Cancer Treatment Pathway Research Articles

The Hippo pathway as a drug target in gastric cancer

The Hippo tumor suppressor pathway is critical for balancing cellular differentiation and proliferation in response to cell-cell contact, mechanical signals and diffusible signals such as lysophosphatidic acid. Hippo pathway signaling is frequently dysregulated in gastric cancer (GC), as well as many other kinds of solid tumors, contributing to multiple aspects of malignant progression including unchecked cell division and metastasis. Considering the importance of this Hippo pathway in cancer, its pharmacological disruption may be of huge benefit in the fight against this disease. In this review, we summarize the components of the Hippo pathway, its crosstalk with other major oncogenic signaling pathways, common mechanisms of its dysregulation, as well as potential therapeutic approaches of targeting this pathway for cancer treatment, specifically in a GC context.

Abstract A178: Targeting the ATM-mediated DNA damage response pathway for cancer treatment

Abstract Epigenetic modulators have emerged as potent therapeutic agents for treatment of patients with cancers. We have developed dual-function small molecules targeting activation of ATM, the DNA damage response transducer, ataxia telangiectasia mutated gene product, and inhibition of histone deacetylases (HDACi). The goal is to develop a single-molecule therapeutic that optimizes the protective effects of ATM activation in normal tissue while targeting HDAC inhibition to sensitize cancerous tissue to radiation. The candidate compound SP-1-161 is a hydroxamic acid that was rationally designed by optimizing ATM activation in the cap domain. In vitro assays against a panel of Class I and Class II HDAC enzymes identified SP-1-161 as a pan-HDAC inhibitor with nanomolar potency (IC50 = 8 nM). Western analysis confirms that SP-1-161 increases acetylated histone H3/H4 and α-tubulin and activates ATM (p-ATM/S1987) in MCF7 cells. The cytotoxicity values (IC50) were in low micro-molar ranges in normal breast epithelial (184A1) and breast cancer (MCF7) cell lines. Radiation clonogenic survival assays demonstrated that the compound protected nonmalignant 184A1 cells (from D0 = 1 Gy to D0 =1.4 Gy) while increasing sensitivity of malignant MCF7 cells to IR (from D0=1.6 Gy to D0=1.12 Gy). Furthermore, in vivo plasma pharmacokinetics following oral administration revealed the area under the curve of 415.79 ng/ml × h with the half-life 1.94 h. Together, our results demonstrate that SP-1-161 is an unprecedented radiation chemotherapeutic agent for treating cancers and protecting normal cells, potentially by targeting the DDR signaling pathways. Citation Format: Scott Grindrod, Alfredo Velena, Mira Jung. Targeting the ATM-mediated DNA damage response pathway for cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A178.

Basic understanding and therapeutic approaches to target toll-like receptors in cancerous microenvironment and metastasis.

Toll-like receptors (TLRs) are transmembrane components that sense danger signals, like damage- and pathogen-associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders. In pathological conditions, such as cancer, they can present both tumor and receptor-specific roles. Although the roles of individual TLRs in various cancers have been described, the effects of targeting TLRs to treat cancer and prevent metastasis are still controversial. A growing body of literature has suggested contribution of both activators and inhibitors of TLR signaling pathway for cancer treatment, dependent on several context-specific factors. In short, TLRs can play dual roles with contradictory outcomes in neoplastic conditions. This hampers the development of TLR-based therapeutic interventions. A better understanding of the interwoven TLR pathways in cancerous microenvironment is necessary to design TLR-based therapies. In this review, we consider the molecular mechanisms of TLRs signaling and their involvement in tumor progression. Therapeutic modalities targeting TLRs for cancer treatment are discussed as well.

Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment. Mol Cancer Ther; 16(11); 2399-409. ©2017 AACR.

Effect of a See and Treat clinic on skin cancer treatment time.

