplatin (CDDP) is a highly potent and important anticancer drug in lung cancer treatment. Long-term use of an anticancer agent causes resistance in cancer cells, and CDDP resistance involves multiple mechanisms. As the mechanism of resistance development differs depending on the cancer cell types, we aimed to evaluate the detailed mechanism of resistance to CDDP in two types of lung cancer cells: SBC-3 and A549 cells. The CDDP-resistant SBC-3/DDP and A549/DDP cells were established through continuous treatment with a gradually increasing dose of CDDP. The viability of SBC-3/DDP and A549/DDP cells treated with CDDP was 3.68 and 2.08 times higher than that of the respective parental cells. Moreover, SBC-3/DDP cells showed significantly increased cystine/glutamate transporter (xCT) mRNA level, and A549/DDP cells showed markedly increased sex determining region Y-box 2 (SOX2) mRNA level. Moreover, the uptake of cystine, a substrate of xCT, was higher in SBC-3/DDP cells than in SBC-3 cells, and cystine uptake in A549/DDP cells was not different from that in A549 cells. In addition, co-treatment with CDDP and sulfasalazine, an xCT inhibitor, showed lower the concentration of 50% inhibition for cell viability than CDDP alone in SBC-3 and SBC-3/DDP cells, but not in A549 and A549/DDP cells. Furthermore, SBC-3 cells transiently overexpressing xCT were resistant to CDDP, and xCT knockdown in A549/DDP cells did not significantly change the level of SOX2 mRNA and viability of cells upon CDDP treatment. In conclusion, the two lung cancer cell lines showed different mechanisms of resistance to CDDP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported., Methods: The intent-to-treat population enrolled in Japan was analyzed., Results: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm., Conclusions: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC., Trial Registration Id: ClinicalTrials.gov. No. NCT01761266.

Ketone bodies, including acetoacetate and β-hydroxybutyrate (βOHB), are produced from acetyl coenzyme A in the liver and then secreted into the blood. These molecules are a source of energy for peripheral tissues during exercise or fasting. βOHB has been reported to inhibit histone deacetylases (HDACs) 1, 3, and 4 in human embryonic kidney 293 cells. Thus, βOHB may regulate epigenetics by modulating HDACs. There have been several reports that the administration of βOHB or induction of a physiological state of ketosis has an antitumor effect; however, the mechanism remains unclear. The aim of this study was to investigate whether βOHB enhances cisplatin-induced apoptosis in hepatocellular carcinoma (HCC) cells by modulating activity and/or expression of HDACs. We found that βOHB significantly enhanced cisplatin-induced apoptosis and cleavage of caspase-3 and -8 in HCC cells. Further, βOHB significantly decreased the expression of HDCA 3/5/6 and survivin in liver hepatocellular (HepG2) cells. In HDAC3/6 gene silencing, survivin expression was significantly decreased, and cisplatin-induced cleavage of caspase-3 was significantly enhanced compared with control in HepG2 cells. In conclusion, βOHB enhanced cisplatin-induced apoptosis via HDAC3/6 inhibition/survivin axis in HepG2 cells, which suggests that βOHB could be a new adjuvant agent for cisplatin chemotherapy., (Copyright © 2019. Production and hosting by Elsevier B.V.)

