Chemotherapeutic Agents In Patients Research Articles

254P - Anti-mullerian hormone (AMH) levels and antral follicle counts (AFC) may predict ovarian reserves before systemic chemotherapy (SC) in women with breast cancer (BC): A prospective clinical study

BackgroundSystemic chemotherapy (SC) has a negative effect on ovarian functions. The aim of this study is to investigate the effect of SC on anti-müllerian hormone (AMH) levels, antral follicle counts (AFC) and ovarian volumes (MOV) in patients with BC. MethodsThe demographic, clinical and pathological features of premenopausal breast cancer (BC) patients who were operated in the Istanbul Florence Nightingale Hospital were recorded. AMH levels, AFC and MOV measurements were performed before and after adjuvant SC in 3-month periods. The patients who did not have menstruel cycles for 6 months or longer had been classified as chemotherapy induced amenorrhea (CIA). The effects of different chemotherapy regimens on AMH, AFC and MOV in terms menstruel cycles resumption and CIA were investigated. ResultsSeventy one patients were eligible for the study, and median age of them was 38 years (ranged from 23 to 51 years). Median follow-up was 37 months (ranged from 20 to 51 months), CIA developed in 62% of patients. AMH, AFC, and MOV significantly decreased one year after SC (p<0.0001). AMH before chemotherapy (median: 1,520 vs 0,755, p=0.001), at the end of first year (median: 0,073 vs 0,010ng/ml, p=0.030) and pre-treatment AFC (median12 vs 4,50, p=0.026) was lower in patients with CIA comparing those without CIA. In multivariate logistic regression analysis, AMH levels (OR:0.273, 95%: 0.102 – 0.733, p=0.010) and AFC (OR: 1,180, 95% CI; 1,016-1,369, p=0.030) before SC were the most valuable and earliest factors to predict CIA. There were no significant relationships between age of the patients (≤30vs>30 ), BMI (30vs> 30), SC regimen and number of cycles (4 vs>4) and CIA (p>0.05).Table254P muitivariet analyses with logistic regrettion for CIATableUNIVARIETMULTIVARIETOR95% CIOR95% CIER0,190,038-0,8910,0350,0020,000- 0,1110,002HER 20.800,435-2,9361,130ALND PERFORMED1,750,653-4,7020,265AMH-10,640,454-0,9140,0140,2730,102- 0,7330,010AMH-50,230,063-0,8120,0230,0090,000- 0,7540,037AFC-10,870,780-0,9610,0070,7350,572- 0,9440,016AFC-50,930,741-1,1650,527MOV-11,000,987-1,0210,686MOV-50,980,854-1,1580,790TAXANE/W&İTHOUTTAXANE0,710,267-1,9100,503TC/AC0,850,209-3,4910,825AGE 354,661,613-13,4980,004CHEMONUMBER0,240,080-0,7660,017BMI 252,570,929-7,1180,069 ConclusionsSC significantly decreases AMH and AFC values independently of chemotherapeutic agents in patients with BC. The low AMH levels and less AFC before SC may predict CIA. Legal entity responsible for the studyİstanbul Demiroğlu Bilim University. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

High rate of clinical improvement of actinic cheilitis with laser, surgery, and chemotherapeutic agents in patients who have a favorable prognosis

High rate of clinical improvement of actinic cheilitis with laser, surgery, and chemotherapeutic agents in patients who have a favorable prognosis

Chidamide, Decitabine, Cytarabine, Aclarubicin, and Granulocyte Colony-Stimulating Factor (CDCAG) in Adults with Relapsed/Refractory Acute Myeloid Leukemia: Final Results from a Phase 1/2 Study

