Melatonin Synergizes with Sorafenib to Suppress Pancreatic Cancer via Melatonin Receptor and PDGFR-ß/STAT3 Pathway.

BACKGROUND/AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors with poor prognosis. Conventional chemotherapies including gemcitabine have failed owing to weak response and side effects. Hence novel treatment regimens are urgently needed to improve the therapeutic efficacy. In this study, we aimed to assess the anticancer activity of melatonin and sorafenib as a novel therapy against PDAC. METHODS: We used various apoptosis assay and PDAC xenograft model to assess anticancer effect in vitro and in vivo. We applied phospho-receptor tyrosine kinase (RTK) array and phospho-tyrosine kinase array to explore the mechanism of the combined therapy. Western blotting, proximity ligation assay, and immunoprecipitation assay were also performed for validation. RESULTS: Melatonin synergized with sorafenib to suppress the growth of PDAC both in vitro and in vivo. The effect was due to increased apoptosis rate of PDAC cells that was accompanied by mitochondria dysfunction. The enhanced anticancer efficacy by the co-treatment could be explained by blockade of PDGFR-ß/STAT3 signaling pathway and melatonin receptor (MT)-mediated STAT3. CONCLUSIONS: Melatonin reinforces the anticancer activity of sorafenib by downregulation of PDGFR-ß/STAT3 signaling pathway and melatonin receptor (MT)-mediated STAT3. The combination of the two agents might be a potential therapeutic strategy for treating PDAC.

Prognostic Value of the Pretreatment Advanced Lung Cancer Inflammation Index (ALI) in Diffuse Large B Cell Lymphoma Patients Treated with R-CHOP Chemotherapy.

BACKGROUND: The Advanced Lung Cancer Inflammation Index (ALI, body mass index × albumin/neutrophil-to-lymphocyte ratio) has been demonstrated to be a prognostic factor of survival in some solid cancers. We retrospectively investigated the usefulness of the ALI to predict chemotherapy response and survival in 212 patients with diffuse large B cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. METHODS: Patients were allocated to a low ALI group (n = 82, 38.7%) or a high ALI group (n = 130, 61.3%) according to an optimal pretreatment ALI cut-off value of 15.5 as determined by receiver operating curve analysis. RESULTS: The low ALI group displayed more adverse clinical characteristics, lower rates of complete remission (54.9 vs. 75.4%, p = 0.008), and poorer 5-year progression-free (PFS, 58.1 vs. 77.3%, p = 0.006) and overall (OS, 64.2 vs. 80.2%, p = 0.008) survival. Multivariate analysis showed that low ALI was found to independently predict shorter PFS and OS. Interestingly, a low ALI reverted to a high ALI during treatment in 58 patients (27.4%), and the 5-year OS of these patients was better than that of patients whose ALI remained low (n = 24, 72.5 vs. 24%, p < 0.001). CONCLUSIONS: ALI might be an easily available marker for predicting clinical outcomes in DLBCL patients treated with R-CHOP chemotherapy.

A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy-induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09.

PURPOSE: Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G-CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim. METHODS: In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1. RESULTS: The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 ± 1.79 days vs. 1.54 ± 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non-inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 ± 1.18 days vs. 1.80 ± 1.05 days; difference, -0.15 ± 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (≥2000/µL) was significantly shorter than that of pegfilgrastim (8.85 ± 1.45 days vs. 9.83 ± 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly. CONCLUSIONS: Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression.

Factor V Deficiency in Korean Patients: Clinical and Laboratory Features, Treatment, and Outcome.