Background/aim: Chemotherapy with docetaxel (DTX) is used for castration-resistant prostate cancer (CRPC), but it is inadequate., Materials and Methods: We evaluated the effect of the combination treatment DTX and the mTOR inhibitor temsirolimus (TEM) in the PC3 prostate cancer cell line, by focusing on the induction of autophagy and apoptosis., Results: TEM induced autophagy but not apoptosis even at a high dose, whereas DTX induced apoptosis. The combination of low-dose DTX and TEM caused a 34% suppression in cell proliferation compared to monotherapy with a higher dose of DTX. The induction of apoptosis was increased by their combination. The combination with DTX overcame the induction of autophagy by TEM. The combination treatment suppressed tumor growth 72% less than the control group after 14 days of treatment in vivo., Conclusion: The combination of TEM and DTX induced apoptosis by overcoming autophagy and enhanced the anticancer effect compared to monotherapy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Reduced-intensity conditioning is widely used with hematopoietic stem cell transplantation for non-malignant diseases: however, the optimal conditioning to ensure stable engraftment has not been established. In this study, we retrospectively compared the impact of low-dose (1-6 Gy) irradiation and in vivo T-cell depletion on the clinical outcome of 523 patients with non-malignant disease who underwent a first allogeneic hematopoietic stem cell transplantation using fludarabine-based reduced-intensity conditioning. Use of low-dose irradiation, but not of anti-thymocyte globulin/anti-lymphocyte globulin, showed a beneficial effect on overall survival (adjusted hazard ratio: 0.56; 95% confidence interval: 0.35-0.91, P = 0.018). Furthermore, use of low-dose irradiation was strongly associated with lower transplant-related mortality (adjusted hazard ratio: 0.55; 95% confidence interval: 0.32-0.96, P = 0.034). The addition of low-dose irradiation to the conditioning regimen was beneficial, at least to the short-term clinical outcome. A large prospective study with long-term follow-up is now required to extend these findings and establish the optimal hematopoietic stem cell transplant conditioning for patients with at least some subgroups of non-malignant diseases.

Background: This study was performed to evaluate the relationships between potential prognostic factors and post-surgery survival in patients with colorectal cancer liver metastasis (CRLM). In particular, this study investigated the value of neoadjuvant chemotherapy as an independent predictor of cancer-specific survival., Methods: The study participants included 147 patients who underwent resection for CRLM. Demographics, treatments, and relationships between potential prognostic factors and the survival rate were analyzed using a prospective database., Results: The overall 1-, 3- and 5-year cancer-specific survival rates for post-surgery CRLM patients were 94.3%, 71.2%, and 53.5%, respectively. Multivariate analysis revealed that a positive surgical margin and extrahepatic metastasis were independent negative prognostic factors. The administration of neoadjuvant chemotherapy prior to liver surgery did not significantly improve post-surgery outcomes of patients with CRLM. In a subgroup analysis, the time to recurrence in the remnant liver after hepatectomy for CRLM was significantly less in the neoadjuvant group than in the upfront surgery group., Conclusions: Neoadjuvant chemotherapy was not predictive of cancer-specific survival. The achievement of macroscopically and microscopically negative resection remains the main aim of surgery.

Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. The marine spongean sesquiterpene phenols dictyoceratin-A ( 1 ) and -C ( 2 ) have been shown to induce hypoxia-selective growth inhibition in cultured cancer cells and exhibit in vivo antitumor effects. These compounds inhibit the accumulation of hypoxia-inducible factor-1α (HIF-1α), which is a drug target in hypoxia-adapted cancer cells, under hypoxic conditions. However, the target molecules of compounds 1 and 2 , which are responsible for decreasing HIF-1α expression under hypoxic conditions, remain unclear. In this study, we synthesized probe molecules for compounds 1 and 2 to identify their target molecules and found that both compounds bind to RNA polymerase II-associated protein 3 (RPAP3), which is a component of the R2TP/Prefoldin-like (PEDL) complex. In addition, RPAP3-knockdown cells showed a phenotype similar to that of compound-treated cells., Competing Interests: The authors declare no conflict of interest.

The tumor microenvironment is considered as one of the important targets for anticancer drug discovery. In particular, nutrient deficiency may be observed in tumor microenvironment; biakamides A-D (1-4) isolated from marine sponge Petrosaspongia sp. as growth inhibitors against cancer cells adapted to glucose-deprived conditions have potential as new drugs and tools for elucidating adaptation mechanisms to these conditions. In this paper, we investigated structure-activity relationship (SAR) of biakamide to create easily accessible analog and gain insights about participation of the substructures to growth-inhibitory activity toward development of anticancer drug. This work revealed that 14,15-dinor-biakamide C (5), which is easily accessible, has similar activity to natural biakamide C (3). In addition, detailed SAR study showed the terminal acyl chain is important for interacting with target molecule and amide part including thiazole ring has acceptability to convert structures without losing activity.