Background:There is no standard cytoreductive regimen for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Increasing evidence indicates the importance of epigenetic modification in the pathogenesis of myeloid neoplasms, and the epigenetic changes can be pharmacologically reversed by epigenetic modulating drugs (Halpern, Othus et al. 2017). Hypomethylating agents and histone deacetylase inhibitors showed chemo-sensitization when combined with conventional chemotherapeutics in patients with R/R AML (Halpern, Othus et al. 2017, Li, Wang et al. 2017). We conducted a phase 1/2 study of chidamide (a histone deacetylase inhibitor), decitabine (a hypomethylating agent), cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) for patients with R/R AML.Methods:This multicenter clinical trial evaluated the safety and efficacy of CDCAG regimen in patients with R/R AML (NCT02886559). Adults (age: 18-60) with R/R AML were eligible if they had not received treatment within 4 weeks prior to the enrollment. ECOG performance status ≤ 3 and expected survival time ˃ 3 months were required. All patients were treated with chidamide 30 mg on days 1, 4, 8, and 11; decitabine 20 mg/m2 on days 1-5; cytarabine 50 mg/m2 on days 1-7 if WBC ≥ 20×109/L, and on days 3-7 if WBC < 20×109/L; aclarubicin 10 mg/m2 on days 3-7; and granulocyte colony-stimulating factor, 300 ug/d until WBC > 20×109/L. Treatment cycles were repeated every 28 days. Patients could be treated for up to two cycles. Genomic DNA from patients at enrollment was examined for mutations by the target sequencing panel, which covered the coding sequences of 127 known genes relevant to the pathogenesis of AML (Annoroad Gene Technology Co., Ltd).Results:Ninety-three patients, median age 40 (range: 18-60) years, with primary refractory (n = 37), early relapsed disease (n = 38), or late relapsed disease (n = 18) were enrolled. Among the 56 patients with relapsed AML, 40 were experiencing their first relapse, 15 the second relapse, and 1 patient the third. They received a median of 5 (1-17) therapies cycles prior to the enrollment. Patients were enrolled on median 8.8 (1.3-63.8) months after initial diagnosis.Overall, 24/93 (26%, 95% confidence interval [CI]: 16.9-34.7%) patients achieved a complete remission (CR) and 19/93 (20%, 95% CI: 12.2-28.4%) patients achieved a CR with incomplete blood count recovery (CRi), for an objective overall response rate of 46% (95% CI: 36.1-56.4%). Among the 43 CR/CRi patients, the 6-month disease-free survival (DFS) rate was 56% (95% CI: 41.0-70.7%), and the median DFS was 305 (95% CI: 258-NA) days. Patients achieving an CR/CRi had a significant improvement in median overall survival (OS) (259 vs 563 days; P < 0.001; hazard ratio [HR], 3.6) compared with nonresponders. The 6-month OS estimate was 52% (95% CI: 41.5-61.8%), and the median OS was 266 (95% CI: 235-398) days. Overall, we detected 184 mutations in 76 patients. Most commonly mutated genes were FLT3-ITD, CEBPA, WT1, RUNX1, and DNMT3A. Within patients with mutation, the CR/CRi rate was 55.6% in patients with epigenetic modifier gene mutations, and only 36.7% in patients with other mutations. Serious adverse events (SAE) occurred in 12 (13%) patients, with 4 patients experienced early death (death within 28 days). Only 1 patient died during consolidation.Conclusions:The CDCAG regimen was well tolerated and effective in relapsed/refractory AML. Compared with patients with other mutations, patients with epigenetic modifier gene mutations might benefit from the CDCAG regimen.DisclosuresChidamide tables were provided by Chipscreen Biosciences Ltd and decitabine was provided by Shandong New Time Pharmaceutical Co., Ltd. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chemotherapeutic agents eligible for prior dosing in pancreatic cancer patients requiring hemodialysis: a systematic review .

New chemotherapeutic agents prolong survival of patients with pancreatic ductal adenocarcinoma (PDAC). Although their incidence is rising, patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) are not included in the phase III trials evaluating the effects of these chemotherapies. Many experts recommend applying chemotherapy after HD using a reduced dose. Alternatively, the concept of prior dosing allows for the application of dialyzable chemotherapeutic drugs using a normal dose, with an HD followed shortly after to mimic normal renal function. In this work, we provide guidance for clinicians on how to use chemotherapy in patients with PDAC on HD and how to identify substances suitable for prior dosing. We systematically searched PubMed, from inception to September 2016, for published studies describing patients with ESRD on HD who received chemotherapies commonly applied in PDAC, including gemcitabine, fluorouracil (5-FU), capecitabine, oxaliplatin, irinotecan, docetaxel, erlotinib, sunitinib, S-1, and afatinib. Applied dosages, described toxicities, application time relative to HD, and pharmacokinetic measurements of the drug and its metabolites were assessed. Quantitative analysis of the drug plasma concentrations, including half-life during and in between HD and fraction of the drug eliminated during HD, were assessed. We identified 56studies describing 128 patients with ESRD undergoing HD during chemotherapeutic treatment. Quantitative pharmacokinetic analysis revealed that the following substances are dialyzable and thus suitable for application using the prior-dosing method: gemcitabine, 5-FU, oxaliplatin, irinotecan, and S-1. This work supports the application of dialyzable chemotherapeutic agents in patients with PDAC in standard dose when HD is performed shortly after the infusion. .