Due to rarity of factor V (FV) deficiency, there have been only a few case reports in Korea. We retrospectively analysed the clinical-laboratory features of FV deficiency in 10 Korean patients. Between January 1987 and December 2013, 10 case reports published in a Korean journal or proceedings of Korea Society on Thrombosis and Hemostasis were reviewed. Severity is defined as mild (> 5% of factor activity), moderate (1%-5%), and severe (< 1%). The median age at diagnosis, six males and four females, was 26 years (range, 1 month-73 years). Six of 10 patients were classified as moderate, three as mild, and one as severe disease. Eight patients were diagnosed as inherited FV deficiency. The most frequent symptoms were mucosal tract bleedings (40%) such as epistaxis, and menorrhagia in female. Hemarthroses and postoperative bleeding occurred in one and four patients, respectively. Life-threatening bleeding episodes occurred in the peritoneal cavity (n = 2), central nerve system (n = 1), and retroperitoneal space (n = 1). No lethal haemorrhages happened to patients with mild disease. The majority of bleeding episodes were controlled with local measures and fresh-frozen plasma replacement. Two acquired FV deficient-patients showing life-threatening haemorrhages received the immunosuppressive therapy, but one of them died from postoperative bleeding complications. Despite the small sample size of this study due to rarity of the disease, we found that Korean patients with FV deficiency had similar clinical manifestations and treatment outcomes shown in previous studies.

Vactosertib, TGF-ß receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a pronounced extracellular matrix (ECM)-rich response, which is produced by an excessive amount of transforming growth factor ß (TGF-ß), resulting in tumor progression and metastasis. In addition, TGF-ß signaling contributes to rapidly acquired resistance and incomplete response to gemcitabine. Recently, selective inhibitors of the TGF-ß signaling pathway have shown promise in PDAC treatment, particularly as an option for augmenting responses to chemotherapy. Here, we investigated the synergistic anticancer effects of a small-molecule TGF-ß receptor I kinase inhibitor (vactosertib/EW-7197) in the presence of gemcitabine, and its mechanism of action in pancreatic cancer. Vactosertib sensitized pancreatic cancer cells to gemcitabine by synergistically inhibiting their viability. Importantly, the combination of vactosertib and gemcitabine significantly attenuated the expression of major ECM components, including collagens, fibronectin, and α-SMA, in pancreatic cancer compared with gemcitabine alone. This resulted in potent induction of mitochondrial-mediated apoptosis, gemcitabine-mediated cytotoxicity, and inhibition of tumor ECM by vactosertib. Additionally, the combination decreased metastasis through inhibition of migration and invasion, and exhibited synergistic anti-cancer activity by inhibiting the TGF-ß/Smad2 pathway in pancreatic cancer cells. Furthermore, co-treatment significantly suppressed tumor growth in orthotopic models. Therefore, our findings demonstrate that vactosertib synergistically increased the antitumor activity of gemcitabine via inhibition of ECM component production by inhibiting the TGF-ß/Smad2 signaling pathway. This suggests that the combination of vactosertib and gemcitabine may be a potential treatment option for patients with pancreatic cancer.

DAAM2 polymorphism is closely related to the clinical outcomes of allogeneic hematopoietic stem cell transplantation.

Disheveled associated activator of morphogenesis 2 (DAAM2) is one of the key proteins of WNT/plantar cell polarity signaling pathway which is closely linked to oncogenesis, cellular proliferation and regeneration, and stem cell renewal. This study investigated the association of DAAM2 genetic polymorphism with the clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We selected candidate single nucleotide polymorphisms (SNPs) by DNA chip analysis using Illumina Infinium Human-1 microarrays™ on 15 patients who underwent allogeneic HSCT with (N = 7) or without (N = 8) acute graft versus host disease (GvHD). Six SNPs (rs2504787, rs2504086, rs2504082, rs3004067, rs882559, and rs3004070) of DAAM2 were associated with acute GvHD prevalence, and the genotyping was extended to larger population (N = 228). Medical records were reviewed to see the correlation of these SNPs with the clinical outcomes of the patients. In rs2504082 and rs882559, treatment-related mortality was significantly lower in major homozygote than other genotypes (29.3% in AA vs. 44.3% in AG or GG, p = 0.0214; 23.0% in CC vs. 39.9% in CG or GG, p = 0.0072, respectively). Acute GvHD incidence and engraftment time were significantly different according to the specific genotype of selected SNPS in this study. This study is the first report regarding the clinical value of DAAM2 polymorphism as a predictive marker of clinical outcomes of allogeneic HSCT.

A case of inguinal sparganosis mimicking myeloid sarcoma.