Background: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, leucovorin) treatment significantly improved overall survival in the recent phase III study and became a standard therapy for metastatic pancreatic cancer. However, treatment for locally advanced pancreatic cancer is still controversial. We conducted subset analyses from a nation-wide multicenter observational study in Japan to evaluate the tolerability and efficacy of FOLFIRINOX in patients with locally advanced pancreatic cancer and to investigate independent prognostic factors with pre-treatment variables., Methods: The study included 66 patients with unresectable locally advanced pancreatic cancer from 27 institutions in Japan who received FOLFIRINOX as first-line treatment between December 20, 2013 and December 19, 2014 and surveyed until December 2015., Results: The median age was 63 with the Eastern Cooperative Oncology Group performance status of 0 or 1. Major Grade 3 or 4 adverse events included neutropenia (64%), leukopenia (33%), febrile neutropenia (15%), and diarrhea (15%). Severe adverse event occurred in 14 patients (11%) without fatal event. The median overall survival and progression-free survival times were 18.5 and 7.6 months, respectively. The objective response rate 15.2% and the disease control rate was 81.9%. A high modified Glasgow prognostic score (mGPS, ≥1) (95%CI 1.96-12.5) and female (95%CI 0.20-0.97) were identified as independent poor prognostic factors., Conclusions: First-line FOLFIRINOX treatment for locally advanced pancreatic cancer seems to be effective with acceptable toxicities. A high mGPS may be associated with poor survival in patients with locally advanced pancreatic cancer who receive FOLFIRINOX. This study was registered at the UMIN Clinical Trials Registry (UMIN000014658)., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most common brain tumor; however, no effective treatment for it is available yet. Monocarboxylate transporters, which are highly expressed in GBM, play a role in transporting antitumor agents, such as 3-bromopyruvate (3-BrPA). Valproate, primarily used to treat epilepsy, has been considered a possible treatment option for malignant GBM. In this study, we aimed to investigate the combined effects of 3-BrPA and valproate on GBM cell growth and elucidate the underlying mechanisms. Valproate enhanced 3-BrPA-induced cell death in T98G cells, used as a GBM model. Multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) mRNA levels significantly increased after valproate treatment. 3-BrPA-induced cell death, which was enhanced by valproate, was inhibited in the presence of MK571, a MRP inhibitor, or Ko143, a BCRP inhibitor. In addition, treatment with 3-BrPA and valproate for 48 h reduced cellular ATP levels compared to those in the 3-BrPA alone treatment group. However, cellular ATP levels were recovered in the presence of MK571 or Ko143, compared to those in the 3-BrPA and valproate treatment groups. In conclusion, we suggested that valproate enhanced 3-BrPA-induced cell death. This might be attributable to the increase in cellular ATP consumption owing to valproate-induced MRP2 or BCRP expression., (Copyright © 2018. Published by Elsevier B.V.)