Safety of Alemtuzumab After Exposure to Chemotherapeutic Agents in Patients with Multiple Sclerosis - Experience of a single MS center (P5.367)

Safety of Alemtuzumab After Exposure to Chemotherapeutic Agents in Patients with Multiple Sclerosis - Experience of a single MS center (P5.367)

Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo

Background/Aims: This study aimed at investigating the effects of metformin on the growth and metastasis of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. Methods: Two human ESCC cell lines EC9706 and Eca109 were selected and challenged with metformin in this study. Western blot assay was performed to detect th level of Bcl-2, Bax and Caspase-3. Scratch wound assay, transwell assay and Millicell invasion assay were used to assay the invasion and migration of EC9706 and Eca109 cells. Nude mice tumor models were used to assay the growth and lung metastasis of ESCC cells after metformin treatment. The plasma glucose level was also assayed. Results: We found that metformin significantly inhibited proliferation and induced apoptosis of both ESCC cell lines in a dose- and time-dependent manner, and the expression of Bcl-2 was down-regulated and Bax and Caspase-3 were up-regulated. Metformin significantly inhibited the invasion and migration of EC9706 and Eca109 cells (p < 0.05). mRNA and protein levels of MMP-2 and MMP-9 decreased significantly upon treatment with metformin of 10mM for 12, 24 and 48h in a time-dependent manner (p < 0.05). In line with in vitro results, in vivo experiments demonstrated that metformin inhibited tumorigenicity, inhibited lung metastasis and down-regulated the expression of MMP-2 and MMP-9. Moreover, we showed that metformin treatment did not cause significant alteration in liver and renal functions and plasma glucose level. Conclusion: Our study for the first time demonstrated the anti-invasive and anti-metastatic effects of metformin on human ESCC cells both in vitro and in vivo, which might be associated with the down-regulation of MMP-2 and MMP-9. As a whole, our results indicate the potential of metformin to be developed as a chemotherapeutic agent for patients with ESCC and might stimulate future studies on this area.

Second-Line Therapy for Advanced Colorectal Cancer: EGFR vs. Continuation of VEGF Inhibition

We review second-line biological therapies for metastatic colorectal cancer (mCRC), including their mechanisms of action, adverse events, survival outcomes, optimal chemotherapy combinations, and sequencing of agents. The advent of biological therapeutics targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways has enhanced the benefits afforded by the plethora of chemotherapeutic agents for patients with mCRC over the past 10 years, nearly tripling the median OS. Individual biomarkers predicting prognosis and response to VEGF vs. EGFR therapy have been identified. For patients who progress on first-line VEGF therapy, evidence suggests that continued VEGF inhibition may be as efficacious as changing to EGFR therapy with less adverse effects. However, for patients who progress after first-line EGFR therapy, early studies suggest changing to agents targeting the VEGF pathway. Biological options for patients with mCRC who progressed on first-line concomitant chemotherapy and biologic therapy depend on individual tumor characteristics and choice of first-line therapy. Future research should focus on prognostic and predictive biomarkers to better inform choice of first-line and sequential therapy beyond progression.

Accuracy of glomerular filtration rate estimationequations in patients with hematopathy.

Renal dysfunction is a common side-effect of chemotherapeutic agents in patients with hematopathy. Although broadly used, glomerular filtration rate (GFR) estimation equations were not fully validated in this specific population. Thus, this study was designed to further assess the accuracy of various GFR equations, including the newly 2012 CKD-EPI equations. Referring to 99mTc-DTPA clearance method, three Scr-based (MDRD, Peking, and CKD-EPIScr), three Scys C-based (Steven 1, Steven 2, and CKD-EPIScys C), and three Scr-Scys C combination based (Ma, Steven 3, and CKD-EPIScr-Scys C) equations were included. Bias, P30, and misclassification rate were applied to compare the applicability of the selected equations. A total of 180 Chinese hematological patients were enrolled. Mean bias, absolute mean bias, P30, misclassification rate and Bland-Altman plots of the CKD-EPIScr-Scys C equation were 7.90 mL/minute/1.73 m2, 17.77 mL/minute/1.73 m2, 73.3%, 38% and 79.7 mL/minute/1.73 m2, respectively. CKD-EPIScr-Scys C predicted the most precise eGFR both in lymphoma and leukemia subgroups. Additionally, CKD-EPIScys C equation in the rGFR ≧ 90 mL/minute/1.73 m2 subgroup and Steven 2 equation in the rGFR<90 mL/minute/1.73 m2 subgroup provided more accurate estimates in each subgroup. The CKD-EPIScr-Scys C equation could be recommended to monitor kidney function in hematopathy patients. The accuracy of GFR equations may be closely related with GFR level and kidney function markers, but not the primary cause of hematopathy.

Abstract 4146: Selinexor synergizes with DNA damaging agents through down-regulation of key DNA damage response genes

Abstract Background: Selinexor is a first-in-class, orally bioavailable SINE (Selective Inhibitor of Nuclear Export) compound currently in phase 1/2 clinical trials of patients with solid and hematological malignancies. SINE compounds bind exportin 1 (XPO1/CRM1) and inhibit nuclear export, resulting in nuclear retention of major tumor suppressor proteins (TSPs). We previously found through Reverse Phase Protein Array analysis that selinexor treatment alters the level of key DNA damage response (DDR) proteins. We also observed enhanced anti-tumor activity when combining selinexor with standard DNA damaging agents (DDA) in pre-clinical models and clinical studies. We hypothesize that a reduction in DDR protein expression by selinexor drives the synergy observed in combination with DDAs. Methods: Solid and hematological cancer cell lysates treated with selinexor +/- DDAs (cisplatin, doxorubicin, docetaxel and gemcitabine) were analyzed by immunoblotting and qPCR. Comet assay and γH2A.X staining were analyzed by immunofluorescence to evaluate DNA damage. Mice bearing MDA-MB-231 (triple negative breast cancer) tumors were treated with sub-toxic doses of selinexor (2.5 mg/kg), cisplatin (4 mg/kg) or docetaxel (4 mg/kg) alone or in combination. Tumor growth and mouse weight were followed for 25 days. Results: Selinexor reduced the expression of DDR mRNA and proteins involved in single-stranded (SSB) and double-stranded break (DSB) repair as early as 2 hours post treatment. We observed a dose-dependent correlation between the degree of DDR protein reduction and selinexor cytotoxicity in vitro. Selinexor prevented DDR activation following exposure to DDAs and led to synergistic cell death. Treatment of cells with selinexor plus DDA showed enhanced activity in comet assays and an increase in γH2A.X staining when compared to treatment with the single agents. Exposure to selinexor 6 - 24 hours after DDA treatment inhibited the DDR mechanism and was more synergistic than the opposite order (Sel → DDA) or simultaneous treatment. In a MDA-MB-231 xenograft, treatment with selinexor, docetaxel (SSB) or cisplatin (DSB) alone resulted in 66.7%, 51.5% or 26.6% TGI, respectively when compared to vehicle control whereas sequential treatment of docetaxel or cisplatin followed by selinexor resulted in 93.9% TGI or 9.6% tumor regression, respectively. No significant weight loss was seen in any of the groups by the end of the study. IHC staining and immunoblot analysis of tumor tissue and sections showed a reduction of DDR proteins. Conclusion: Selinexor synergizes with DDAs by increasing both SSB and DSB through inhibition of relevant DDR proteins. This data supports clinical development of selinexor in combination with standard chemotherapeutic agents in patients with solid and hematological malignancies. The results also suggest that sequential treatment of patients with DDAs followed by selinexor might be more beneficial. Citation Format: Trinayan Kashyap, Christian Argueta, Boris Klebanov, Oscar Gonzalez, Erkan Baloglu, Yosef Landesman, Margaret Lee, Humphrey Gardner, Sharon Shacham, William Senapedis. Selinexor synergizes with DNA damaging agents through down-regulation of key DNA damage response genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4146. doi:10.1158/1538-7445.AM2017-4146

