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The PtIV prodrug iproplatin has been actively loaded into liposomes using a calcium acetate gradient, achieving a 3‐fold enhancement in drug concentration compared to passive loading strategies. A strain‐promoted cycloaddition reaction (azide‐ dibenzocyclooctyne) was used to attach iproplatin‐loaded liposomes L(Pt) to gas‐filled microbubbles (M), forming an ultrasound‐responsive drug delivery vehicle [M−L(Pt)]. Ultrasound‐triggered release of iproplatin from the microbubble‐liposome construct was evaluated in cellulo. Breast cancer (MCF‐7) cells treated with both free iproplatin and iproplatin‐loaded liposome−microbubbles [M−L(Pt)] demonstrated an increase in platinum concentration when exposed to ultrasound. No appreciable platinum uptake was observed in MCF‐7 cells following treatment with L(Pt) only or L(Pt)+ultrasound, suggesting that microbubble‐mediated ultrasonic release of platinum‐based drugs from liposomal carriers enables greater control over drug delivery., Actively loading platinum(IV) prodrug iproplatin into liposomes has been achieved using a calcium acetate gradient. Microbubble‐mediated release and accumulation of the prodrug in MCF7 cancer cells following ultrasound treatment demonstrates that this strategy can enable greater control over drug delivery.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95%CI 1.820-7.359, P

G-quadruplexes (G4s) are prevalent in oncogenes and proposed to be potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex ( Pt1 ), whose affinity to G4-DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1 /VEGF-G4 (a promoter G4) reveals that Pt1 matches 3'-G-tetrad of VEGF-G4 through Cl - -dissociation and loop rearrangement of VEGF-G4. Binding rate constants are determined by coordination bond breakage/formation and correlate fully with affinities. The selective rate-determining binding step, Cl - -dissociation upon G4-binding which is 2~3 orders of magnitude higher than dsDNA. We further demonstrate that Pt1 potently targets G4 in living cells, effectively represses VEGF expression and inhibits vascular growth in zebrafish. We present adaptive G4-binding activation and selectivity controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.

Objectives Treatment of both platinum resistant high grade (HG) and low‐grade (LG) ovarian cancer (OVCA) poses significant challenges as neither respond well to conventional chemotherapy leading to morbidity and mortality. Identification of novel agents that can overcome chemoresistance is therefore critical. Previously, we have demonstrated that OVCA has basal upregulated unfolded protein response (UPR) and that targeting cellular processes leading to further and persistent upregulation of UPR leads to cell death. ONC201 is an orally bioavailable Dopamine Receptor D2 inhibitor demonstrating anticancer activity and was found to induce UPR. Given its unique properties, we hypothesized that ONC201 would overcome platinum resistance in OVCA. Methods Cisplatin sensitive and resistant HG OVCA and two primary LG OVCA cell lines were studied. Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Apoptosis and mitochondrial membrane potential were investigated using flow cytometry. Analysis of pathway inhibition was performed by Western Blot. mRNA expression of UPR related genes were measured by qPCR. In vivo studies were completed utilizing axillary xenograft models. Co‐testing with conventional chemotherapy was performed to study synergy. Results ONC201 significantly inhibited cell viability and migration in a dose dependent manner with IC50’s from 1‐20 µM for both cisplatin sensitive and resistant HG and LG‐OVCA cell lines. ONC201 lead to upregulation of the pro‐apoptotic arm of the UPR, specifically ATF‐4/CHOP/ATF3 and increased the intrinsic apoptosispathway. The compensatory, pro‐survival PI3K/AKT/mTOR pathway was downregulated. In vivo, weekly dosing of single agent ONC201 decreased xenograft tumor size by ~50% compared to vehicle. ONC201 also demonstrated significant synergy with paclitaxel in a highly platinum resistant OVCA cell‐line (OV433). Conclusions Our findings demonstrate that ONC201 can effectively overcome chemoresistance in OVCA cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. This is a promising, orallybioavailable therapeutic agent to consider in clinical trials for patients with both HG and LG OVCA., ONC201 can effectively overcome chemoresistance in both high‐grade and low‐grade ovarian cancer cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. A weekly oral dose of ONC201 lowers the tumor burden in mice. This is a promising therapeutic agent in OVCA treatment and might consider for clinical translation.

International audience; Aim Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3-year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial. Method PRODIGE 22 was a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild-type RAS patients, a third arm testing perioperative FOLFOX-cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and time to recurrence (TTR). Results Overall, 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients represented our intention-to-treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow-up was 54.3 months. Three-year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3-year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed. Conclusion Perioperative FOLFOX has no detrimental effect on long-term oncological outcomes and may be an option for some patients with locally advanced CC.

Despite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)-ferrocene hybrids that display multi-pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi-modal mechanism of action of these hybrid agents lead to non-apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.

IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum‐based chemotherapy as first‐line treatment for advanced non‐small‐cell lung cancer (NSCLC). Key eligibility criteria for the phase 3, open‐label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non‐squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co‐primary study endpoints were overall survival (OS) and investigator‐assessed progression‐free survival (PFS) per RECIST 1.1 in the intention‐to‐treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7‐30.8) mo in the PP arm (n = 53; hazard ratio [HR], 0.63 [95% CI, 0.36‐1.14]). PFS was 12.8 (95% CI, 8.6‐16.6) mo in the APP arm vs 4.5 (95% CI, 4.1‐6.7) mo in the PP arm (HR, 0.33 [95% CI, 0.21‐0.58]). Grade 3/4 treatment‐related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum‐based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs., The global phase 3 IMpower132 study evaluated atezolizumab plus pemetrexed and platinum‐based chemotherapy vs chemotherapy alone for first‐line treatment of advanced non‐squamous NSCLC. A subgroup analysis of 101 Japanese patients showed that atezolizumab plus chemotherapy was well tolerated in these patients and provided overall treatment benefit vs chemotherapy alone. These results are consistent with the global study.