Background/aim: MK615 extracted from Prunus mume was reported to have anti-inflammatory effects. In this article, we examined the in vivo antitumor effect of MK615 (an extract from Japanese apricot) using mouse tumor xenografts and focusing on the downregulation of PD-L1 (programmed death-ligand 1), a ligand of programmed cell death-1, a surface protein of activated T cells., Materials and Methods: B16/BL6 melanoma cells were injected into C57BL/6 or BALB/c-nu/nu mice to establish lung metastasis. BALB/c-nu/nu mice (nude mice) were used as a T cell-deficient model. The mice were given MK615 or saline orally every other day for approximately 8 weeks, and their survival was observed. NF-κB (nuclear factor-κB) and PD-L1 expressions of metastatic lung tissues were also examined., Results: The survival rate was improved only in the MK615-treated C57BL/6 mice ( P < .05), not in the saline-given control mice or BALB/c-nu/nu mice. The downregulations of NF-κB and PD-L1 were observed in both MK615-treated C57BL/6 and BALB/c-nu/nu mice. These results suggest that the antitumor effects of MK615 are associated with T cell-mediated immunity activated by MK-615-induced PD-L1 downregulation in tumor cells., Conclusion: MK615 is beneficial for a prolonged host survival time in the B16/BL6 melanoma xenograft model associated with T cell-mediated antitumor immunity.

Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic tumor. Previously, the kinase inhibitor dasatinib was shown to have potent growth inhibitory activity against HS cells in vitro, possibly via targeting the EPHA2 receptor. Here, the in vivo effect of dasatinib in HS cells was investigated using a xenograft mouse model. Moreover, the expression status of EPHA2 was examined in six HS cell lines, ranging from insensitive to highly sensitive to dasatinib. In the HS xenograft mouse model, dasatinib significantly suppressed tumor growth, as illustrated by a decrease in mitotic and Ki67 indices and an increase in apoptotic index in tumor tissues. On Western blot analysis, EPHA2 was only weakly detected in all HS cell lines, regardless of sensitivity to dasatinib. Dasatinib likely results in the inhibition of xenograft tumor growth via a mechanism other than targeting EPHA2. The findings of this study suggest that dasatinib is a targeted therapy drug worthy of further exploration for the treatment of canine HS., (© 2017 John Wiley & Sons Ltd.)

A 51-year-old man with chronic myeloid leukemia undergoing treatment with dasatinib received colonoscopy for a positive fecal occult blood test. Colonoscopy revealed more than 100 erythematous, multilobulated polyps with mucoid discharge. Endoscopic mucosal resection was performed for diagnosis, and the histological analysis of polyps showed hyperplastic glands and proliferative smooth muscle cells. Our findings suggested that the polyposis was caused by inflammation triggered due to the adverse effects associated with dasatinib. The patient discontinued dasatinib;the follow-up colonoscopy performed four months later revealed significantly improved polypoid lesions in the colon. The erythematous heads of the polyps and mucoid discharge disappeared. The cessation of dasatinib seemed to contribute to the improvement of inflammatory reactive polyposis;therefore, we inferred that the polyposis was caused by dasatinib in the present case.

Purpose: Pretreatment with magnesium (Mg) has been reported to attenuate cisplatin (CDDP)-induced nephrotoxicity (CIN). This attenuation involves modulation of the expression of renal transporters, resulting in reduced renal platinum accumulation after a single round of CDDP treatment. In this study, we investigated whether Mg co-administration ameliorates CIN after multiple doses of CDDP as effectively as after a single dose., Methods: Rats were divided into control, Mg alone, CDDP alone, and CDDP with Mg groups. Rats received CDDP (2.5mg/kg), MgSO 4 (40mg/kg), or saline once per week for three weeks. Seven days after the third round of treatment, the kidneys were excised, and the expression of renal transporters and renal platinum accumulation were analyzed., Results: CDDP significantly elevated serum creatinine levels, which were significantly reduced by Mg co-administration. Renal platinum accumulation was significantly lower in the CDDP-Mg group than in the CDDP group. Expression of renal organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1), which are involved in CDDP transport, did not differ between the groups. However, the expression of copper transporter 1 (rCtr1) was significantly downregulated after Mg co-administration., Conclusion: Mg co-administration significantly attenuated CIN by reducing renal platinum accumulation even after multiple rounds of treatment with CDDP as effectively as in a model of a single CDDP administration. However, the specific underlying mechanism was different between single and multiple administrations, further studies will be needed to identify what contributes to this difference and to elucidate how Mg regulates the expression of renal transporters., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A 77-year-old man with castration-resistant prostate cancer (CRPC) received abiraterone acetate in October 2014. He visited our outpatient clinic because of general malaise and anorexia 27 days after starting abiraterone acetate. The lab test showed hepatic dysfunction (aspartate transaminase, AST 440 U/l, alanine transaminase, ALT 420 U/l) and the elevation of liver enzymes continued on the next day even after stopping abiraterone acetate. Three days later, he was hospitalized due to severe elevation of liver enzymes (AST 1,171 U/l, ALT 1,487 U/l) , and the decreased prothrombin activity (60.5%). The result of the lab test were negative for viral and autoimmune hepatitis. Three days after admission, he entered hepatic coma (grade III) and prothrombin activity decreased (23.2%) , compatible with fulminant hepatitis. Plasma exchange and steroid pulse therapy were started the next day, but he died 39 days after starting abiraterone acetate. In addition, the result of drug-induced lymphocyte stimulation test performed 3 days before his death was possibly positive.