We report here a case of inguinal sparganosis, initially regarded as myeloid sarcoma, diagnosed in a patient undergone allogeneic hematopoietic transplantation (HSCT). A 56-year-old male patient having myelodysplastic syndrome was treated with allogeneic HSCT after myeloablative conditioning regimen. At day 5 post-HSCT, the patient complained of a painless palpable mass on the left scrotum and inguinal area. Pelvic magnetic resonance imaging and computed tomography revealed suspected myeloid sarcoma. Gun-biopsy was performed, and the result revealed eosinophilic infiltrations without malignancy. Subsequent serologic IgG antibody test was positive for sparganum. Excisional biopsy as a therapeutic diagnosis was done, and the diagnosis of sparganosis was confirmed eventually. This is the first report of sparganosis after allogeneic HSCT mimicking myeloid sarcoma, giving a lesson that the physicians have to consider the possibility of sparganosis in this clinical situation and perform adequate diagnostic and therapeutic approaches.

Managing Side Effects of Cytotoxic Chemotherapy in Patients With High Grade Gliomas.

Cytotoxic chemotherapy has been a mainstay of cancer treatment since the 1940s. In the recent era of emergent targeted therapies and immunotherapies, many cytotoxic chemotherapy agents including temozolomide are still one of main weapons for the treatment of high grade gliomas. However, cytotoxic chemotherapy often causes side effects. Proper management of chemotherapy-induced toxicity can have a significant impact on a patient's quality of life and clinical outcomes. Many supportive care advances have transformed our ability to give full doses of chemotherapy, which is important for achieving their full efficacy. Prevention and treatment strategies have been developed for many chemotherapy-related toxicities. This review focused on managing gastrointestinal toxicity, chemotherapy-induced nausea and vomiting, and hematologic toxicities such as thrombocytopenia during cytotoxic chemotherapy treatment in high-grade brain tumors.

Treatment Pattern, Financial Burden, and Outcomes in Elderly Patients with Acute Myeloid Leukemia in Korea: A Nationwide Cohort Study.

Although approximately 50% of patients with acute myeloid leukemia (AML) are diagnosed over the age of 60 years, there is currently no established consensus on the treatment of elderly AML patients. Herein, we aimed to explore the incidence, medical expenditure, treatment, and outcomes of elderly AML patients in Korea by analyzing a nationwide cohort. We employed the Korean National Health Insurance Service-Senior cohort, which represents 10% of a random selection from a total of 5.5 million subjects aged 60 years or older. AML patients were identified according to the main diagnostic criteria of acute leukemia. Treatment for AML was divided into high- (high-dose cytarabine ± idarubicin) and low- (low-dose cytarabine or hypomethylating agents) intensity chemo-therapy and classified according to the chemotherapeutics protocol. We analyzed the survival outcomes and medical expenditures. Among 558,147 elderly patients, 471 were diagnosed with AML, and 195 (41.4%) were treated with chemotherapy. The median age was 65 years, and the median overall survival (OS) was 4.93 months (95% confidence interval, 4.47-5.43). Median OS was longer in patients undergoing chemotherapy than those in the best supportive care group (6.28 vs. 3.45 months, p < 0.001), and the difference was prominent in patients aged < 70 years. Twenty-eight (5.9%) patients received high-intensity chemotherapy, while 146 (31.0%) received low-intensity chemotherapy. The difference in median OS according to dose intensity was 4.6 months, which was longer in the high-intensity chemotherapy group (9.8 vs. 5.2 months in low-intensity group); however, the difference was not statistically significant. Patients who received high-intensity chemotherapy recorded longer hospital stays and incurred greater expenses on initial hospitalization. Elderly AML patients in Korea exhibited clinical benefits from chemotherapy. Although patients should be carefully selected for intensive treatment, chemotherapy, including low-intensity treatment, can be considered in elderly patients. Moreover, prospective studies on new agents or new treatment strategies are needed.

Association of Smoking Status with Efficacy of First-line Immune Checkpoint Inhibitors in Advanced Non-small Cell Lung Cancers: A Systematic Review and Meta-analysis.