Background TAS-102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. Methods This investigator-initiated, open-label, single-arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Forty-one patients were treated with TAS-OX. No dose-limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS-102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. In the intention-to-treat population, the ORR was 2.4% (95% CI, 0%-12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival was 2.7 months (95% CI, 2.4-4.8 months) and median overall survival was 6.8 months (95% CI, 5.7-10 months). Conclusions TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression-free survival and overall survival were encouraging in this heavily pretreated population. Lay summary For metastatic colorectal cancer, the treatment combination of TAS-102 and oxaliplatin was found to be well-tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.

DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti‐PD‐1/PD‐L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti‐PD‐1/PD‐L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum‐based chemotherapy. DDR alterations (including ATM) were associated with a non‐significantly higher ORR to PD‐1/PD‐L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non‐significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations were associated with a non‐significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD‐1/PD‐L1 blockade versus 24% ORR in patients with, DDR alterations are associated with higher ORR and nonsignificantly prolonged OS in patients with advanced UC receiving PD‐1/PD‐L1 inhibitors. However, presence of ATM alterations correlated with shorter OS, irrespective of a nonsignificant trend towards higher ORR to anti‐PD‐1/PD‐L1 agents.

Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-3 and platelet-derived growth factor receptor-a/-b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC-C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC-C is a randomised controlled, double-blinded, phase II trial in mCRC patients that received a first-line non-oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1-d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty-three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32-1.30; P = .2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48-2.23; P = .9387; DCR: F + P: 50% vs F + N: 66,7%; P = .2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second-line therapy of mCRC.

OBJECTIVE To evaluate the clinical usefulness of Immunotherapy Response Evaluation Criteria in Solid Tumours (iRECIST) in patients with metastatic urothelial carcinoma (UC) treated with pembrolizumab. The iRECIST is designed to accurately capture the tumour response treated with immunotherapy. PATIENTS AND METHODS We conducted a multicentre retrospective study evaluating the clinical utility of iRECIST in 91 patients with metastatic UC treated with second-line pembrolizumab. The objective response (OR) and time to progression (TTP) in accordance with both iRECIST and RECIST version 1.1 were compared with overall survival (OS) and risk of all-cause mortality, and analysed using log-rank and multivariable Cox regression models, respectively. Predictive performance of the criteria was studied using Harrell's concordance index (c-index). The clinical usefulness of each criterion was compared using decision curve analysis. RESULTS Of 57 patients with progressive disease per RECIST, a considerable number of patients were reclassified to immune stable disease (six, 10.5%), immune partial response (two, 3.5%), and immune complete response (two, 3.5%) per iRECIST. Multivariable Cox regression models showed that both OR (hazard ratio [HR] 0.10, 95% confidence interval [CI] 0.03-0.35; P = 0.001) and TTP (HR 0.59, 95% CI 0.46-0.77; P

Aquation free energy profiles of neutral cisplatin and cationic monofunctional derivatives, including triaminochloroplatinum(II) and cis-diammine(pyridine)chloroplatinum(II), were computed using state of the art thermodynamic integration, for which temperature and solvent were accounted for explicitly using density functional theory-based canonical molecular dynamics (DFT-MD). For all the systems, the "inverse-hydration" where the metal center acts as an acceptor of hydrogen bond has been observed. This has motivated to consider the inversely bonded solvent molecule in the definition of the reaction coordinate required to initiate the constrained DFT-MD trajectories. We found that there exists little difference in free enthalpies of activation, such that these platinum-based anticancer drugs are likely to behave the same way in aqueous media. Detailed analysis of the microsolvation structure of the square-planar complexes, along with the key steps of the aquation mechanism, is discussed.

BACKGROUND/PURPOSE To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. METHODS Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). RESULTS A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4). CONCLUSIONS Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.

Histological ‘phenotypic subtypes’ that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I–III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I–III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease‐free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II–III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893‐patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p

Cost-effectiveness is traditionally treated as a static estimate driven by clinical trial efficacy and drug price at launch. Prior studies suggest that cost-effectiveness varies over the drug's lifetime. We examined the impact of "learning by doing," one of the least studied drivers of changes in cost-effectiveness across the product life cycle. We combined time-series trends in effectiveness over time by cancer regimen using the Surveillance, Epidemiology, and End Results-Medicare database. We estimated the time-varying effects of treatments in colorectal and pancreatic cancer over their life cycle, including FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) and gemcitabine, on survival of patients. Mean prices over time by strength and dosage form were calculated using historical wholesale acquisition costs. We found consistent downward trends in the mortality hazard ratios, which suggest that effectiveness improves over time. In the case of first-line FOLFOX for colorectal cancer, the implied incremental cost-effectiveness ratio based on the observational data fell from $610,000 per life year gained in 2004 to $27,000 per life year gained in 2011. Cost-effectiveness estimated at launch is unlikely to be representative of cost-effectiveness over the drug's lifetime. In the drugs studied, the impact of time-varying clinical effectiveness dominated the impact of changing prices overtime.