The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day -5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n = 9), muscle spasms (n = 5), alopecia, decreased appetite (n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea (n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Imatinib-resistance is a major therapeutic problem in human chronic myeloid leukemia, human gastrointestinal stromal tumors, and canine mast cell tumors. In the present study, we identified the secondary mutation c.2006C>T in c-KIT exon 14 in a mast cell tumor obtained from a dog carrying c.1663-1671del in exon 11 and showing resistance to imatinib. The mutation in exon 14 resulted in substitution of threonine with isoleucine at position 669, which was located at the center of the ATP binding site as a gatekeeper and played an important role in binding to imatinib. Transfectants were constructed to survey the functions of these mutations in exons 11 and 14. The transfectant with mutant KIT encoded by c-KIT carrying c.1663-1671del showed constitutive ligand-independent phosphorylation that was suppressed by imatinib, indicating a gain-of-function mutation. Furthermore, the transfectant with mutant KIT encoded by c-KIT carrying both c.1663-1671del and c.2006C>T caused ligand-independent phosphorylation, which was not suppressed by imatinib. From these results, we concluded that the mutation c.2006C>T in c-KIT exon 14 was an imatinib-resistance mutation in a canine mast cell tumor. These findings revealed, for the first time, a mechanism of imatinib resistance in a clinical case of canine mast cell tumor., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Chemotherapy is an indispensable therapeutic approach for colorectal cancer both in the adjuvant and metastatic setting. Although chemotherapy-induced nausea and vomiting (CINV) is one of the most crucial adverse events, many aspects of CINV in patients with colorectal cancer remain unclear., Methods: This multicenter, prospective, observational study analyzed the data of 190 colorectal cancer patients scheduled for moderately emetogenic chemotherapy (MEC). The patients recorded the incidence of CINV and severity of nausea by visual analogue scales daily for 7 days after receiving chemotherapy., Results: All 190 patients received MEC and 99% of patients received antiemetic therapy in compliance with guidelines. Acute CINV was well controlled. 13 (6.8%) patients suffered from acute nausea and 4 (2.1%) experienced acute vomiting, whereas the prevalence of delayed CINV was relatively high. Delayed nausea occurred in 71 (37.4%) patients and delayed vomiting in 24 (12.6%). History of motion sickness was a significant independent risk factor for delayed nausea (Odd ratio 3.89, 95% confidence interval 1.49-10.19, p = 0.0056)., Conclusions: The compliance with CINV guidelines in colorectal cancer chemotherapy was quite high and led to good control of chemotherapy-induced vomiting in Japan. However, the incidence of delayed nausea remained high in patients receiving MEC.