Background: Although smoking status has potential as a biomarker for immune checkpoint blockade in advanced non-small cell lung cancer (NSCLC), its clinical significance remains obscure. This meta-analysis aims to assess the impact of the smoking status on the efficacy of first-line immunotherapy and to find better treatment in never-smoker and ever-smoker patients. Methods: We searched the MEDLINE, EMBASE, and Cochrane database for trials comparing immunotherapy with conventional chemotherapy as front-line treatment for advanced NSCLC. Random-effects models were used to pool estimates of hazard ratios (HRs) for overall survival with 95% confidence intervals (CIs). Predefined subgroup analysis was performed to investigate the difference in the efficacy between the single checkpoint blockade and checkpoint inhibitor plus chemotherapy combination in the never-smokers and current/former smokers. Results: Twelve trials involving 6,446 patients were included in the analysis. A statistically significant overall survival benefit over conventional chemotherapy was found for both checkpoint inhibitor monotherapy (HR, 0.71; 95% CI, 0.59-0.85) and checkpoint inhibitor plus chemotherapy (HR, 0.75; 95% CI, 0.63-0.90) in the current/former smoker group. There was no subgroup difference between monotherapy and combination treatment (p=0.67). However, there was an inconsistent survival outcome in the never-smoker group; checkpoint blockade monotherapy did not show significantly better efficacy than chemotherapy alone (HR, 1.05; 95% CI, 0.81-1.37), but combination treatment showed an overall survival benefit (HR, 0.64; 95% CI, 0.43-0.94). A significant subgroup difference existed between monotherapy and combination therapy (p=0.04). Similarly, there was a significant difference in efficacy of monotherapy between the current/former smoker and never-smoker group (p=0.01), but the efficacy of the combination treatment was comparable between the two groups (p=0.45). Conclusion: Smoking status, which is easily available information, could be used as a guide in clinical practice to choose better treatment in the front-line setting for advanced NSCLC patients.

A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which promotes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitivity. In this study, we developed a novel DDR1 inhibitor, KI-301690 and investigated whether it could improve the anticancer activity of gemcitabine, a cytotoxic agent widely used for the treatment of pancreatic cancer. KI-301690 synergized with gemcitabine to suppress the growth of pancreatic cancer cells. Importantly, its combination significantly attenuated the expression of major tumor ECM components including collagen, fibronectin, and vimentin compared to gemcitabine alone. Additionally, this combination effectively decreased mitochondrial membrane potential (MMP), thereby inducing apoptosis. Further, the combination synergistically inhibited cell migration and invasion. The enhanced anticancer efficacy of the co-treatment could be explained by the inhibition of DDR1/PYK2/FAK signaling, which significantly reduced tumor growth in a pancreatic xenograft model. Our results demonstrate that KI-301690 can inhibit aberrant ECM expression by DDR1/PYK2/FAK signaling pathway blockade and attenuation of ECM-induced chemoresistance observed in desmoplastic pancreatic tumors, resulting in enhanced antitumor effect through effective induction of gemcitabine apoptosis.

A Serum Marker for Early Pancreatic Cancer With a Possible Link to Diabetes.

BACKGROUND: Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well established. METHODS: Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin's diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic patients) and evaluated according to PC status, stages, and diabetic status, which was compared with that of CA19-9. RESULTS: Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic area under the curve (AUC) of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early-stage and non-metastatic PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995). CONCLUSIONS: Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility.

Lidocaine enhances the efficacy of palbociclib in triple-negative breast cancer.

The use of anesthetics in the surgical resection of tumors may influence the prognosis of cancer patients. Lidocaine, a local anesthetic, is known to act as a chemosensitizer and relieve pain in some cancers. In addition, palbociclib, a potent cyclin-dependent kinase (CDK) 4/6 inhibitor, has been approved for chemotherapy of advanced breast cancer. However, recent studies have revealed the acquired resistance of breast cancer cells to palbociclib. Therefore, the development of combination therapies that can extend the efficacy of palbociclib or delay resistance is crucial. This study investigated whether lidocaine would enhance the efficacy of palbociclib in breast cancer. Lidocaine synergistically suppressed the growth and proliferation of breast cancer cells by palbociclib. The combination treatment showed an increased cell cycle arrest in the G0/G1 phase by decreasing retinoblastoma protein (Rb) and E2F1 expression. In addition, it increased apoptosis by loss of mitochondrial membrane potential as observed by increases in cytochrome c release and inhibition of mitochondria-mediated protein expression. Additionally, it significantly reduced epithelial-mesenchymal transition and PI3K/AKT/GSK3ß signaling. In orthotopic breast cancer models, this combination treatment significantly inhibited tumor growth and increased tumor cell apoptosis compared to those treated with a single drug. Taken together, this study demonstrates that the combination of palbociclib and lidocaine has a synergistic anti-cancer effect on breast cancer cells by the inhibition of the PI3K/AKT/GSK3ß pathway, suggesting that this combination could potentially be an effective therapy for breast cancer.