Many plastic surgery departments in Australasia have experienced increasing referrals for management of skin lesions. This has driven a demand for new strategies to decrease patient waiting time and administrative costs. The aim of this study was to determine if a purpose-built See and Treat skin cancer clinic could provide a faster skin cancer treatment pathway with comparable clinical outcomes and acceptability to patients. This was a prospective observational study of patients treated through the See and Treat clinic with a retrospective control cohort. The prospective 'See and Treat' cohort included a consecutive series of 106 patients, while the retrospective cohort included a consecutive series of 200 patients. Patient demographics, time from referral to surgery and operative measures were analysed. One hundred patients in the prospective cohort completed an anonymous satisfaction survey regarding their treatment. The average time from referral to surgery was reduced from 121 days in the retrospective cohort to 60 days in the See and Treat cohort (P < 0.001). Rates of complete excision of malignant and premalignant lesions were not different between the two groups, being 93% (178/191) and 91% (76/84), respectively (P = 0.609). Ninety-five percent (95/100) of patients were satisfied with their See and Treat experience overall. We show that a considerable reduction in the time between referral and surgery can be achieved through a See and Treat clinic without compromise of the success of surgical treatment. Moreover, such a treatment pathway has been shown to be acceptable, and largely preferable, to patients.

Eugenol inhibits oxidative phosphorylation and fatty acid oxidation via downregulation of c-Myc/PGC-1\u03b2/ERR\u03b1 signaling pathway in MCF10A-ras cells

Alteration in cellular energy metabolism plays a critical role in the development and progression of cancer. Targeting metabolic pathways for cancer treatment has been investigated as potential preventive or therapeutic methods. Eugenol (Eu), a major volatile constituent of clove essential oil mainly obtained from Syzygium, has been reported as a potential chemopreventive drug. However, the mechanism by which Eu regulates cellular energy metabolism is still not well defined. This study was designed to determine the effect of Eu on cellular energy metabolism during early cancer progression employing untransformed and H-ras oncogene transfected MCF10A human breast epithelial cells. Eu showed dose-dependent selective cytotoxicity toward MCF10A-ras cells but exhibited no apparent cytotoxicity in MCF10A cells. Treatment with Eu also significantly reduced intracellular ATP levels in MCF10A-ras cells but not in MCF10A cells. This effect was mediated mainly through inhibiting oxidative phosphorylation (OXPHOS) complexs and the expression of fatty acid oxidation (FAO) proteins including PPARα, MCAD and CPT1C by downregulating c-Myc/PGC-1β/ERRα pathway and decreasing oxidative stress in MCF10A-ras cells. These results indicate a novel mechanism involving the regulation of cellular energy metabolism by which Eu may prevent breast cancer progression.

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.

The Small Molecules Targeting Ubiquitin-Proteasome System for Cancer Therapy.

The ubiquitin-proteasome system (UPS) is the major pathway for degrading the intracellular proteins. The 2004 Nobel Prize in Chemistry was awarded to Rose, Hershko, and Ciechanover to highlight the fundamental importance of UPS. The alterations in this process have been shown to contribute to the cancer progression. Hence, UPS has become a popular target for developing chemotherapeutics against tumours. The application of bortezomib showed high efficiency in treating haematological malignancies by interfering with UPS activity. Many compounds are being screened and evaluated in recent pharmacological advances, either as single agents or in synergy with other drugs, and more to be revealed. In the present review, we exhibit the crucial ingredients involved in UPS and discuss the current situation of small molecules targeting various components of ubiquitination pathway in cancer treatment.

Discovery of Hedgehog Antagonists for Cancer Therapy.

The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly. A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented. Given the selectivity of small molecules targeting, this pathway for cancer treatment compared to kinase, tubulin or HDAC inhibitors, several such antagonists have been discovered, of which some are in preclinical development and clinical studies. Most of the reported small molecules primarily antagonize the Smoothened receptor although agents targeting Gli1 transcription factor and Shh ligand have also been discovered. Till date, nine Smo antagonists have been evaluated in clinical trials.GDC- 0449/Vismodegib and NVP-LDE225/Erismodegib, were granted approval by the U.S. Food and Drug Administration (U.S. FDA) for the treatment of basal cell carcinoma. The challenge is to identify agents that target the pathway downstream of Smo and develop strategies to overcome acquired drug resistance to the current Smo inhibitors with deeper understanding of the resistance mechanisms.