Biakamides A-D, novel unusually unique polyketides, were isolated from an Indonesian marine sponge (Petrosaspongia sp.) with a constructed bioassay using PANC-1 human pancreatic cancer cells. Through detailed analyses of the one- and two-dimensional NMR spectra of biakamides, planar chemical structures possessing a terminal thiazole, two N-methyl amides, a chloromethylene, and a substituted butyryl moiety were obtained. After elucidation of the configuration of the secondary alcohol moiety in biakamides A and B, the absolute stereostructures of the two secondary methyl groups in biakamides A-D were determined by the asymmetric total syntheses of all possible stereoisomers from the optically pure monoprotected 2,4-dimethyl-1,5-diol. Biakamides A-D showed selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions in a concentration-dependent manner. The primary mode of action of biakamides was found to be inhibition of complex I in the mitochondrial electron transport chain.

Canine malignant melanoma (CMM) is a highly aggressive and fatal neoplasm. To identify potential therapeutic compounds and/or targets, 320 compounds were screened for their growth inhibitory activity in a CMM line (CMM-1) using a chemical library known to target specific signaling pathways/cell growth-related molecules. Among the compounds screened, the F1Fo ATPase inhibitor oligomycin showed potent growth inhibitory effects in CMM-1 cells, while exhibiting less toxic effects in a non-neoplastic control cell line (MDCK cells). The growth inhibitory effect of oligomycin A was then examined using six CMM lines and MDCK cells. Three CMM lines were highly sensitive to oligomycin A, with around 3000-20 000 times lower IC 50 compared with oligomycin A-resistant CMM lines and MDCK cells. Oligomycin A-sensitive CMM-1 cells exhibited much greater oligomycin A-induced decreases in cellular ATP compared to oligomycin A-resistant cell lines. Although the oligomycins are clinically unsuitable because of its in vivo toxicity, these findings implicate the potential of F1Fo ATPase as a therapeutic target in a subset of CMM., (© 2016 John Wiley & Sons Ltd.)

Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (Vα24 + iNKT) cells, which have been shown to act as cellular adjuvants and thus exert anti-tumor activity in mice and humans, and to re-differentiate the iNKT cell-derived iPSCs into functional iNKT cells. These iPSC-derived iNKT cells (iPS-Vα24 + iNKT cells) can be activated by ligand-pulsed dendritic cells (DCs) and produce a large amount of interferon-γ upon activation, as much as parental Vα24 + iNKT cells, but exhibit even better cytotoxic activity against various tumor cell lines. The iPS-Vα24 + iNKT cells possess significant anti-tumor activity in tumor-bearing mice and can activate autologous NK cells upon activation by ligand-pulsed DCs in the NOG mouse model in vivo, further extending their therapeutic potential. This study thus provides a first proof of concept for the clinical application of human iPS-Vα24 + iNKT cells for cancer immunotherapy. Stem Cells 2016;34:2852-2860., (© 2016 AlphaMed Press.)

Background: The aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen., Methods: The patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000 mg/m(2)) twice daily on days 1-14 and oxaliplatin (130 mg/m(2)) on day 1 every 21 days (Q3W group) or capecitabine (2,000 mg/m(2)) twice daily on days 1-7 and oxaliplatin (85 mg/m(2)) on day 1 every 14 days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs)., Results: A total of 46 patients were enrolled in the trial-22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4 months in both groups (hazard ratio [HR] 1.053; p = 0.880). The median PFS and OS were 3.3 and 9.2 months in the Q2W group and 4.3 and 12.1 months in the Q3W group, respectively (HR 1.15; p = 0.153 and 0.672; p = 0.836). The most common grade 3-4 AEs in the Q3W and Q2W groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively., Conclusion: There was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative.