Treatment selection markers are generally sought for when the benefit of an innovative treatment in comparison with a reference treatment is considered, and this benefit is suspected to vary according to the characteristics of the patients. Classically, such quantitative markers are detected through testing a marker-by-treatment interaction in a parametric regression model. Most alternative methods rely on modeling the risk of event occurrence in each treatment arm or the benefit of the innovative treatment over the marker values, but with assumptions that may be difficult to verify. Herein, a simple non-parametric approach is proposed to detect and assess the general capacity of a quantitative marker for treatment selection when no overall difference in efficacy could be demonstrated between two treatments in a clinical trial. This graphical method relies on the area between treatment-arm-specific receiver operating characteristic curves (ABC), which reflects the treatment selection capacity of the marker. A simulation study assessed the inference properties of the ABC estimator and compared them with other parametric and non-parametric indicators. The simulations showed that the estimate of the ABC had low bias, power comparable to parametric indicators, and that its confidence interval had a good coverage probability (better than the other non-parametric indicator in some cases). Thus, the ABC is a good alternative to parametric indicators. The ABC method was applied to data of the PETACC-8 trial that investigated FOLFOX4 versus FOLFOX4 + cetuximab in stage III colon adenocarcinoma. It enabled the detection of a treatment selection marker: the DDR2 gene.

Fluorescence microscopy has emerged as an attractive technique to probe the intracellular processing of Pt-based anticancer compounds. Herein, we reported the first through-bond energy transfer (TBET) fluorescent probe NPR1 designed for sensitive detection and quantitation of PtII complexes. The novel TBET probe was successfully applied for ratiometric fluorescence imaging of anticancer PtII complexes such as cisplatin and JM118 in cells. Capitalizing on the ability of the probe to discriminate between PtII complexes and their PtIV derivatives, the probe was further applied to study the activation of PtIV prodrug complexes that are known to release active PtII species after intracellular reduction.

Basic and clinical studies on small bowel adenocarcinoma (SBA) are limited due to the rare nature of this cancer. We established a patient‐derived xenograft (PDX) model from the tumor tissue of an advanced SBA patient with liver and peritoneal metastasis, and a cell line from the PDX. In the PDX model, compared to the control group, 5‐fluorouracil (5‐FU) treatment resulted in statistically significant tumor growth inhibition (TGI), while oxaliplatin (OHP) and irinotecan had no significant inhibitory effects. In combination with 5‐FU, OHP showed the highest rate of TGI. The IC50 for OHP was significantly lower than those for paclitaxel, gemcitabine, and trifluorothymidine in the PDX‐derived cell line when compared to in HT29, a colon cancer cell line. Genetic analysis of the patient tumor, PDX tumor, and the cell line demonstrated consistency in the microsatellite status and mutations in TP53, APC, HRAS, CSF1R, FGFR3, FLT3, PDGFRA, and RET genes. However, the PDX tumor alone had additional mutations, indicating that the PDX‐derived cell line may support the unstable genetic status of the PDX. Our findings confirmed the effectiveness of the combination of OHP and 5‐FU, which is a common treatment for advanced SBA and advanced colorectal cancer, in a preclinical model. This preclinical model of SBA can help in further understanding the biology of SBA., Our data indicated that 5‐FU was the key drug for treatment and OHP alone had the additional effect in combination with 5‐FU.

Progression-free survival (PFS) has been increasingly used as a primary endpoint for early clinical development. The aim of the present work was to develop a model where target lesion dynamics and risk for nontarget progression are jointly modeled for predicting PFS. The model was developed based on a pooled platinum-resistant ovarian cancer dataset comprising four different treatments and a wide range of dose levels. The target lesion progression was derived from tumor growth dynamics based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The nontarget progression hazard was correlated to the first derivative of target lesion tumor size with respect to time. The PFS time was determined by the first occurring event, target lesion progression, or nontarget progression. The final joint model not only captured target lesion tumor growth dynamics but also predicted PFS well. A similar approach can potentially be used to predict PFS in future oncology studies.

Active transport of ions uphill, creating a concentration gradient across a cell membrane, is essential for life. It remains a significant challenge to develop synthetic systems that allow active uphill transport. Here, a transport process fuelled by organometallic compounds is reported that creates a pH gradient. The hydrolysis reaction of PtII complexes results in the formation of aqua complexes that established rapid transmembrane movement ("flip-flop") of neutral Pt-OH species, leading to protonation of the OH group in the inner leaflet, generating OH- ions, and so increasing the pH in the intravesicular solution. The organoplatinum complex effectively transports bound hydroxide ions across the membrane in a neutral complex. The initial net flow of the PtII complex into the vesicles generates a positive electric potential that can further drive uphill transport because the electric potential is opposed to the chemical potential of OH- . The OH- ions equilibrate with this transmembrane electric potential but cannot remove it due to the relatively low permeability of the charged species. As a result, effective hydroxide transport against its concentration gradient can be achieved, and multiple additions can continuously drive the generation of OH- against its concentration gradient up to ΔpH>2. Moreover, the external addition of different anions can control the generation of OH- depending on their anion binding affinity. When anions displayed very high binding affinities towards PtII compounds, such as halides, the external anions could dissipate the pH gradient. In contrast, a further pH increase was observed for weak binding anions, such as sulfate, due to the increase of positive electric potential.

Objective The aim of this study was to evaluate the effect of the interval between CRT and surgery on radiation proctitis, the pathologic response, and postoperative morbidity. Methods This was a cohort study from a phase III, randomized controlled trial (FOWARC study, NCT01211210). Data were retrieved from the leading center of the trial. Patients were divided into the short‐interval (≤7 weeks) group and the long‐interval (>7 weeks) group. The rate of radiation proctitis, pathologic complete regression (pCR) and morbidities were calculated for each group. Multivariate analysis was used to verify the impact of interval on radiation proctitis. Results Surgery was performed in 60 patients after an interval of ≤7 weeks and in 97 patients after an interval of >7 weeks. The two groups according to interval were comparable in terms of baseline demographic and clinicotherapeutic characteristics. Radiation proctitis was identified by imaging in 9 (15.0%) patients in short‐interval group and in 31 (32.0%) patients in long‐interval group (P = .018). Multivariate analysis confirmed the correlation between long interval and radiation proctitis (P = .018). The long interval was significantly associated with longer median operation time compared to the short interval (P = .022). The rates of pCR and postoperative complications were not different between two groups. Conclusions A longer interval after CRT may be associated with higher rate of radiation proctitis and longer operation time. Moreover it did not increase the rate of pCR., A longer interval after CRT may be associated with higher rate of radiation proctitis and more difficult surgical resection. Moreover it did not increase the rate of pCR.