Impact of Positron Emission Tomography and Endoscopic Ultrasound Length of Disease Difference on Treatment Planning in Patients with Oesophageal Cancer

AimsTreatment decision making and planning in patients with oesophageal cancer are guided by radiological measurement of length of disease (LoD). This study aimed to investigate differences in positron emission tomography (PET) and endoscopic ultrasound (EUS) LoD. Their prognostic significance was also assessed. Materials and methodsLoD was measured from PET and EUS staging investigations by one observer for each modality. Bland–Altman analysis and Wilcoxon signed rank tests assessed agreement and differences in measurements. In terms of radiotherapy planning, the proportion of cases with a clinically significant difference of more than 2 cm between PET and EUS was also calculated. Univariable and multivariable analysis assessed association with overall survival. A P-value < 0.05 was considered statistically significant. ResultsConsecutive patients (n = 160, median age 66.0 years [range 24–83], males = 124, adenocarcinomas = 115) staged with PET/CT and EUS between 2011 and 2014 were included. PET tended to under-measure LoD compared with EUS. The median PET and EUS LoD was 6.4 and 8.0 cm, respectively. PET and EUS LoD was significantly different (Z = −7.021, P < 0.001). EUS LoD was more than 2 cm longer than PET LoD in 61 cases (38.1%). In eight cases (5.0%), PET LoD was more than 2 cm longer than EUS LoD. Both variables had prognostic significance in univariable analysis, but were not independent predictors of overall survival. ConclusionThere are significant differences in PET and EUS measurement of LoD. This could affect clinical decision making and radiotherapy treatment planning. Clinically significant differences between EUS and PET LoD could lead to a risk of geographical miss in up to 38.1% of cases if the PET/CT measurement alone had been used for radiotherapy planning. These results highlight the continued benefit of EUS in the oesophageal cancer staging and treatment pathway.

Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: molecular basis and pathophysiological consequences.

Cancer cells reprogram their metabolism to maintain both viability and uncontrolled proliferation. Although an interplay between the genetic, epigenetic and metabolic rewiring in cancer is beginning to emerge, it remains unclear how this metabolic plasticity occurs. Here, we report that in prostate cancer cells (PCCs) microRNAs (miRNAs) greatly contribute to deregulation of mitochondrial fatty acid (FA) oxidation via carnitine system modulation. We provide evidence that the downregulation of hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378 induced an increase in both expression and activity of CPT1A, CACT and CrAT in malignant prostate cells. Moreover, the analysis of human prostate cancer and prostate control specimens confirmed the aberrant expression of miR-124-3p, miR-129-5p and miR-378 in primary tumors. Forced expression of the miRNAs mentioned above affected tumorigenic properties, such as proliferation, migration and invasion, in PC3 and LNCaP cells regardless of their hormone sensitivity. CPT1A, CACT and CrAT overexpression allow PCCs to be more prone on FA utilization than normal prostate cells, also in the presence of high pyruvate concentration. Finally, the simultaneous increase of CPT1A, CACT and CrAT is fundamental for PCCs to sustain FA oxidation in the presence of heavy lipid load on prostate cancer mitochondria. Indeed, the downregulation of only one of these proteins reduces PCCs metabolic flexibility with the accumulation of FA-intermediate metabolites in the mitochondria. Together, our data implicate carnitine cycle as a primary regulator of adaptive metabolic reprogramming in PCCs and suggest new potential druggable pathways for prevention and treatment of prostate cancer.

Abstract 1159: Targeting novel mucin synthesis pathway for pancreatic cancer treatment

Abstract Pancreatic cancer (PC) is most fatal and is the fourth leading cause of cancer related deaths in USA with a least five year survival of &amp;lt;7%. Although several overexpressed mucin subtypes (MUC1, MUC4, MUC5AC, and MUC16) that impede drug delivery to PC have been targeted with limited results, core enzymes involved in mucin biosynthesis have yet to be evaluated as potential targets. The core 2 β 1,6 N-acetylglucosaminyltransferase (GCNT3/C2GNT) plays a significant role in mucin glycan biosynthesis. We analyzed GCNT3 expression on 180 specimens from individuals with PC (90) or matched controls (90). Patients with low GCNT3 expression survived longer than patients with high GCNT3 expression (median survival: 17.5 vs. 10.5 months, p=0.036). We observed a significant increase in GCNT3 mRNA expression (103.16 folds; p&amp;lt;0.0001) in correlation with increased mucins subtypes (p&amp;lt;0.05) in the pancreatic tumors from genetically engineered mouse (GEM) compared with pancreata from wild-type mice, as determined by Next-generation Sequencing/RNAseq analysis. In in silico studies, blind docking simulations revealed that a novel drug talniflumate binds to GCNT3 with a better docking affinity of -8.3 kcal/mol. We synthesized talniflumate and determined quality/purity using NMR, HRMS, and HPLC for in vitro and in vivo studies. Pancreata from 6-week-old Kras GEM (N=6/group) treated with talniflumate showed a significant decrease in GCNT3 and mucin expression in PanIN lesions. In human PC MiaPaCa cell line, talniflumate reduced GCNT3 expression and the number of mucin-positive cells (38% p&amp;lt;0.0001). Further, PC cells (BxPc3 and Panc1) were treated with talniflumate for 24 hrs for mucin disruption followed by radioactive 3H gemcitabine treatment for 2 hrs. The cells treated with talniflumate showed 40% (p&amp;lt;0.03) and 50% (p&amp;lt;0.025) increased 3H gemcitabine uptake in BxPc3 and Panc1 cells compared to respective controls. GCNT3 CRISPR knock out PC cells and talniflumate treated PC cells showed a reduction in cell proliferation and significantly reduced spheroid formation (p&amp;lt;0.05). In in vivo, we did not observe any overt toxicity upon talniflumate treatment as determined by liver enzyme toxicity and body weight gain (N=5 mice/group). BxPC3 cells implanted nude mice (N=5 mice/group) treated with talniflumate or GCNT3 siRNA showed a marked reduction in xenograft tumors compared with untreated controls. Both talniflumate and GCNT3 siRNA significantly inhibited xenograft tumor weight (48% p&amp;lt;0.002 with siRNA, 63% p&amp;lt;0.0001 with talniflumate) and tumor volume (75% p&amp;lt;0.0001 with both siRNA and talniflumate) and GCNT3 enzyme activity (28% p&amp;lt;0.03). Transcriptome analysis of xenograft tumors (N=3/group) treated with GCNT3 SiRNA or talniflumate showed reduced GCNT3 and top hits related to mucin expression. These results justify the use of talniflumate for mucin synthesis disruption, thereby enhancing the uptake of gemcitabine and thereby efficacy for PC treatment. Citation Format: Altaf Mohammed, Naveena B. Janakiram, Venkateshwar Madka, Gaurav Kumar, Scott Edgar, Gopal Pathuri, Taylor Bryant, Yuting Zhang, Hariprasad Gali, Yan Daniel Zhao, Stan Lightfoot, Chinthalapally V. Rao. Targeting novel mucin synthesis pathway for pancreatic cancer treatment [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 1159. doi:10.1158/1538-7445.AM2017-1159

Abstract 4893: AKT1 signaling negatively regulates invasion and metastasis of non-small cell lung cancer cells carrying mutations in KRAS or EGFR

Abstract Signaling driven by the phosphoinositide-3 kinase (PI3K) and AKT/protein kinase B (PKB) pathway plays an important role in cancer development and progression, and thus this pathway is an attractive therapeutic target. Although many different inhibitors targeting either PI3K or AKT have been developed, the therapeutic benefit of these inhibitors in the clinic remains elusive, in part because of the perplexing role of AKT signaling in the regulation of cell motility, invasion and metastasis. AKT activation is known to promote migration, invasion and metastasis; however under certain circumstances and different cellular systems, it also exhibits an inhibitory activity on these cellular processes and the underlying cause of these conflicting results is unclear. Through analysis of the Reverse Phase Protein Array (RPPA) performed on a series of non-small cell lung cancer (NSCLC) brain metastasis models generated via intracardiac injection in mice, we identified AKT1 (one of three AKT family members) as a critical negative regulator of A549 tumor metastasis. AKT1 tyrosine phosphorylation (but not AKT2 or AKT3) inversely correlated with the metastatic potential of A549 cells which carry a KRAS mutation. Using AKT1 siRNAs, we demonstrated that inhibition of AKT1 significantly enhanced migration and invasion of KRAS- or EGFR-mutant NSCLC cells, but not wild type KRAS and EGFR cells. Similarly, the AKT inhibitor MK-2206 also enhanced the migration and invasion of KRAS- or EGFR-mutant NSCLC cells in vitro, and promoted metastasis of KRAS-mutant A549 cells in vivo. The PI3K-AKT pathway is downstream of both EGFR and KRAS, whose constitutive activation caused by mutations likely alter the signal output of PI3K-AKT pathway and thus the activity on cell invasiveness. Therefore, our results provide a sound explanation that under certain genetic backgrounds (as we demonstrated here with KRAS or EGFR mutations) the AKT signaling may switch from being a promoter to an inhibitor of cell migration, invasion and metastasis. This observation may have strong clinical implications for the development of inhibitors of this pathway for cancer treatment. Furthermore, we found that AKT1 blockade induced phosphorylation of Myristoylated alanine-rich C-kinase substrate (MARCKS) and elevation of Laminin subunit gamma-2 (LAMC2), which in turn inhibited AKT phosphorylation and promoted cell invasiveness. In contrast, MARCKS or LAMC2 knockdown abrogated the activities of migration and invasion induced by AKT1 inhibition. This study unravels an anti-metastatic role of AKT1 in NSCLC cells with KRAS or EGFR mutation, and provides mechanistic insights for the understanding of the potentially contrasting roles of AKT signaling in the regulation of cell invasiveness. Citation Format: Guanhua Rao, Mariaelena Pierobon, In-Kyu Kim, Wei-Hsun Hsu, Jianghong Deng, Yong-Wha Moon, Emanuel F. Petricoin, Yu-Wen Zhang, Yisong Wang, Giuseppe Giaccone. AKT1 signaling negatively regulates invasion and metastasis of non-small cell lung cancer cells carrying mutations in KRAS or EGFR [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 4893. doi:10.1158/1538-7445.AM2017-4893

Overview of Cancer Stem Cells and Stemness for Community Oncologists

Advances in cancer research in the past have led to an evolving understanding of cancer pathogenesis and the development of novel drugs that significantly improve patient outcomes. However, many patients still encounter treatment resistance, recurrence, or metastasis and eventually die from progressing disease. Experimental evidence indicates that a subpopulation of cancer cells, called cancer stem cells (CSCs), possess “stemness” properties similar to normal stem cells, including self-renewal, differentiation, and proliferative potential. These stemness properties are lost during differentiation and are governed by pathways such as STAT3, NANOG, NOTCH, WNT, and HEDGEHOG, which are highly dysregulated in CSCs due to genetic and epigenetic changes. Promising results have been observed in preclinical models targeting these CSCs through the disruption of stemness pathways in combination with current treatment modalities. This has led to anti-CSC–based clinical trials in multiple stages of development. In this review, we discuss the role of CSCs and stemness pathways in cancer treatment and how they relate to clinical observations. Because CSCs and the stemness pathways governing them may explain the negative clinical outcomes observed during treatment, it is important for oncologists to understand how they contribute to cancer progression and how they may be targeted to improve patient outcomes.

Covalent diphenylalanine peptide nanotube conjugated to folic acid/magnetic nanoparticles for anti-cancer drug delivery

Micro and nanotubes obtained from the self-assembly of diphenylalanine peptides (FNTs) were conjugated to folic acid/magnetic nanoparticles (FA/MNPs) and evaluated as a potential system for anti-cancer drug delivery. The conjugates were obtained by providing a covalent linkage through the amine groups on FNTs with the carboxylic groups on FA/MNPs. The anti-cancer therapeutic 5-fluorouracil (5-FU), and anti-inflammatory cargo flufenamic acid (FFA), were loaded in peptide arrays during their self-assembly in the liquid phase. AFM and CLSM analysis indicated the presence of FA aggregates on FNTs. The data revealed that the cargo 5-FU, was distributed in dendrite peptide nanotubes whereas the non-polar cargo FFA, was homogeneously embedded in the structure of large discrete micro tubes. FTIR spectra of FA-MNPs/FNTs showed peak of amide II at 1623 cm−1 indicating covalent interactions between amines and carboxylic groups and confirmed the successful conjugation of the nanoparticles and peptide assemblies. The results indicated that 5-FU has been released from FNTs within 4 h, and incorporation of 5-FU in FNTs hydrogels has significantly slowed the release rate within the first 2 h. Our approach offers a new pathway for cancer treatment in which several functionalities are embedded in a single carrier.

Continuity of care in oncology. Quantitative analysis of data from patients treated in two different settings in Emilia--Romagna.

In order to ensure high-quality treatment for patients with cancer it is vital to implement organisational models (pathways and networks) and that guarantee continuity of care. Appropriate assessment tools that promote the evaluation and analysis of care pathways from the patients' perspective are available. Hence the aim of this study was to verify whether or not the coordination between the various stages and care providers in a cancer treatment pathway is perceived by our patients. Patients being treated for cancer of the lung, breast or colorectal tract by the Ferrara University Hospital (FUH) and the wider Romagna regional health service (RRHS), Italy, were administered the OPTION evaluation questionnaire. Univariate descriptive statistics of patients' sociodemographic features and care pathways were generated, and means and standard deviations were calculated for patient responses to OPTION items 1-19 on continuity of care throughout their treatment pathway. Responses from 341 patients (37.2 % treated by the FUH and 62.8% by the RRHS) were obtained. All mean scores provided for items 1-19 were above 4 on a Likert scale of 1-5, showing that the patients' perception of the continuity of their care was very positive on the whole. The highest mean scores were given for items regarding their emotional experience, while the lowest were given for those regarding information and integration with the GPs. Organisational efforts to promote patient-centred continuity of oncological care improved the experience of patients in our sample. Our data suggest that integration with the GPs still remains a problem, both from an organisational standpoint and in the perception of the patient being treated for cancer at one of the facilities under investigation. Although our findings are non-controlled and not generalisable to other geographical areas, they do show how such tools can be used to monitor and analyse patient's experience with continuity of care with a view to continual improvement in care provision.

Integrated care pathway for rectal cancer treatment: health care resource utilization, costs, and outcomes.

Managed Flow C20 (MFC20) is an integrated care pathway (ICP) for rectal cancer implemented at a public teaching hospital. This study aims to quantify resource utilization and estimate direct costs and outcomes associated with the use of this ICP. We evaluated consecutive rectal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery, comparing the period before the ICP implementation (Pre-MFC20 group) and after (MFC20 group). We assessed times between treatment steps and quantified the resources utilized, as well as their costs. There were 112 patients in the Pre-MFC20 group and 218 in the MFC20 group. The mean treatment intervals were significantly shorter in the MFC20 group - from the first medical consultation to nCRT (48.3 vs. 87.5 days; P < 0.001); and from nCRT to surgery (14.8 vs. 23.0 weeks; P < 0.001) - as was the mean total treatment time (192.0 vs. 290.2 days; P < 0.001). Oncology consultations, computed tomography, MRI, and radiotherapy sessions were utilized more frequently in the Pre-MFC20 group (P < 0.001). The median per-patient cost was US$11 180.92 in the Pre-MFC20 group, compared with US$10 412.88 in the MFC20 group (P = 0.125). Daily hospital charges and consultations were the major determinants of the total cost of the treatment. There was no statistical difference in overall survival in the time periods examined. Implementation of a rectal cancer ICP reduced all treatment intervals and promoted rational utilization of oncology consultations and imaging, without increment in per-patient costs or detrimental effects in overall survival.

The potential application of ctDNA for improved cancer management, treatment and diagnosis within the Pacific

Abstract The burden of cancer among Pacific peoples living in New Zealand and in the Pacific remains a significant health concern. Given the health inequalities that exist for Pacific peoples and the global burden of cancer, it remains a priority to consider the medical situation for cancer patients in the Pacific. It is acknowledged that within resource constrained environments, the diagnosis, treatment and management of cancer patients is fraught with unique challenges and difficulties. A novel cancer detection method known as circulating tumour DNA (ctDNA) monitors small fragments of tumour DNA found in the blood circulation. These fragments can be isolated and quantified to obtain information providing data concerning cancer progression and treatment response. It is anticipated this simple method of detecting and monitoring cancer will enhance the precision of cancer care for patients, and will eventuate into a particularly useful tool within resource constrained environments such as the Pacific. The purpose of this work was to identify the diagnostic, treatment and pharmacologic options currently available for cancer patient within the main and rural Hospitals in Tonga and to explore the potential utility of ctDNA to support the management, treatment and diagnosis of cancer patients. Cancer diagnosis, treatment and management pathways were available in Tonga but options were limited. The potential diagnostic utility of the ctDNA technology was an element of intense interest as cancer presentation is typically late with medical, nursing and support staff operating within resource constrained environments. The potential application of ctDNA for improved support of cancer patients in Tonga remains a highly appealing possibility.

PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients.

Immune checkpoint inhibitors that block the PD-1/PD-L1 signaling pathway have been used to treat a wide variety of cancers. Although results have been promising, significant inter-individual and inter-tumor variability has been observed. It is believed that better clinical outcome could be achieved if the treatment was individually designed based on the functional status of the PD-1/PD-L1 signaling and the cellular immunity. In this study, we analyzed the mRNA expression of PD-1 and other immunomodulatory genes in peripheral blood from cancer patients, and immunomodulatory gene expression during radiotherapy and immunomodulation therapy with cytokines. Our results show that the PD-1 mRNA expression is significantly increased in peripheral blood in cancer patients. Anti-cancer treatments can significantly modulate the PD-1 expression, but this is largely dependent on the initial immune status. Moreover, the PD-1 expression on peripheral lymphocytes can be immunoactivation-derived. These results suggest that the regulation and expression pattern of PD-1/PD-L1 signal is complicated which will influence the effect of blockade of the PD-1/PD-L1 signaling pathway for cancer treatment. Through combined analysis of PD-1, CTLA-4, and other immune markers in peripheral blood, we may accurately evaluate the functional status of PD-1/PD-L1 signaling and cellular immunity, thereby providing clues for guiding anti-PD-1 or anti-PD-L1 treatment.

Updates on the role of receptor activator of nuclear factor κB/receptor activator of nuclear factor κB ligand/osteoprotegerin pathway in breast cancer risk and treatment.

Treatment with bisphosphonates and denosumab is the standard of care in bone metastatic disease. In addition, the adjuvant therapy of denosumab or bisphosphonates is very effective to prevent loss of bone mineral density, for example in osteoporosis. However, it is still unclear if this therapy has an influence on preventing cancer. Since the identification of novel genes in the 1980s, it took about 30 years until denosumab, as a fully human mAb against receptor activator of nuclear factor (NF)-κB ligand (RANKL), could be introduced to clinical practice. The discovery of the receptor activator of NF-κB/RANKL/osteoprotegerin pathway in the 1990s is an example of how modern databases of genes were utilized to discover new pathways relevant to a variety of diseases. The essential role of this pathway for the function, differentiation and survival of osteoclasts, and the influence on the bone microenvironment helped to understand the vicious circle of bone resorption and destruction in many skeletal diseases. In the following review, we discuss the important role of rational targeting concerning receptor activator of NF-κB/RANKL/osteoprotegerin and the bisphosphonate therapy and provide an update for the related treatment of patients suffering from breast cancer and further implications for clinical practice and research using denosumab as a potential chemoprevention in BRCA1-related breast cancer.