Herein we report on a case of synchronous large gastrointestinal stromal tumor (GIST) and adenocarcinoma of the stomach treated with radical surgery following neoadjuvant therapy with imatinib mesylate. A 58-year-old man was referred to our hospital with a large mass in the peritoneal cavity. Abdominal computed tomography showed a large mass measuring 21×20×14 cm in the left upper peritoneal cavity. Esophagogastroduodenoscopy revealed a large elevated lesion in the upper body and a depressed lesion in the lower gastric body near the lesser curvature. Biopsy specimens revealed GIST in the large elevated lesion and signet-ring cell carcinoma in the depressed lesion. Because of the large size of the GIST, the patient was treated with neoadjuvant therapy with imatinib mesylate (400 mg/day) for 5 months. After confirmation of a marked decrease in tumor size following imatinib mesylate therapy, the patient underwent total gastrectomy and regional lymph-node dissection with distal pancreatectomy and splenectomy. Pathological examination confirmed the diagnosis of high-risk GIST and signet-ring cell carcinoma invading the muscularis propria with one lymph-node metastasis. At the time of writing, the patient was receiving postoperative chemotherapy using oral fluoropyrimidine (S-1) without evidence of disease recurrence for 4 months after surgery. In addition to the present case, we provide a retrospective review of another 15 patients who were diagnosed with synchronous GIST in the stomach and primary gastric adenocarcinoma., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Attention must be paid to chemotherapy for cancer patients in a hyperglycemia state. It is difficult for chemotherapy to cure cancer in patients in a hyperglycemia state. This study was carried out to determine the change in cell viability after treatment with bromopyruvate, which is an alkylating drug with anti-tumor activity, in a high glucose condition., Methods: The function of l-lactate and bromopyruvate transport was studied using human colon cancer cell lines (LoVo and HT-29) and radiolabeled l-lactate and bromopyruvate. Cell viability was monitored by the trypan blue exclusion assay. The expression level of human monocarboxylate transporter 1 (hMCT1) was evaluated by Western blot analysis., Results: Bromopyruvate-induced cell death was suppressed by a high glucose condition. l-Lactate and bromopyruvate uptake were suppressed by a high glucose condition. hMCT1 as a bromopyruvate carrier was functionally expressed in the cells. However, the expression of hMCT1 was suppressed by a high glucose state., Conclusions: Down-regulation of hMCT1 by a high glucose state is one of the possibilities of the bromopyruvate resistance. We should pay scrupulous attention to cancer chemotherapy for patients who have developed diabetes., (Copyright © 2015. Published by Elsevier Ltd.)

In the course of searching for selective growth inhibitors of the cancer cells adapted to nutrient starvation, a new 3-alkylpyridine alkaloid named N-methylniphatyne A (1) was isolated from an Indonesian marine sponge of Xestospongia sp. The chemical structure of 1 was determined on the basis of the spectroscopic analysis and comparison with the synthesized 1 and its analogues. Compound 1 showed the cytotoxic activity against PANC-1 cells under the condition of glucose starvation with IC50 value of 16 µM, whereas no growth-inhibition was observed up to 100 µM under the general culture conditions.

Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure-activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.

Although imatinib has therapeutic activity for certain subsets of patients with mastocytosis, it is not always curative. Here, molecular mechanisms that confer imatinib resistance to neoplastic mast cells were investigated using an imatinib-sensitive canine neoplastic mast cell line VI-MC carrying a KIT c.1523A>T activating mutation. Two imatinib-resistant sublines were established by culturing VI-MC cells in increasing concentrations of imatinib (1 μM resistant, rVI-MC1; 10 μM resistant, rVI-MC10). Both sublines had a second KIT mutation c.2443G>C. Recombinant KIT with the second mutation was insensitive to 1 μM but sensitive to 10 μM imatinib. The effect of imatinib on the phosphorylation of KIT and its downstream signalling proteins was then examined using these sublines. KIT and ERK were constitutively phosphorylated in both sublines, and their phosphorylation was suppressed by 10 μM imatinib in rVI-MC1 cells. However, KIT but not ERK phosphorylation was suppressed in rVI-MC10 cells. The phosphorylation of ERK in rVI-MC10 cells was also not diminished by the Src family kinase (SFK) inhibitor dasatinib. This second mutation in KIT may play an important role in imatinib resistance in neoplastic mast cells. Furthermore, KIT/SFK-independent activation of ERK would be involved in imatinib resistance when the neoplastic cells are exposed to higher concentrations of imatinib., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Surgical procedure for malignant pleural mesothelioma (MPM) remains controversial. We reviewed our protocol including pleurectomy/decortication (P/D) for patients with malignant pleural mesothelioma who were intolerable to extrapleural pneumonectomy (EPP)., Patients and Methods: From June 2010 to April 2014, 14 patients with MPM were intended to treat with multimodality therapy including surgery. Four patients who were intolerable to EPP received a protocol consisting of P/D and intraoperative intrapleural hyperthermic cisplatin perfusion, followed by systemic chemotherapy. Ten patients received trimodality treatment of EPP, systemic chemotherapy, and intensity modulated radiation therapy for hemithorax. Surgical outcomes of acute operative results and interim survivals were examined and compared between the groups., Results: All patients obtained macroscopic complete resection and received multimodality treatment in P/D and EPP groups. Operation time was longer in P/D group; however, there were no differences in ICU stays or hospitalizations. Four patients in P/D group and seven patients in EPP group experienced postoperative complications; however, there was no operative morality. EPP group suffered from cardiac complications and P/D group had prolonged airleak. Full walk recovery was obtained earlier in P/D group. One patient in P/D group had a local recurrence 11 months after surgery, while the other three patients survived 23-41 months with no evidence of diseases., Conclusions: P/D and intraoperative intrapleural cisplatin perfusion achieved a favorable macroscopic resection in patients with MPM who were intolerable to EPP. Postoperative complications were manageable and survival could be promising. Further study warrants with a larger number of patients.

Esophageal carcinoma is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths, with one of the worst prognoses of any form of cancer. Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. This study therefore evaluated the effects of metformin on the proliferation, in vitro and in vivo, of human esophageal adenocarcinoma cells, as well as the microRNAs associated with the antitumor effects of metformin. Metformin inhibited the proliferation of the esophageal adenocarcinoma cell lines OE19, OE33, SK-GT4 and OACM 5.1C, blocking the G0 to G1 transition in the cell cycle. This was accompanied by strong reductions in G1 cyclins, especially cyclin D1, cyclin-dependent kinase (Cdk)4, and Cdk6, and decreases in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor and insulin-like growth factor-1 receptor, as well as angiogenesis-related proteins, such as vascular endothelial growth factor, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2. Metformin also markedly altered microRNA expression. Treatment with metformin of athymic nude mice bearing xenograft tumors reduced tumor proliferation. These findings suggest that metformin may have clinical use in the treatment of esophageal adenocarcinoma.

We report the adverse events and efficacy of traditional (4 weeks on 2 weeks off) and alternative sunitinib treatment schedules for Japanese patients with metastatic renal cell carcinoma. We retrospectively investigated 54 patients who received sunitinib for metastatic renal cell carcinoma between May 2006 and June 2012: 32 received a traditional treatment schedule and 22 received an alternative schedule. According to the Memorial Sloan-Kettering Cancer Center risk classification, five patients had favorable prognoses, 42 had intermediate prognoses and seven had poor prognoses. The mean observation periods were 16.3 and 20 months for the traditional and alternative schedule groups, respectively. Adverse events were significantly less common in the alternative schedule group, including most high-grade events. In the traditional and alternative schedule groups, median times to failure were 4.1 and 11.6 months (P = 0.040), median progression-free survival times were 4.1 and 11.3  months (P = 0.031), and median overall survival times were 12.0 and 32.1 months (P = 0.018), respectively. Each of these measures was better in the group of patients who received an alternative treatment schedule, suggesting that individualized changes to the sunitinib administration schedule can be effective., (© 2014 The Japanese Urological Association.)