Outcomes in 102 patients that present to the emergency department with chemotherapy-induced febrile neutropenia.

OBJECTIVE: Febrile neutropenia (FN) is a major toxic responseto chemotherapy requiring prompt medical attention. There are a limited number of reports on clinical outcome in patients with FN that present to emergency departments. METHODS: We retrospectively evaluated clinical manifestations, therapeutic outcomes, and risk factors for FN in 102 adult patients that presented to the emergency department between 1 January 2006 and 31 March 2009. FN was defined as a body temperature>38°C and a neutrophil count >0.5×109/L on the day of fever onset or the day after. RESULTS: Mean age of the patients was 57 years. Mean absolute neutrophil count (ANC) was 436.8/mm3 (range: 0-1000/mm3). In all, 23 of the patients (22.5%) died due to complications related to FN. There were not a statistical difference in therapeutic outcome among tumor types, performance status, sex, depth of neutropenia, or time from emergency department presentationto initiation of antibiotic therapy. Age was an important prognostic factor for therapeutic outcome. Mean age of fatal cases was 65 years versus 56 years for non-fatal cases (p=0.016). Bacteremia was noted in 19 patients, 10 (53%) of which died. The mortality rate was significantly higher in thepatients with blood culture-proven bacteria than in those whose blood culture yielded no organism (p=0.013). CONCLUSION: FN patients that presented to the emergency department had a high mortality rate that increased with age. Given the increasing age of patients diagnosed with cancer as well as therapeutic interventions, the high mortality rate associated withchemotherapy-induced FN in elderly patients requires further study in order to reduce the risk of death.

Intracellular KRAS-specific antibody enhances the anti-tumor efficacy of gemcitabine in pancreatic cancer by inducing endosomal escape.

KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape. In addition, the anticancer effect of RT22-ep59 was observed in the high-EpCAM-expressing pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells, but it had little effect on the low-EpCAM-expressing pancreatic cancer cells. Additionally, co-treatment with RT22-ep59 and gemcitabine synergistically inhibited cell viability, migration, and invasion in 3D-cultures and exhibited synergistic anticancer activity by inhibiting the RAF/ERK or PI3K/AKT pathways in cells with high-EpCAM expression. In an orthotopic mouse model, combined administration of RT22-ep59 and gemcitabine significantly inhibited tumor growth. Furthermore, the co-treatment suppressed cancer metastasis by blocking EMT signaling in vitro and in vivo. Our results demonstrated that RT22-ep59 synergistically increased the antitumor activity of gemcitabine by inhibiting RAS signaling by specifically targeting KRAS. This indicates that co-treatment with RT22-ep59 and gemcitabine might be considered a potential therapeutic strategy for pancreatic cancer patients harboring KRAS mutation.

2020 Korean guidelines for the management of metastatic prostate cancer.

In 2017, Korean Society of Medical Oncology (KSMO) published the Korean management guideline of metastatic prostate cancer. This paper is the 2nd edition of the Korean management guideline of metastatic prostate cancer. We updated recent many changes of management in metastatic prostate cancer in this 2nd edition guideline. The present guideline consists of the three categories: management of metastatic hormone sensitive prostate cancer; management of metastatic castration resistant prostate cancer; and clinical consideration for treating patients with metastatic prostate cancer. In category 1 and 2, levels of evidence (LEs) have been mentioned according to the general principles of evidence-based medicine. And grades of recommendation (GR) was taken into account the quality of evidence, the balance between desirable and undesirable effects, the values and preferences, and the use of resources and GR were divided into strong recommendations (SR) and weak recommendations (WR). A total of 16 key questions are selected. And we proposed recommendations and described key evidence for each recommendation. The treatment landscape of metastatic prostate cancer is changing very rapid and many trials are ongoing. To verify the results of the future trials is necessary and should be applied to the treatment for metastatic prostate cancer patients in the clinical practice. Especially, many prostate cancer patients are old age, have multiple underlying medical comorbidities, clinicians should be aware of the significance of medical management as well as clinical efficacy of systemic treatment.