Management of patients with end-stage renal disease undergoing chemotherapy: recommendations of the Associazione Italiana di Oncologia Medica (AIOM) and the Società Italiana di Nefrologia (SIN)

BackgroundThe overall risk of some cancers is increased in patients receiving regular dialysis treatment due to chronic oxidative stress, a weakened immune system and enhanced genomic damage. These patients could benefit from the same antineoplastic treatment delivered to patients with normal renal function, but a better risk/benefit ratio could be achieved by establishing specific guidelines. Key considerations are which chemotherapeutic agent to use, adjustment of dosages and timing of dialysis in relation to the administration of chemotherapy.MethodsWe have reviewed available data present in the literature, including recommendations and expert opinions on cancer risk and use of chemotherapeutic agents in patients with end-stage renal disease. Experts selected by the boards of the societies provided additional information which helped greatly in clarifying some issues on which clear-cut information was missing or available data were conflicting.ResultsData on the optimal use of chemotherapeutic agents or on credible schemes of polychemotherapy in haemodialysed patients are sparse and mainly derive from case reports or small case series. However, recommendations on dosing and timing of dialysis can be proposed for the most prescribed chemotherapeutic agents.DiscussionThe use of chemotherapeutic agents as single agents, or in combination, can be safely given in patients with end-stage renal disease. Appropriate dosage adjustments should be considered based on drug dialysability and pharmacokinetics. Coordinated care between oncologists, nephrologists and pharmacists is of pivotal importance to optimise drug delivery and timing of dialysis.

The Effect of Marigold Leaves and Doxorubicin Toward Cell Cycle and Apoptosis of T47D Cells

Doxorubicin is a commonly used chemotherapeutic agent in patients with breast cancer. The risk of side effect using of doxorubicin such as cardiomyopathy and congestive heart failure which can lead to death. One of the approach to overcome overloaded use of doxorubicin is the combined use with a chemopreventive agent (cochemotherapy), including the leaf extract of marigolds (Cosmos caudatus Kunth.). This research aims to reviewing the effect of the methanol extract of leaves of marigolds on the cytotoxic activity of doxorubicin in modulating cell cycle and apoptosis of breast cancer cells T47D. Determination of the cytotoxic activity of methanol extract of leaves of marigolds and doxorubicin as well as a combination of both conducted by MTT assay. modulation surveillance of cell cycle and apoptosis induction is done by using flowcytometry and analyzed by FACS Calibur program. Cytotoxicity assay single treatment of the methanol extract of leaves of marigolds produce use values of IC50 504,840 μg/ml, whereas IC50 values doxorubicin is 141,055 nM. The synergistic effect was shown a combination of methanol extract leaves marigolds and doxorubicin at concentrations of 84,17 μg/ml -23,5 nM; 84,17 μg/ml -47 nM; 126,25 μg/ml -23,5 nM; 252,5 μg/ml -35,25 nM and 252,5 μg/ml -71 nM with a combination index value (CI) consecutively of 0,5; 0,6; 0,6; 0,6 and 0,6. Observations modulation of cell cycle and apoptosis induction combination of methanol extract leaves marigolds and doxorubicin at concentrations of 84,17 μg/ml -23,5 nM, said that a combination of the methanol extract of leaves of marigolds and doxorubicin to inhibit the proliferation of cells in G2 / M phase and able to induce apoptosis of breast cancer cells T47D.Keywords: methanol extract of leaves of marigolds, doxorubicin, flowcytometry, cell cycle, apoptosis.

Metastatic Atypical and Anaplastic Meningioma: A Case Series and Review of the Literature.

Atypical (World Health Organization grade II) and anaplastic (World Health Organization grade III) meningiomas are rare, accounting for less than 5% of all meningiomas. Histologic grading has a significant impact on prognosis, risk of recurrence, and the need for adjuvant radiation or chemotherapy. Extracranial metastases are even more infrequent and occur in 0.1% of all cases. Retrospective chart review of 168 patients with diagnosis of WHO grade II and III meningiomas was performed. Six patients with histologically confirmed metastatic disease were identified. We discuss the clinical, radiologic, and histopathologic clinical course of 6 patients with metastasis to the lung, liver, and spine from all patients with atypical or anaplastic meningioma treated at Johns Hopkins Hospital from 1993 to2014. We reviewed the literature pertaining to this phenomenon and subsequently assessed the clinical benefits of adjuvant chemotherapeutic agents in patients with meningioma with metastatic disease.

Chemoresponse Assay in Head and Neck Cancer Patients: A Three-Year Follow Up.

The majority of patients with advanced head and neck cancer receiving chemotherapy show partial response or frank resistance. Therefore, assessing the individuals' tumour reactivity to the eligible chemotherapeutic compounds carries the potential of personalizing the patient treatment and minimizing ineffective regimens which lead to excess toxicity and cost, treatment delays and possibly causing the tumour to be cross resistant to additional drugs. To determine the effectiveness of a phenotypic chemoresponse assay in predicting response to chemotherapy in a retrospective series of head and neck cancer patients whose tumour specimens had been tested with ChemoFx assay (Precision Theraputic Inc.). Twenty-two tumour specimens were submitted to Precision Theraputics Inc. for chemoresponse testing, all of which have been histologically confirmed as squamous cell carcinoma of the head and neck. Selection of treatment was at the discretion of the treating physician and the results of the assay were not used to determine the therapy. A portion of the patients' solid tumour was established in primary culture, then exposed to increasing doses of different chemotherapeutic agents. The resultant cell counts in the treated wells were used to indicate the tumours' response to the agent and based on the dose response score curve, the test was scored as "responsive," "intermediate response," or "non-responsive." Of the 22 tumour samples submitted, 16 (72.7%) showed adequate cell yield in cultures and subsequently underwent in vitro chemoresponse assays and are reported in this study. Of the 16 cases reviewed, 5 were excluded due to inadequate follow up. A predictable response assay was either a good response to chemotherapy in patients whose tumour specimens showed sensitivity to the chemotherapeutic agents or failure in patients whose tumours showed either intermediate response or non responsiveness to the chemotherapeutic agent/agents. Of the 11 patients reported in this study, nine showed a predictable chemoresponse assay (81.8% predictability of effective treatment). Three patients had a predictable good response and six who failed their chemotherapy regimen within six months of treatment and their chemoresponse assay showed an inadequate response to the chemotherapeutic agents they were treated with. At three years follow up, all patients who had a predictable poor response succumbed to their disease except one, whose test showed intermediate response. While the current report has its limitation, we conclude, based on our findings, that chemoresponse assays may be useful adjuncts in the guiding the selection of chemotherapeutic agents in patients with head and neck cancer.

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells.

Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells - primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors.

Glucocorticoids may compromise the effect of gefitinib in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown remarkable benefits in non-small cell lung cancer (NSCLC) patients with drug-sensitive mutations in the EGFR gene. Responsive patients are usually continuously prescribed with TKIs until disease progression. Glucocorticoids (GCs) are potent homeostasis maintaining drugs and are frequently used in cancer patients to alleviate discomforts caused by anti-cancer therapies. Several previous studies reported that concomitant use of GCs may compromise the efficacy of chemo-therapeutics in patients with solid tumors. Little is known in the concomitant use of target therapy with GCs in treating NSCLC. In this study, we hypothesized that concomitant use of GCs in EGFR-TKI therapy may be detrimental and addressed this issue using cell cultures and xenograft studies followed by a retrospective population study based on data from the Taiwan national health insurance system. In cell cultures and xenograft studies, GCs were shown to unequally compromise the anti-cancer efficacy of TKIs in both PC9 and NCI-H1975 NSCLC cells models. In the retrospective population study, patients with similar disease status that were co-medicated with GCs had a significantly higher risk of disease progression.

Retraction Note to: Urinary parameters predictive and electrolyte disturbances of cisplatin-induced acute renal associated with cancer as a critical target of the chemotherapeutic agent in patients with solid tumors.

Cisplatin (CP) is a remarkably effective Pt-based anticancer drug, but it also exhibits severe toxic side effects, including nephrotoxicity and ototoxicity, and CP nephrotoxicity is a major constraint for the treatment of solid tumors. This study was designed to evaluate the electrolyte and biochemical changes in dogs with acute kidney injury (acute renal failure) following administration of CP as a chemotherapeutic agent to exhibit broad efficacy in solid tumors. A total of 10 adult male dogs were selected (treated dogs = 7 and control dogs = 3). Cisplatin-treated animals were received 0.75 mg/kg via intravenous for 5 consecutive days. Urine and blood samples on days 0 (pre-dosing), 1, 2, 3, 4, 7, 10, 14, and 28 (post-dosing) were collected. For tracking the signs of toxicity with cisplatin, clinical examination was performed for 2 times a day. Serum samples were assayed urea, creatinine, sodium, chloride, potassium, calcium, phosphorus, and urine samples were used to measure creatinine. Serum creatinine levels indicating renal function (glomerular filtration rate) was 0.66 and 0.94 mg/dL in day 0, respectively, in treatment and control animals. After day 2, a significant change in creatinine was observed in treatment animals. On the end day of the study control and treatments, creatinine was measured with mean of 1.35 and 1.00 mg/dL, respectively. Electrolyte disturbances were observed after several days of cisplatin administration including changes in levels of sodium, potassium, phosphorus, calcium, and chloride. Clinical observations also identified CP toxicity. This study for the first time showed that compensation electrolyte abnormalities in dogs following administration of cisplatin is essential to prevent deaths by daily monitoring and measurement of electrolytes in patients. This may be advantageous if repetitive cycles of chemotherapy or subsequent administration of high dose chemotherapy were planned.

Flow Cytometry of Breast Cancer Resistant Protein and microRNA in Breast Cancer Patients Post Metformin Effect

The goal of the present study is to investigate the role of metformin (MF) as a target of miRNAs in breast cancer resistant protein (BCRP) inhibition in an attempt to develop treatment strategies that may improve the response of breast cancer (BC) patients to chemotherapy (CT). In order to fulfill this target, non-diabetic female subjects were categorized into three groups: control group (group 1) (n=5), CT group of BC patients (group 2) (n=25) and CT plus MF group of BC patients (group 3) (n=25). All patients were subjected to full history taking, laboratory studies including mammogram, chest X-ray, pelvic-abdominal ultrasound and isotopic bone scan, in addition to ER and PR states. CT group was treated with neoadjuvent CT in the form of 5-FU (500 mg/m2), Adriamycin (50 mg/m2) and cyclophosphamide (500 mg/m2). Flow cytometry (FC) of BCRP and MiRNA was carried out on blood samples at every cycle of treatment for all partners. The results showed the presence of miRNA was higher than the presence of BCRP in the normal healthy control group. In most cases of CT and CT plus MF groups (group 2, 3) it was well noticed that the amount of BCRP in the blood samples exceeded that of miRNA illustrated the dysregulation of miRNA in BC patients and also to prove the basic role of BCRP as a multidrug resistance (MDR) for chemotherapeutic agents in patients with BC. It is concluded that the role of MF was well proved in targeting of miRNA to reinforce BC medication, so oncologists can be advised to use MF equivalent to CT in the recommended doses.

AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells.

Chinese medicines are emerging as an attractive new generation of anticancer drugs. Here, we explored the impact of salvianolic acid B (SalB), the major water-soluble compounds of Danshen, on apoptosis and autophagy of human hepatocellular carcinoma cells (HCC). We also investigated the related molecular mechanisms. We found that SalB exhibits potent ability to inhibit HCC cells viability in a concentration-dependent manner, and to induce apoptosis via the mitochondrial apoptosis pathway. Additionally, SalB could also induce autophagy. Furthermore, pretreatment with the autophagy inhibitor chloroquine or 3-methyladenine showed the potential in attenuating the apoptosis rate induced by SalB. Mechanistically, SalB treatment inhibited the AKT/mTOR signaling cascade in vitro. Overexpression of AKT abolished the effects of SalB on HCC cells, suggesting a critical role of the AKT/mTOR signaling pathway in SalB-induced biological effects. Our results indicated that the mitochondrial pathway was involved in SalB-induced apoptosis of HCC cells. Moreover, the AKT/mTOR signaling pathway was involved in SalB-induced autophagy, which promoted apoptosis. This study may provide a promising strategy for using SalB as a chemotherapeutic agent for patients with HCC.

Efficacy and toxicity profile of maintenance pemetrexed in patients with stage IV adenocarcinoma lung in Indian population.

Context:Lung cancer has been the most common cancer in the world for several decades. Pemetrexed is recommended as an option for the maintenance treatment in metastatic adenocarcinoma lung, if disease has not progressed immediately following platinum-based chemotherapy.Aims:To study efficacy and toxicity profile of pemetrexed as a maintenance chemotherapeutic agent in patients with stage IV adenocarcinoma lung, not progressing after first line chemotherapy. Settings and Design: This was an observational, prospective. We enrolled patients with stage IV adenocarcinoma lung who has not progressed on first line chemotherapy, from September 2013 to August 2014 at a tertiary care cancer institute in North India.Materials and Methods:In all, 108 patients with stage IV adenocarcinoma lung were started on induction pemetrexed/platinum chemotherapy. 60 patients with no disease progression & ECOG PS 0-2 were started on Pemetrexed maintenance. Progression free survival (PFS) and toxicity profile were recorded.Results:The mean number of maintenance cycles was 8.3 (range 2-28). 13 (21.6%) patients took >10 maintenance cycles. Pemetrexed maintenance therapy resulted in progression free survival (PFS) of 5.4 months. PFS on pemetrexed was consistent for all patient subgroups, including induction response: complete/partial responders (n-31) and stable disease (n-29). 14 patients had grade III/IV adverse events with anemia being the most common in 3/60 patients (5%). 3 patients (5%) developed renal dysfunction out of which 1 was grade III.Conclusions:Pemetrexed continuation maintenance chemotherapy is active and well tolerated. Pemetrexed maintenance should be considered in patients with advanced adenocarcinoma lung patients who have not progressed on completion of induction chemotherapy.

A pharmacokinetic analysis of cisplatin and 5-fluorouracil in a patient with esophageal cancer on peritoneal dialysis

Very little is known about the pharmacokinetics of chemotherapeutic agents in patients also being treated with continuous ambulatory peritoneal dialysis. We sought to evaluate the pharmacokinetics of cisplatin and 5-fluorouracil in plasma and peritoneal dialysate in a patient being treated for esophageal adenocarcinoma. A single patient with esophageal adenocarcinoma and on peritoneal dialysis for end-stage renal disease was treated with cisplatin 25mg/m(2) on day 1 of weeks 1 and 5 and continuous infusional 5-fluorouracil 1000mg/m(2)/day on days 1-4 of weeks 1 and 5 along with daily radiation therapy. Intense plasma and dialysate sampling was performed during the week 5 administration, followed by quantitation of platinum by atomic absorption spectrophotometry and 5-fluorouracil by LC-MS/MS. Following systemic administration, clearance of ultrafilterable (active) platinum over the first 6h was 20.8L/h, which is lower than previously reported clearance levels of ultrafilterable platinum. Total platinum AUC was 131μgh/mL, also higher than an AUC previously reported for total platinum in patients with normal renal function. Platinum-related material was detected in the peritoneal cavity, but this is likely inactive. 5-Fluorouracil penetrated the intraperitoneal cavity, but the contribution of peritoneal dialysis to drug clearance was negligible at 0.072%. Administration of intravenous cisplatin and 5-fluorouracil chemotherapy to a patient treated with continuous ambulatory peritoneal dialysis is feasible, but clearance in dialysate is nominal, thus suggesting that dose reduction is indicated for cisplatin. Systemic drug administration results in limited intraperitoneal penetration of 5-fluorouracil and inactive platinum species.