Early identification of metastatic or recurrent colorectal cancer (CRC) patients who will be sensitive to FOLFOX (5‐FU, leucovorin and oxaliplatin) therapy is very important. We performed microarray meta‐analysis to identify differentially expressed genes (DEGs) between FOLFOX responders and nonresponders in metastatic or recurrent CRC patients, and found that the expression levels of WASHC4, HELZ, ERN1, RPS6KB1, and APPBP2 were downregulated, while the expression levels of IRF7, EML3, LYPLA2, DRAP1, RNH1, PKP3, TSPAN17, LSS, MLKL, PPP1R7, GCDH, C19ORF24, and CCDC124 were upregulated in FOLFOX responders compared with nonresponders. Subsequent functional annotation showed that DEGs were significantly enriched in autophagy, ErbB signaling pathway, mitophagy, endocytosis, FoxO signaling pathway, apoptosis, and antifolate resistance pathways. Based on those candidate genes, several machine learning algorithms were applied to the training set, then performances of models were assessed via the cross validation method. Candidate models with the best tuning parameters were applied to the test set and the final model showed satisfactory performance. In addition, we also reported that MLKL and CCDC124 gene expression were independent prognostic factors for metastatic CRC patients undergoing FOLFOX therapy., We performed the microarray meta‐analysis to identify common differentially expressed genes between FOLFOX responders and non‐responders in metastatic or recurrent colorectal cancer patients, and built prediction models with machine learning algorithms.

Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell‐to‐cell crosstalk or phenotypic alterations including the acquisition of platinum‐resistance in OvCa cells. Herein, we report how OvCa‐associated mesothelial cells (OCAMs) induce platinum‐resistance in OvCa cells through direct cell‐to‐cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF‐β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum‐sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell‐to‐cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF‐β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell‐to‐cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum‐resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination., What's new? The clinical characteristics of refractory advanced ovarian cancer suggest that the peritoneum acts as an anchoring point for metastatic tumors, enabling persistent ovarian cancer (OvCa) cell survival. This study shows that ovarian cancer‐associated mesothelial cells (OCAMs) and OvCa cells invade the extracellular matrix of the peritoneum. OCAMs were further found to directly influence persistent OvCa cell survival via FN1 signaling. FN1 on the surface of OCAMs induced activation of the Akt signaling pathway, thereby fueling platinum resistance in OvCa cells. The findings highlight the potential for targeting OCAMs as a novel therapeutic strategy for preventing peritoneal dissemination of ovarian cancer.

Background Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin‐based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin‐induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin‐based chemotherapy. Methods In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI‐CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ‐CIPN20), time to grade 2 neurotoxicity (NCI‐CTCAE or the oxaliplatin‐specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3‐year disease‐free survival (DFS) and adverse events. Results There were no significant differences between the arms in the rate of NCI‐CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ‐CIPN20 or time to grade 2 neurotoxicity using NCI‐CTCAE and the oxaliplatin‐specific neuropathy scale. GM1 substantially decreased participant‐reported acute neurotoxicity (sensitivity to cold items [P, Neuropathy is the most prominent dose‐limiting toxicity of oxaliplatin. Patients receiving Monosialotetrahexosylganglioside (GM1) were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity.

OBJECTIVES To determine the safety and efficacy of the combined regimen of paclitaxel and ifosfamide plus nedaplatin for patients with refractory or relapsed germ cell tumors and impaired renal function. METHODS Of a total of 68 patients who received paclitaxel, ifosfamide and nedaplatin chemotherapy for germ cell tumors, those with an estimated glomerular filtration rate

Enhanced sampling molecular dynamics has been used to model the reduction mechanism of the antitumoral Asplatin Pt(IV) complex, c,c,t-[PtCl2(NH3)2(OH)(aspirin)] in the presence of l-ascorbic acid as reducing agent. In order to overcome the timescale problem, characteristic of many chemical reactions, we enhanced the sampling of the free energy landscape using Metadynamics. To achieve such a goal, the selection of adequate collective variables is crucial for the application of the method. Recently, a new method called Multi-Class Harmonic Linear Discriminant Analysis (MC-HLDA) has been proposed as a tool for constructing collective variables (CVs) for complex chemical processes. The method reduces the dimensionality of the variable space by generating appropriate linear combinations of several relevant chemical descriptors. The aim of this work is to assess the ability and performance of this method in describing the fundamental features of complex chemical reactions such as the Asplatin reduction mechanism in a compact, simple, and physically transparent manner. © 2019 Wiley Periodicals, Inc.

More than 70 % of women with ovarian cancer are diagnosed with advanced-stage disease, which is initially treated with cytoreductive surgery, and combination chemotherapy with platinum-based compounds. Most patients initially respond to platinum-based therapy, but eventually up to 80 % of this responsive cohort becomes refractory due to the development of platinum resistance. This review discusses current and potential therapeutic approaches that exploit biomaterial-based applications to combat platinum resistance either by enhancing the delivery of platinum-based drugs or prodrugs, delivering other toxic non-platinum-based bioactive factors (by themselves or in combination with platinum-based drugs) or by delivering other bioactive factors that re-sensitize resistant ovarian cancer cells to these drugs. The types of materials that are used, the bioactive factors applied (i.e., drug or gene delivery), and the specific agents that are employed to target these types of cancer cells are discussed. We conclude that the unique attributes of biomaterial-based applications can be further explored toward overcoming platinum-resistant ovarian cancer as monotherapy, or in combination with other treatment strategies.

Aggregated β-amyloid (Aβ) is widely considered as a key factor in triggering progressive loss of neuronal function in Alzheimer's disease (AD), so targeting and inhibiting Aβ aggregation has been broadly recognized as an efficient therapeutic strategy for curing AD. Herein, we designed and prepared an organic platinum-substituted polyoxometalate, (Me4 N)3 [PW11 O40 (SiC3 H6 NH2 )2 PtCl2 ] (abbreviated as PtII -PW11 ) for inhibiting Aβ42 aggregation. The mechanism of inhibition on Aβ42 aggregation by PtII -PW11 was attributed to the multiple interactions of PtII -PW11 with Aβ42 including coordination interaction of Pt2+ in PtII -PW11 with amino group in Aβ42 , electrostatic attraction, hydrogen bonding and van der Waals force. In cell-based assay, PtII -PW11 displayed remarkable neuroprotective effect for Aβ42 aggregation-induced cytotoxicity, leading to increase of cell viability from 49 % to 67 % at a dosage of 8 μm. More importantly, the PtII -PW11 greatly reduced Aβ deposition and rescued memory loss in APP/PS1 transgenic AD model mice without noticeable cytotoxicity, demonstrating its potential as drugs for AD treatment.

Background Thymic carcinomas (TCs) are rare aggressive tumors with no standard first‐line treatment. This study was conducted to determine the optimal chemotherapy regimen for advanced TC. Methods This retrospective study included 67 patients treated for stage IV TC in 2006–2015. The primary endpoints were the objective response rate (ORR) and progression‐free survival (PFS) with different chemotherapy regimens. Multivariate Cox regression analysis was used to identify factors associated with PFS, including metastatic status, radiotherapy post‐chemotherapy, primary lesion resection before chemotherapy, and chemotherapy regimen. Results A total of 36 patients received a paclitaxel‐platinum regimen, 31 received a gemcitabine‐platinum regimen, 14 underwent primary lesion resection, and 33 underwent radiotherapy. ORR was 31% (11/36) and 29% (9/31) in the paclitaxel‐platinum and gemcitabine‐platinum groups, respectively (P = 0.890). Median PFS, one‐year PFS rate, and two‐year PFS rate were 7.0 months, 26%, and 6% with paclitaxel‐platinum treatment and 12 months, 48%, and 24% with gemcitabine‐platinum treatment (log‐rank P = 0.030). Median PFS, one‐year PFS rate, and two‐year PFS rate were 18.0 months, 57%, and 33% with surgical resection and 7.3 months, 31%, and 7% without resection (log‐rank P = 0.030). Median PFS, one‐year PFS rate, and two‐year PFS rate were 13.0 months, 52%, and 20% with radiotherapy and 4.3 months, 22%, and 7% without radiotherapy (log‐rank P = 0.001). In multivariate analysis, metastatic status (hazard ratio [HR], 0.33, P = 0.004), surgical resection (HR, 0.32; P = 0.004), and radiotherapy (HR, 0.32; P

BACKGROUND The first-line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination of nedaplatin and amrubicin would be a promising treatment approach for patients with SCC. Therefore, a phase II study of this chemotherapeutic combination was designed to evaluate its efficacy and safety for treatment-naive patients with advanced SCC. METHODS A total of 21 treatment-naive patients with stage IIIB/IV or postoperative recurrent SCC were enrolled from six institutions. Nedaplatin (100 mg/m2 ) on day 1 and amrubicin (25 mg/m2 ) on days 1-3 were administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR), while the secondary endpoints included overall survival (OS), progression-free survival (PFS), and drug toxicities. RESULTS Partial response was observed in seven of 21 cases (ORR, 33.3%; 95% confidence interval [CI], 14.5-52.2). Disease control rate, which includes stable disease, was 71.4%. Median OS and PFS was 14.6 and 4.1 months, respectively. This regimen did not cause any treatment-related deaths. Grade 3/4 neutropenia developed in 8 of 21 cases (38.1%); however, febrile neutropenia developed in only 9.5% of the cases. Grade 3/4 gastrointestinal or neuromuscular toxicities were not observed. CONCLUSION The efficacy of the combination of nedaplatin and amrubicin was comparable to that of other conventional chemotherapeutic regimens for treatment-naive patients with advanced SCC, and no severe gastrointestinal or neuromuscular toxicities were observed. This combination therapy may be an alternative treatment approach, particularly in patients who cannot tolerate gastrointestinal or neuromuscular toxicities.

A series of Pt(II) complexes trans-[Pt(PPh(2)allyl)(2)(k(1)-S-SR)(2)], 1, PPh(2)allyl = allyldiphenylphosphine, SR = pyridine-2-thiol (Spy, 1a), 5-(trifluoromethyl)-pyridine-2-thiol (SpyCF(3)-5, 1b), pyrimidine-2-thiol (SpyN, 1c), benzothiazole-2-thiol (Sbt, 1d), benzimidazole-2-thiol (Sbi, 1e), were synthesized. They were characterized by NMR, HR ESI-MS and X-ray crystallography. These complexes were treated by human cancer cell lines (A549, SKOV3, MCF-7) and shown the promising antitumor effects in comparison with cisplatin. These compounds were showed suitable selectivity between tumorigenic and non-tumorigenic (MCF-10A) cell lines. Analyses of cell cycle progression and apoptosis were conducted for 1a, the best cytotoxic compound, to screen dose/time response and to study the effects of the antiproliferative mechanism. The electrophoresis mobility shift assay was performed to assess the direct interaction of 1a with DNA and the strong genotoxic ability was indicated through comet assay method.

The targeted delivery of chemotherapeutic drugs is a major challenge in the clinical treatment of cancer. Herein, we constructed a multifunctional DNA nanoplatform as a versatile carrier of the highly potent platinum-based DNA intercalator, 56MESS. In our rational design, 56MESS was efficiently loaded into the double-bundle DNA tetrahedron through intercalation with the DNA duplex. With the integration of a nanobody that both targets and blocks epidermal growth factor receptor (EGFR), the DNA nanocarriers exhibit excellent selectivity for cells with elevated EGFR expression (a common biomarker related to tumor formation) and combined tumor therapy without obvious systemic toxicity. This DNA-based platinum-drug delivery system provides a promising strategy for the treatment of tumors.

New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor PtII complex targeting a tumor-associated protein, rather than DNA, under cellular conditions. Complex [(bis-NHC)Pt(bt)]PF6 (1 a; Hbt=1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis-NHC-ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active-site cysteine of ASNS.

Background Compared with single‐drug TACE, our previous phase III study demonstrated that triple‐drug transarterial chemoembolization (TACE) prolonged overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). The aim of this study was to find which patients can benefit from the triple drugs TACE compared with single‐drug TACE. Methods Patients in the triple‐drug TACE arm received sponge embolization and emulsions composed of 50 mg epirubicin, 50 mg lobaplatin, 6 mg mitomycin C, and lipiodol, while patients in the single‐drug TACE arm received sponge embolization and emulsions composed of 50 mg epirubicin and lipiodol. From July 2007 to November 2009, 244 patients (224 men and 20 women; age ranged from 21 to 75 years) from our phase III study formed the initial cohort. From January 2010 to June 2015, external validation cohort was composed of 449 patients (411 men and 38 women; age ranged from 18 to 75 years) from another institution. The validation cohort after propensity score matching (PSM) (n = 374) was analyzed. Cox proportional hazard model was used to evaluate the interaction term between treatments for each subgroup. This retrospective study was approved by the institutional review board at each center. Results No difference was observed in the baseline characteristic of three cohorts. This exploratory analysis showed that triple‐drug TACE brought a survival benefit in the initial cohort, validation cohort (before PSM), and validation cohort (after PSM) compared with single‐drug TACE. The outcomes of three cohorts all showed that a significantly greater OS triple‐drug chemotherapy benefit versus single‐drug chemotherapy was seen in patients with large tumors (larger than 10 cm) while no survival difference was seen in patients with small tumors (10 cm or smaller). Conclusions Triple‐drug TACE seems to benefit patients with HCC larger than 10 cm in particular compared with single‐drug TACE.

Jagged1, the essential ligand of the Notch signalling pathway, is highly expressed in metastatic prostate cancer, and its high expression in breast cancer is linked to poor survival rates. However, the mechanism of Jagged1′s involvement in platinum‐resistant ovarian cancer has not been thoroughly elucidated to date. The purpose of the present study was to investigate the roles of Jagged1 in the platinum resistance of ovarian cancer and its possible mechanisms. Compared with a platinum responsive group of ovarian epithelial cell carcinomas, we found the positive staining intensity of Notch1, Notch2, Jagged1, STAT3 and Epithelial‐mesenchymal transition (EMT) proteins were lower in a platinum‐resistant group. The DDP‐resistant ovarian cancer cell line (C13K) had a higher IC50 of DDP than its parental cell line (OV2008) (P

MCM8 and MCM9 are paralogues of the MCM2-7 eukaryotic DNA replication helicase proteins and play a crucial role in a homologous recombination-mediated repair process to resolve replication stress by fork stalling. Thus, deficiency of MCM8-9 sensitizes cells to replication stress caused, for example, by platinum compounds that induce interstrand cross-links. It is suggested that cancer cells undergo more replication stress than normal cells due to hyperstimulation of growth. Therefore, it is possible that inhibiting MCM8-9 selectively hypersensitizes cancer cells to platinum compounds and poly(ADP-ribose) polymerase inhibitors, both of which hamper replication fork progression. Here, we inhibited MCM8-9 in transformed and nontransformed cells and examined their sensitivity to cisplatin and olaparib. We found that knockout of MCM9 or knockdown of MCM8 selectively hypersensitized transformed cells to cisplatin and olaparib. In agreement with reported findings, RAS- and human papilloma virus type 16 E7-mediated transformation of human fibroblasts increased replication stress, as indicated by induction of multiple DNA damage responses (including formation of Rad51 foci). Such replication stress induced by oncogenes was further increased by knockdown of MCM8, providing a rationale for cancer-specific hypersensitization to cisplatin and olaparib. Finally, we showed that knocking out MCM9 increased the sensitivity of HCT116 xenograft tumors to cisplatin. Taken together, the data suggest that conceptual MCM8-9 inhibitors will be powerful cancer-specific chemosensitizers for platinum compounds and poly(ADP-ribose) polymerase inhibitors, thereby opening new avenues to the design of novel cancer chemotherapeutic strategies.

Background A retrospective study was conducted to assess the efficacy and toxicity of lobaplatin‐etoposide (EL) chemotherapy for small cell lung cancer (SCLC). Methods The clinical data of 50 patients treated in our department from May 2014 to March 2018 were obtained. Untreated patients with SCLC administered LBP intravenously (IV) at 30 mg/m2 on day 1 and etoposide IV at 100 mg/m2 on days 1, 2, and 3 were enrolled. The treatment was cycled every 21 days. Results The median overall and progression‐free survival rates of the 50 patients were 11.67 (range: 7.30–16.04) and 6.8 (range: 5.25–8.35) months, respectively, with an overall response rate of 66% and a disease control rate of 90%. The most frequent drug‐related adverse effects were leukopenia and neutropenia, and no grade 3/4 hepatotoxicity or nephrotoxicity was observed. Conclusion These results indicate that LBP‐containing chemotherapy is effective and tolerable for SCLC in terms of response and survival.

Compounds condensing DNA and RNA molecules can essentially affect important biological processes including DNA replication and transcription. Here, this work shows with the aid of total intensity light scattering, gel electrophoresis, and atomic force microscopy (AFM) that the substitution-inert polynuclear platinum complexes (SI-PPCs), particularly [{trans-Pt(NH3 )2 (NH2 (CH2 )6 - NH3 + )}2 -μ-{trans-Pt(NH3 )2 (NH2 (CH2 )6 NH2 )2 }]8+ (Triplatin NC), exhibit an unprecedented high potency to condense/aggregate fragments of DNA and RNA as short as 20 base pairs. SI-PPCs condensates are distinctive from those generated by the naturally occurring polyamines (commonly used DNA compacting/condensing agents). Collectively, the results further confirm that SI-PPCs are very efficient inducers of condensation of DNA and RNA, including their short fragments that might have potential in gene therapy, biotechnology, and bionanotechnology. Moreover, the data confirm the structural advantages of the phosphate clamp, with a well-defined rigid DNA recognition motif in initiating condensation and aggregation phenomena on oligonucleotides.

Several mobile phase additives (i.e., organic acids and their ammonium salts) were used to modulate the chromatographic retention of cyanocobalamin and its cis-diaminemonochloroplatinum(II) conjugate, depending on the specific nature of the stationary phase. Regardless of the mobile phase additive, the positively charged cyanocobalamin-cis-diaminemonochloroplatinum(II) conjugate was systematically less retained than cyanocobalamin on a conventional octadecyl-silica column. In contrast, the amide-embedded C18 column exhibited a progressive increase in the conjugate retention time upon changing the mobile phase additive from organic (acetic, formic and trifluoroacetic) acids to ammonium salts, ultimately leading to an inversion of the elution order. This change of retention was interpreted by invoking the interplay between hydrophobic interactions, hydrogen bonding between the conjugate and the polar amide groups and the ion-pairing ability of the lyophilic counterions, whereby the acetate anion was found to be the most suitable to control the solute retention.

Panitumumab is approved for RAS wild‐type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first‐line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab‐based maintenance after oxaliplatin discontinuation in RAS wild‐type patients. First‐line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression‐free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5‐fluorouracil/leucovorin (5‐FU/LV) maintenance was 21 (interquartile range: 11–41) weeks; that of 5‐FU/LV ± bevacizumab maintenance was 16 (6–31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3–50.4) and 39.1 (34.2–63.0) months for panitumumab plus 5‐FU/LV maintenance and 24.1 (17.7–33.0) and 28.9 (21.0–32.0) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3–23.6) and 15.4 (11.6–18.4) months for panitumumab plus 5‐FU/LV maintenance and 12.6 (9.4–16.2) and 13.1 (9.5–16.6) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7–42.8) and 33.5 (24.5–54.9) months for panitumumab plus 5‐FU/LV maintenance and 16.4 (12.4–24.1) and 23.3 (15.7–26.3) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8–19.2) and 9.7 (5.8–14.8) months and 7.1 (5.6–10.2) and 7.0 (3.9–10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5‐FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first‐line treatment. Prospective studies are warranted., What's new? Panitumumab is an anti‐EGFR antibody used in the treatment of RAS wild‐type metastatic colorectal cancer. But is it useful for long‐term therapy in these patients, especially after more toxic therapies like oxaliplatin are discontinued? In this retrospective analysis, the authors found that a maintenance regimen including panitumumab was well tolerated and may be associated with better outcomes than non‐panitumumab strategies. Patients who received panitumumab‐based maintenance therapy were also more likely to have had a good response to first‐line treatment. The results from this study indicate that further, prospective studies are warranted.

Controlled generation of cytotoxic agents with near-IR light is a current focus of photoactivated cancer therapy, including that involving cytotoxic platinum species. Herein, we present a novel heptamethine cyanine scaffolded Pt(II) complex, IR797-Platin (1), which exhibits unprecedented Pt-O bond scission and enhancement in DNA platination in near-IR light. Complex 1 also displayed significant singlet oxygen quantum yield thereby qualifying as a near-IR photodynamic therapeutic agent. Complex 1 showed 30–60 fold enhancements of cytotoxicity in near-IR light in various cancer cell lines. The cellular imaging properties of 1 were also leveraged to observe its significant co-localization in cytoplasmic organelles. This is the first demonstration of a near-IR light-initiated therapy involving the cytotoxic effects of both active cisplatin and singlet oxygen.

Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third‐line treatment for pretreated metastatic colorectal cancer (mCRC) patients harboring wild‐type KRAS exon 2. Objective response rate (ORR) was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% CI, 0.105‐0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first‐ and second‐line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine, were enrolled. ORR and disease control rate were 25.0% (95% CI: 11.5‐38.4) and 72.5% (95% CI: 56.8‐86.4), respectively. Median progression‐free survival (PFS), overall survival (OS), and number of courses were 5.70 months (95% CI: 2.7‐7.9), 15.1 months (95% CI: 11.8‐19.0), and 10.5 (range: 3.0‐31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). C max mean was 723.2 μg/mL after first dose. High area under the curve (AUC)last variance was associated with t1/2 range of 131.2‐1209.6 hours (median, 174.4 hours). Early tumor shrinkage (ETS) and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS,BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and ETS are predictors for PFS, and whether performance status, synchronous metastasis, and ETS are predictors for OS. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in mCRC patients.

Cancer cells typically shift their metabolism to aerobic glycolysis to fulfill the demand of energy and macromolecules to support their proliferation. Glucose transporter (GLUT) family-mediated glucose transport is the pacesetter of aerobic glycolysis and, thus, is critical for tumor cell metabolism. Yin Yang 1 (YY1) is an oncogene crucial for tumorigenesis; however, its role in tumor cell glucose metabolism remains unclear. Here, we revealed that YY1 activates GLUT3 transcription by directly binding to its promoter and, concomitantly, enhances tumor cell aerobic glycolysis. This regulatory effect of YY1 on glucose entry into the cells is critical for YY1-induced tumor cell proliferation and tumorigenesis. Intriguingly, YY1 regulation of GLUT3 expression, and, subsequently, of tumor cell aerobic glycolysis and tumorigenesis, occurs p53-independently. Our results also showed that clinical drug oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis. Together, these results link YY1's tumorigenic potential with the critical first step of aerobic glycolysis. Thus, our novel findings not only provide new insights into the complex role of YY1 in tumorigenesis but also indicate the potential of YY1 as a target for cancer therapy irrespective of the p53 status.

BACKGROUND AND OBJECTIVES Esophageal squamous cell carcinoma (ESCC) exhibits good reactivity to chemoradiation therapy (CRT). The dysregulation of F-Box and WD Repeat Domain Containing 7 (FBXW7) is associated with therapeutic resistance in cancer cells. However, the correlation between FBXW7 expression and CRT sensitivity in patients with clinical ESCC has been investigated only in few studies. Therefore, this study aimed to elucidate the significance of FBXW7 expression in pretreatment biopsy specimens from patients with ESCC receiving CRT. METHODS We investigated the relationship between FBXW7 expression and CRT sensitivity in 30 pretreatment biopsy specimens with histological grades of post-CRT surgically resected tumors. Furthermore, we evaluated the effects of high FBXW7 expression on the sensitivity to cytotoxic agents, including docetaxel and nedaplatin, and radiation in ESCC cells in vitro. RESULTS High FBXW7 expression before CRT correlated with a good pathological CRT response in patients with advanced ESCC (P

Chagas disease is an endemic illness in Latin America caused by the parasite Trypanosoma cruzi. Current chemotherapies are old and inadequate, and the emergence of drug-resistant strains underscores the need of new drugs. Platinum-based complexes have been shown to be a promising approach against parasitic diseases. In this work, the effect of 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolate-1-oxide Pt(II) hexafluorophosphate, Pt-dppf-mpo, was studied on T. cruzi. A promising antitrypanosomal activity was determined for the CL Brener strain with a low cytotoxicity determined using in vitro-cultured mammal cells. The compound uptake in parasites treated with concentrations of 1× and 10× the IC50 value reached ~75% and 19%, respectively. Pt-dppf-mpo induced necrosis after 24 hr of parasite incubation. This event was preceded by depolarization of mitochondrial membrane potential. Cell vitality assays showed high esterase activity in treated parasites. However, despite this increase in metabolic activity, treated epimastigotes showed rounded morphology and loss of flagellum with a reduction in mobility as compound concentration and/or time of incubation was increased. At last, we demonstrate that Pt-dppf-mpo incubation also affects the trypomastigote infection process as well as the infection persistence evaluated as the number of amastigotes per cell in a dose-dependent manner.

The formation of triple-helical DNA is implicated in the regulation of gene expression. The triplexes are, however, unstable under physiological conditions so that effective stabilizers for the triplex formation are needed. Herein, we describe a new strategy for the stabilization of such triplexes that is based on antitumor substitution-inert polynuclear platinum complexes (SI-PPCs). These compounds were previously shown to bind to DNA through the phosphate clamp-a discrete mode of DNA-ligand recognition distinct from the canonical intercalation and minor-groove binding. We have found that SI-PPCs efficiently inhibit DNA synthesis by DNA polymerase in sequences prone to the formation of pyrimidine- and purine-motif triplex DNAs. Moreover, the results suggest that SI-PPCs are able to induce the formation of triple-helical DNA between duplexes and strands that are not completely complementary to each other. Collectively, these data provide evidence that SI-PPCs are very efficient stabilizers of triple-stranded DNA that might exert their action by stabilizing higher-order structures such as triple-helical DNA.

Lobaplatin is the third-generation platinum drug that has been shown promising antitumor activity in preclinical studies and clinical trials for multiple human cancers except prostate cancer. In this study, we investigated the role of lobaplatin on prostate cancer progression and the underlying molecular mechanism. We treated a variety of prostate cancer cell lines with different doses of lobaplatin and examined cell cycle progression, cell apoptosis, cell proliferation, and cell migration. Moreover, we also assessed the in-vivo antitumor activity of lobaplatin using xenograft mouse model. Importantly, we further dissected the underlying molecular mechanism by examining the expression of AR and ERG, as well as their downstream targets. We found that lobaplatin arrested cell cycle progression in G2/M phase and trigged cell apoptosis. Lobaplatin also dramatically inhibited cell proliferation and migration in vitro. Consistently, lobaplatin significantly suppressed tumor growth in xenograft mouse model. Mechanistically, the expression of AR and ERG, as well as their downstream targets, was markedly decreased upon treatment with lobaplatin in prostate cancer cells. Altogether, our results suggest that lobaplatin displayed favorable antitumor activity on prostate cancer both in vitro and in vivo, providing molecular basis and rational for using lobaplatin to combat human prostate cancer.