MEK blockade overcomes the limited activity of palbociclib in head and neck cancer.

Head and neck cancer (HNC) is characterized with multiple aberrations in cell cycle pathways, including amplification of cyclin D1. Palbociclib (PAL), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has been reported to regulate cell cycle progression in HNC. However, recent studies have revealed the acquired resistance of certain cells to PAL through activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Therefore, we investigated whether the inhibition of MEK/ERK pathway by trametinib (TRA) may overcome the limited efficacy of PAL in HNC. We evaluated the effect of PAL alone and in combination with TRA on the viability of HNC cells, and found that the combination treatment synergistically inhibited the proliferation of HNC cells. The combination treatment induced G0/G1 cell cycle arrest and apoptotic cell death. In particular, apoptosis mediated by the combination treatment was accompanied with an increase in caspase-3 activity and the number of TUNEL-positive apoptotic cells. These results were consistent with the decrease in cell cycle progression and mitogen-activated protein kinase (MAPK) pathway activation. In a xenograft mouse model of HNC, PAL and TRA synergistically inhibited tumor growth and enhanced tumor cell apoptosis, consistent with the increase in the number of TUNEL-positive cells. The anti-proliferative effects were evident in tumor tissues subjected to the combination treatment as compared with those treated with single drug. Taken together, our study demonstrates that the combination of PAL and TRA exerts synergistic anticancer effects and inhibits cell cycle check points and MEK/ERK pathway in HNC, suggestive of their potential application for HNC treatment.

SB365 induces apoptosis and suppresses proliferation of glioblastoma cells.

CONTEXT: Glioblastoma is a malignant brain tumor with limited treatment modalities due to its nature. SB365, Pulsatilla saponin D, is known to induce apoptosis and inhibit the growth of many cancer cells. AIM: We elucidated the anticancer effects of SB365 in glioblastoma cells. METHODS: We examined the antiproliferative activity of SB365 in human glioblastoma cell lines. Apoptosis was evaluated using the Hoechst assay, TUNEL assay, DAPI nuclear staining, and Western blotting analysis. To test the antimetastatic capacity of SB365, cell migration assay was conducted, and hypoxia-inducible factor-1 alpha (HIF-1α) expression and vascular endothelial growth factor (VEGF) level were determined under hypoxic conditions. STATICAL ANALYSIS: Significance of the results was confirmed by a one-way analysis of variance analysis. RESULTS: SB365 treatment suppressed the growth of glioblastoma cells and resulted in apoptotic morphological features such as nuclear condensation and fragmentation, enhancing the expression of cleaved poly (ADP-ribose) polymerase and caspase-3. It also significantly delayed cell migration and decreased the HIF-1α expression and VEGF secretion. CONCLUSION: Our findings thus demonstrate that SB365 induced apoptosis and delayed the growth and migration of human glioblastoma cells. It is considered that SB365 would be a promising therapeutic option for glioblastoma.

PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis.

Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2γ in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2γ as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2γ was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2γ inhibitor, decreased the cell growth of TNF-mediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2γ expression and PI3K/ AKT signaling pathway in both synovial fibroblasts and macrophages. In addition, PBT-6 suppressed macrophage migration via CCL2 and osteoclastogenesis. In CIA mice, it significantly inhibited the progression and development of RA by decreasing arthritis scores and paw swelling. Three-dimensional micro-computed tomography confirmed that PBT-6 enhanced the joint structures in CIA mice. Taken together, our findings suggest that PI3KC2γ is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2γ inhibitor to target inflammatory diseases including RA.

ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a.

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis.