Reason For Treatment Failure Research Articles

Abstract 1785: Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using Cross-Over-Dual-Variable-Domain (CODV) format for the treatment of acute myeloid leukemia (AML)

Abstract Acute myeloid leukemia (AML) is characterized by the accumulation of abnormal blast cells in the bone marrow and blood. While high intensity chemotherapy and allogeneic stem cell transplantation cure a subset of patients with AML, many patients are ineligible or do not respond sufficiently to these therapies. One potential reason for treatment failure in a particular patient may be the inability to reach and eliminate residual leukemic stem cells (LSCs) located in the bone marrow. T-cell mediated cytotoxicity, targeting LSCs with high expression of certain leukemic antigens, represents an attractive therapeutic strategy for relapsed and refractory AML. In this study, the proprietary Cross-Over-Dual-Variable-Domain (CODV) format was applied to a fully humanized IgG1 backbone with reduced Fc functionality, resulting in a bispecific T-cell engager (TCE), CD123-CODV-TCE, that binds to both CD3 on T cells and CD123 (α-chain of the interleukin-3 receptor) on AML blasts and LSCs. CD123-CODV-TCE displayed high affinity for human CD123 and medium affinity for human CD3 proteins. As expected, CD123-CODV-TCE activated CD4-positive and CD8-positive T cells only in the presence of cells expressing the CD123 target, such as THP1 (an AML tumor cell line), and induced killing of these cells with an EC50 in a picomolar range. Potential cytotoxic activity of CD123-CODV-TCE was also evaluated on CD123-expressing normal blood cells such as plasmacytoid dendritic cells (pDC) and monocytes. CD123-CODV-TCE was shown to deplete pDC and monocyte from human Healthy Donor (HD) Peripheral Blood Mononuclear Cells (PBMC) with an EC50 in the picomolar range. This efficacy correlated with the release of numerous cytokines, thus highlighting the potential risk of cytokine release syndrome as described for other TCE's. In an in vivo disseminated AML model using CD123+ Molm13-luc human AML cell line, treatment of the mice with CD123-CODV-TCE suppressed AML tumor growth in the bone marrow compartment following co-injection of primary human T cells. In this murine pre-clinical model, CD123-CODV-TCE displayed favorable pharmacokinetic properties with a terminal half-life of 3 days. To investigate CD123-CODV-TCE activity on myeloid blast cells and LSC, in vivo efficacy studies were performed in NSG mice injected with primary human AML cells obtained from patients. In this model, CD123-CODV-TCE induced the killing of primary AML cells by activating human autologous T cells. Taken together, these results indicate that CD123-CODV-TCE can potently and specifically kill CD123+ leukemic cancer cells in vitro and in vivo. CD123-CODV-TCE therefore represents a potential candidate for future clinical development in relapsed and refractory AML. Citation Format: Helene Bonnevaux, Stephane Guerif, Jana Albrecht, Erwan Jouannot, Laurent Bassinet, Agnès Vergezac, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Anne Caron, Celine Amara, Cedric Barriere, Justine Siavellis, Valerie Bardet, Ernesto Luna, Donald Drake, Ercole Rao, Corina Oprea, Peter Wonerow, Chantal Carrez, Veronique Blanc, Karl Hsu, Dmitri Wiederschain, Paula G. Fraenkel. Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using Cross-Over-Dual-Variable-Domain (CODV) format for the treatment of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1785.

HE4 level in ascites may assess the ovarian cancer chemotherapeutic effect

BackgroundThe clinical treatment of ovarian cancer with ascites is problematic. The main reasons for treatment failure are the susceptibility to intraperitoneal metastasis and chemotherapeutic drug resistance. The purpose and significance of this study is to evaluate which marker might evaluate treatment efficacy and improve the cure rate.ResultsThis study compared a no chemotherapy group with a chemotherapy group regarding the determination of carbohydrate antigen 125 and human epididymis protein 4 in ovarian cancer ascitic supernatants and cross-analyzed routine serum carbohydrate antigen 125 levels. The level of human epididymis protein 4 in the ascites of the chemotherapy group was significantly lower than that of the no chemotherapy group (p < 0.001). Moreover, the expression of ascitic human epididymis protein 4 correlated positively with serum carbohydrate antigen 125 levels (p < 0.001). MDR was positive in 13 of the 30 samples (43.33%) in the chemotherapy group with highly expressed CA125.ConclusionThe level of human epididymis protein 4 in ovarian cancer ascites may reflect the therapeutic effect of ovarian cancer patients, and a high level of human epididymis protein 4 might predict chemoresistance and the possibility of ascites formation. The determination of the expression of human epididymis protein 4 alone or combined with carbohydrate antigen 125 levels in both serum and ascites in ovarian cancer patients with ascites may have important significance for guiding and improving the treatment regimen.

Combination of icariin and oleanolic acid attenuates in vivo and in vitro glucocorticoid resistance through protecting dexamethasone-induced glucocorticoid receptor impairment

Glucocorticoid resistance (GCR) remains a significant problem and is the most important reason for treatment failure of glucocorticoids (GCs).

Abstract A60: Full-length transcripts identification from deep transcriptomic analysis of Bothrops jararaca venom gland

Abstract Introduction: Head and neck cancer is a collective term defined by topographic and anatomic features to describe malignant tumors of the upper aerodigestive tract. Despite the different strategies used in the treatment of head and neck squamous cell carcinoma (HNSCC), the overall survival rate is around 50% and the main reason for treatment failure is the frequent development of loco-regional recurrences, which affect around 30% of HNSCC patients. The increase in cancer diagnosis makes it necessary to search for alternative sources to inhibit tumor progression, as well as the development of more efficient drugs. Identification of natural resources as therapeutic potential may lead to the development of new antitumor treatments. Objectives: The aim was to identify transcripts expressed in venom glands of the Bothrops jararaca snake with therapeutic potential for head and neck squamous cell carcinoma (HNSCC) tumors. Materials and Methods: The mRNA library from B. jararaca was sequenced using Illumina NextSeq 500 platform (76 bp unpaired-end) and NextSeq 500/550 Mid Output v2 kit (150 cycles). Library was constructed using TruSeq Stranded mRNA LT Sample Prep Kit (Illumina). De novo assembly of the B. jararaca transcriptome was performed using Velvet software to assemble the transcriptome contigs. Results: The RNA-seq of B. jararaca venom gland generated 4,401,692 raw reads. The de novo Velvet assembly produced 3,498,133 contigs, which matched against NCBI-Blastn transcripts. From these contigs were identified 3,638 full-length transcripts, from which were selected two potential therapeutic genes, Fosfolipases A2 1 and Fosfolipases A2 2. Conclusions: In conclusion, this transcriptome sequencing identified two potential therapeutic transcripts, Fosfolipases A2 1 and Fosfolipases A2 2, which will be analyzed in HNSCC cell lines. Citation Format: Elisa Alves Messias, Flavia Coltri Eguchi, Bruna Pereira Sorroche, Angela Das Neves Oliveira, Lidia Maria Rebolho Batista Arantes, Ana Carolina De Carvalho, Anita mitico tanaka Azevedo, Kathleen Fernandes Grego, Matias Eliseo Melendez, Andre Lopes Carvalho. Full-length transcripts identification from deep transcriptomic analysis of Bothrops jararaca venom gland [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A60.

Pharmacoeconomic evaluation of micafungin versus caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in Turkey

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Treatment abandonment in children with cancer in Sub‐Saharan Africa: Systematic literature review and meta‐analysis

To establish and quantify the main reasons for treatment abandonment in children with cancer in Sub-Saharan Africa through a systematic review of the literature. Great advances have been made in the treatment of childhood cancer, however this requires that families are able to complete treatment. Failure to do this is referred to as treatment abandonment, which is recognized as a reason for treatment failure. Systematic review and meta-analysis of data on the reasons for treatment abandonment in Sub-Saharan Africa. Ovid MEDLINE 1946 to May Week 1 2017 and Embase 1974 to 2017 Week 19. Additional hand-searching was undertaken. Two reviewers independently screened papers and extracted the data. The R package meta was used to calculate the relative risk of treatment abandonment or the proportion of parents stating a reason. The relative risk of treatment abandonment was highest for not being in a research cohort; followed by mothers only having primary education, being HIV negative, parents not being employed, travel and no insurance. When parents who had abandoned treatment were asked, the most common reason was finance, followed by insurance, transport, lack of social support, their child appearing well, fear and waiting. More data are needed on the extent of treatment abandonment in different countries. Clinicians should encourage parents without insurance to enrol onto the relevant insurance programme straight after diagnosis, provide housing for patients and families close to the treatment centres and to develop treatment at more localized centres.

Abstract 5145: Demystification of obstacles encountered using convection enhanced delivery in preclinical models of diffuse intrinsic pontine glioma

Abstract Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor that arises in the pons of the brainstem. The vital location of the tumor and the presence of the impermeable blood brain barrier (BBB) make treatments ineffective and leads to a high mortality rate of DIPG patients. Convection enhanced delivery (CED) is a promising drug delivery method because of its ability to bypass the BBB that is currently being investigated to deliver therapeutic agents directly to brain tumors. Nonetheless, clinical trials investigating the use of CED to treat patients have not shown prolonged patient survival. Previous studies have determined poor distribution in clinical studies due to reflux or back flow. Additionally, by analyzing the H&amp;E and Ki67 stained brain sections of a DIPG patient that underwent CED, we determined that areas of radiation-induced necrosis within the tumor were a possible reason for treatment failure. In this study, we intend to optimize CED in orthotopic murine model of DIPG. Specifically, we have tested the ideal volume and rate of injection, as well as using the combined approach of using CED and radiation. Ideal injection rate was established by assessing infusion profiles in agarose brain phantoms using various needles, which resulted in the injection rate of 0.3ul/min producing the least back flow. Next, the ideal injection rate and volumes were tested in vivo by injecting non-tumor bearing mice with trypan blue. To assess the infusion rate, brain sections were analyzed at necropsy to determine distributions of the injected dye. To investigate accumulation of CED-mediated payload in necrotic sites, tumor bearing mice were exposed to radiation and then injected with the fluorescent dye, DiI. Formalin fixed brain sections were stained with DAPI and fluorescent images were taken. The results of this study indicate that a rate of 0.5ul/min results in a significantly larger distribution area compared to the 0.3ul/min injection rate (50.71 ± 4.84 compared to 30.47 ± 1.18, p=0.0462). Fluorescent images of brain sections of mice injected with DiI indicated the accumulation of dye in areas where there were no live cells, supporting the assumption that drug injections may be retreating to necrotic pockets and thus preventing equal distribution of the drug in the tumor. Ongoing studies include investigating the survival benefits of using CED to deliver therapeutic agents in tumor-bearing mice. Understanding the obstacles of convection enhanced delivery in murine models can help establish better treatment regimens and devices for patients and provide better preclinical models for drug testing. Citation Format: Jamila S. Gittens, Sridevi Yadavilli, Michael Lin, Eshini Panditharatna, Suresh N. Magge, Roger J. Packer, Javad Nazarian. Demystification of obstacles encountered using convection enhanced delivery in preclinical models of diffuse intrinsic pontine glioma [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 5145. doi:10.1158/1538-7445.AM2017-5145

Abstract 2940: TH17: mediators of metastatic growth acceleration after surgery

Abstract Surgery is known to accelerate the growth and progression of metastases in patients undergoing oncological resections with 50-60% patients having recurrent metastasis after resection making it a major reason for treatment failure. This impedes the efficacy of adjuvant chemotherapy and overall prognosis of the patient. Studies have proved that inflammatory cascade initiated by surgery that increases metastatic growth and progression is mediated through a specific mechanism of neutrophil cell death called Neutrophil Extracellular Traps (NETs). We investigated the mechanism of how NET formation after surgical stress increases metastatic growth by influencing a pro-tumor microenvironment in order to specifically identify targets for perioperative therapy to keep metastases dormant and improve the effect of chemotherapy and overall prognosis. 12 week old male C57BL/6J mice (WT) and mice in which NET formation was inhibited, ie, WT mice injected with DNAse and global homozygous knockout of peptidyl arginine deaminase 4 (PAD4), an essential nuclear protein for NET formation, underwent splenic injection of 100,000 cells of the murine colorectal cancer cell line, MC-38, followed with either 70% hepatic ischemia-reperfusion (IR) for 60 minutes after 7 days or no IR. Livers were harvested at multiple time points and assessed for changes in both innate and adaptive immune cell populations by flow cytometry. On gross examination, the livers of the NET deficient mice had fewer tumors as compared to the WT mice. Mice, which underwent IR after tumor cell injection in both groups showed an increase in nodules formation versus those with just tumor cell injection, however were still more in WT than NET deficient mice. Flow cytometry revealed a decrease in both TH17 (0.36% of T cells in no IR mice vs 0.0036% in IR mice) and CD8 cells (71% of T cells in no IR mice vs 34.8% in IR mice) in mice subjected to IR versus those with only tumor injection. We found that increased tumors after surgical stress, which were mediated by NET formation, were caused due to a decrease in anti-tumor activity of CD8 cells regulated via TH17 cells. If controlled in the perioperative period, it may reduce acceleration in metastatic foci and improve the overall prognosis. We are further investigating the mechanism of NETs influencing the tumor immune environment. Citation Format: Vikas Sud, Samer Tohme, Dirk J. van der Windt, Hai Huang, Allan Tsung. TH17: mediators of metastatic growth acceleration after surgery [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 2940. doi:10.1158/1538-7445.AM2017-2940

Stemness Marker Detection in the Periphery of Glioblastoma and Ability of Glioblastoma to Generate Glioma Stem Cells: Clinical Correlations.

Recent studies suggested glioma stem cells (GSCs) are key contributors to therapeutic resistance of glioblastoma multiforme (GBM) and are responsible for GBM recurrence. We characterized the phenotype of cancer cells in the core and periphery of 20 GBM tumors, correlating clinical outcome to the ability to form GSCs and distinguishing survival based on Ki-67 staining. Similar levels of methylguanine-deoxyribonucleic acid methyltransferase were found in the core and periphery of GBM tumors, whereas Ki-67 was reduced in the periphery. Similar levels of stemness markers in the periphery and in the core of all GBM cultures were found. Only cells expressing >30% SOX2 levels were able to produce neurospheres. Immunophenotypic analysis showed higher levels of stemness markers in GSC cultures than in all GBM primary cultures. GSC invitro production and coexpression of Ki-67 >5% negatively correlated with outcome. Not all GBM cultures can generate GSCs, and this capacity is linked to >30% SOX2 levels. The ability to form spheres negatively correlated to survival, and the detection of >5% Ki-67 levels may be useful to identify patients at risk of disease progression. The presence of GSC-/SOX-2-/Ki-67- cells may be regarded as a new prognostic factor. The presence of stemness markers and methylguanine-deoxyribonucleic acid methyltransferase in the periphery of GBM tumors may be the reason for treatment failure and recurrence. Development of stem cell-targeted therapies and elaboration of more aggressive treatments represent an opportunity to eliminate the GBM source and the nidus of recurrence.

A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS &gt; 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.

Cambridge Brain Mets Trial 1 (CamBMT1): A proof of principle study of afatinib penetration into cerebral metastases (mets) for patients (pts) undergoing neurosurgical resection, combined with low-dose, targeted radiotherapy (RT)—Phase 1b results.

2008 Background: Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure in pts with brain tumours. Preliminary data suggest that low-dose RT may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. CamBMT1 is a phase 1b/2 pre-operative window-of-opportunity trial designed to test if the delivery of afatinib into brain mets might be enhanced by targeted, low dose-RT. Methods: Pts with operable brain mets from breast or lung origin were treated with afatinib for 11 days prior to surgery on day 12. Pts also received a single fraction of targeted RT on day 10 (pts in either 2Gy or 4Gy arm). In phase 1b, afatinib dose (20, 30, or 40mg QD) was escalated in each arm using an accelerated titration design. Primary endpoint: steady-state afatinib concentration in resected brain mets, compared with plasma. Secondary endpoints: safety and tolerability. Results: 10 pts were treated (4 breast, 6 lung), with no dose-limiting toxicities seen, thus completing recruitment to phase 1b. Treatment was generally well tolerated. Median afatinib concentrations on day 12 were: plasma 22.7ng/mL (range 9.94-179); and tumour 405ng/g (range 120-1129). Conclusions: It was feasible to conduct a window-of-opportunity study of afatinib plus RT in pts with operable brain mets. The recommended phase 2 dose of afatinib was 40mg QD for both 2Gy and 4Gy arms. Afatinib concentrations in resected tumour were on average &gt;15-fold higher than those in plasma. Phase 2 of CamBMT1 is now underway in multiple UK sites, and randomises patients into 3 treatment arms (n=20 per arm): 1. afatinib 40mg QD; 2. afatinib 40mg QD + 2Gy# RT; 3. afatinib 40mg QD + 4Gy# RT. Clinical trial information: NCT02768337. [Table: see text]

Pattern of drug utilization and factors influencing long term blood sugar control among diabetics in a tertiary care hospital- an observational study

Background: To study the Pattern of drug prescribing, utilization, analyse effectives of different therapies and factors influencing medication failure and adherence to treatment among diabetics.Methods: The clinical study was conducted in JJM Medical College and Karuna Trust, Davangere, Karnataka. The patients with diabetes as diagnosed by consultant physician were observed for the pattern of blood glucose control. The fasting blood glucose of the patients were recorded at the end of 1st month, 6th month and 12th month of their treatment period. The study period was from June 2012 till August 2014. The study was conducted after institutional ethical clearance and informed consent was taken from all the patients. The pattern of drugs prescribed for the patients were also analysed. The pattern of control among patients with co morbidities were also analysed using paired sample t test.Results: The results showed that the prescribed drugs were able to control the blood glucose levels of the patients. The percentage of patients with FBS in controlled, mild to moderate control and uncontrolled group were 21%, 33.3% and 45.5% in early treatment period and 36%, 40.9%, and 22.7% after one year treatment period (Significant p value). The pattern of drug utilization showed that the most commonly used drugs were the combination of pioglitazone+glimipride+metformin (19%), combination of glibenclamide+ metformin (18%), only insulin (9%), combination of glimipride+metformin (8%) and combination of gliclazide+metformin (5%).Conclusions: The results show that the intervention by the consultant physician was successful in controlling the blood sugar levels and the reasons for failure of treatment and adherence to treatment were helpful for further treatment of patients. Further such studies in a larger sample will help the consultants in their treatment methods.

Low prevalence of DHFR and DHPS mutations in Pneumocystis jirovecii strains obtained from a German cohort.

Pneumocystis pneumonia (PCP) is an opportunistic and potentially life-threatening infection of immunocompromised individuals. A combination of trimethoprim-sulfamethoxazole is widely used for prophylaxis and treatment of PCP. Polymorphisms in the drug targets, the dihydropteroate synthase (DHPS) or the dihydrofolate reductase (DHFR) are presumably a reason for treatment failure. We retrospectively examined the prevalence of DHPS and DHFR mutations in Pneumocystis jirovecii isolates obtained from HIV-infected and non-HIV-infected PCP patients. DHFR and DHPS genes were amplified using semi-nested PCR followed by sequencing. Obtained data were correlated with clinical findings. Sequencing of the DHPS gene was achieved in 81 out of 128 isolates (63%), the DHFR-gene was successfully sequenced in 96 isolates (75%). The vast majority of DHFR and DHPS sequences were either wild-type or showed synonymous single nucleotide polymorphisms. Only one sample contained a double mutation at DHPS codon 55 and codon 57 which was associated with treatment failure in some studies. No linkage of treatment failure to a DHFR or DHPS genotype was observed. In our cohort, 35 of 95 Patients (37%) were HIV-positive and 60 (63%) were HIV-negative. The overall mortality rate was 24% with a much higher rate among non-HIV patients. DHPS and DHFR mutations exist but are infrequent in our cohort. The contribution of gene polymorphisms to treatment failure needs further research. In immunocompromised HIV-negative patients PCP is associated with high mortality rates. Prophylactic treatment is warranted in this patient subset.

Abstract OT1-04-01: Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy

Abstract Background Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure for patients with brain tumors. For most patients who don't respond to treatment, it is not known whether this is due to inadequate drug concentrations in the tumor, or due to drug resistance. Preliminary data suggest that low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug delivery into brain tumors. Afatinib is a potent, irreversible inhibitor of EGFR / HER2 / HER4 and takes approximately 8 days to achieve steady-state concentrations in cancer patients. Aims CamBMT1 has been designed to investigate the delivery of afatinib into brain metastases and whether this might be enhanced by low dose-radiotherapy. Patient Population Key eligibility criteria Patients with operable brain metastases from breast or lung primaries for whom neurosurgical resection would be standard of care, as determined by the local multi-disciplinary team. ECOG PS 0, 1 or 2. Trial design After a phase 1b safety run- in, the phase 2 part of the trial randomises patients (n=60) into 3 pre-operative arms: Arm 1afatinib alone for 11 days, then neurosurgery on day 12Arm 2afatinib for 11 days plus a single 2 Gy fraction on day 10, then neurosurgery on day 12Arm 3afatinib for 11 days plus a single 4 Gy fraction on day 10, then neurosurgery on day 12 Primary endpoint: to compare steady-state afatinib concentration in resected brain metastases, following afatinib administered alone, or in combination with radiotherapy (2 Gy or 4 Gy). Afatinib concentrations are measured in the resected brain metastases and in plasma. Secondary endpoints: safety of afatinib administration in combination with radiotherapy; and multi-sequence MRI (optional) to detect changes in perfusion, vascular density, blood-brain-barrier permeability and interstitial pressure. Exploratory endpoints: molecular profiling of resected brain metastases, for comparison with paired primary lung and breast cancers; the establishment and study of patient-derived xenografts. Statistical methods With 20 patients randomised in each of 3 arms in the phase 2 part of CamBMT1, the trial has a power of 84% at a significance level of 20% (one-sided) to detect an increase in afatinib concentrations with targeted radiotherapy, measured as a Cohen's D (standardised mean difference) ≥0.5. Accrual By the end of q2 2016, phase 1b had nearly completed enrolment. The randomised phase 2 part of CamBMT1 is due to open by q4 2016 at additional Experimental Cancer Medicine Centres. Acknowledgments CamBMT1 is funded by Cancer Research UK, the Brain Tumour Charity and Boehringer-Ingelheim. Citation Format: Baird RD, Ramenatte N, Watts C, Jonson A, Jones L, Biggs H, Harrison E, Oberg I, Bullen G, Williams M, Qian W, Gilbert F, Jodrell D, Caldas C, Karabatsou K, Dunn L, Jena R, Whitfield G, Chalmers A, Jefferies S, Price S. Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-01.

Contribution of nuclear events in generation and maintenance of cancer stem cells: revisiting chemo-resistance

While chemotherapy is often capable of reducing the tumor bulk, disease-free survival of patients is curtailed by recurrence because of chemoresistance. In fact, the cardinal reason of treatment failure can be attributed to chemoresistance, which involves a complex mechanism. In the present scenario, cancer stem cells (CSCs) have been identified to play a pivotal role in chemoresistance. A few reviews have discussed numerous mechanisms of chemoresistance in CSCs and the therapeutic strategies targeting stem cell signaling pathways. References are also there elaborating the applications of therapeutic nanoparticles and epigenetic drugs in targeting CSCs. However, there is a paucity of information in this area that should be explored and addressed. It is a well known fact that the nucleus harbors the entire genome of an organism and is the master regulator of all the genetic and epigenetic programs. In fact, majority of the features of CSCs evolve from cell nucleus. Here we review, the prevailing and emanating concepts of how the key nuclear events like (1) genetic regulation, (2) epigenetic regulation, (3) regulation by microRNAs (miRNA), and (4) DNA repair, can influence CSC properties like (a) induction of EMT (epithelial-mesenchymal transition), (b) self renewal, (c) drug resistance, (d) cellular plasticity, and (e) pluripotency, thereby finally aiding in chemoresistance and cancer recurrence. Information obtained from the discussion will help in revisiting chemoresistance and provide approaches for treating CSCs by targeting nuclear events, thereby improving the prognosis and survival rate of cancer patients in near future.

Novel BCL6 Inhibitor (FX1): Advances in Diffuse Large B-Cell Lymphomas (DLBCLs) Treatment

Diffuse large B-cell lymphomas (DLBCLs) are the most common and aggressive type of all the lymphomas. B cell lymphoma 6 ( BCL6 ) oncogene is highly expressed in DLBCLs and one of the major reasons of treatment failure. Recent findings suggest that specific BCL6 inhibitor (FX1) disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, that in-turn suppressed growth of DLBCLs cells, primary human DLBCLs specimens, as well as induced regression of established tumors in mice derived from DLBCLs cells.

Wilms Tumor Treatment Outcomes: Perspectives From a Low-Income Setting.

PurposeWilms tumor is the commonest renal malignancy in childhood. Survival in high-income countries is approximately 90%, whereas in low-income countries, it is less than 50%. This study assessed treatment outcomes of patients with Wilms tumor at a Kenyan academic hospital.Patients and MethodsWe conducted a retrospective medical record review of all children diagnosed with Wilms tumor between 2010 and 2012. Data on treatment outcomes and various sociodemographic and clinical characteristics were collected.ResultsOf the 39 patients with Wilms tumor, 41% had event-free survival, 31% abandoned treatment, 23% died, and 5% had progressive or relapsed disease. Most patients presented at an advanced stage: stage I (0%), II (7%), III (43%), IV (40%), or V (10%). The most likely treatment outcome in patients with low-stage (I to III) disease was event-free survival (67%), whereas in those with high-stage (IV to V) disease, it was death (40%). No deaths or instances of progressive or relapsed disease were recorded among patients with low-stage disease; their only reason for treatment failure was abandonment of treatment. Stage of disease significantly affected treatment outcomes (P = .014) and event-free survival estimates (P < .001). Age at diagnosis, sex, duration of symptoms, distance to hospital, and health insurance status did not statistically significantly influence treatment outcomes or event-free survival estimates.ConclusionSurvival of patients with Wilms tumor in Kenya is lower compared with that in high-income countries. Treatment abandonment is the most common cause of treatment failure. Stage of disease at diagnosis statistically significantly affects treatment outcomes and survival.

The effect of preoperative induction chemotherapy on long-term survival of patients with advanced squamous cell carcinoma of the oral cavity tongue

Objective:To discuss the long term efficency of preoperative induction chemotherapy(IC)±radiotherapy on patients with resectable stage Ⅲ or Ⅳ squamous cell carcinoma of the oral cavity tongue(SCCOT).Method:During June 1996 to December 2005, 73 patients with locally advanced SCCOT treated preoperatively with IC(3 cycle of cisplatin and 5 fluorouracil) followed by surgery(resection of the primary tumor and neck)±radiotherapy in the Cancer Center of Sun Yat-sen University were enrolled in our study. Five-year overall survival rates(OS), local control rate and reasons of treatment failure were analyzed retrospectively.Result:The follow-up time was 1.9 to 188.0 months, and the median follow-up time was 70.9 months.Among that, 24 cases(32.9%) were still alive, of which 23 patients survival time is more than 10 years until the deadline of the follow-up. After IC, 17 patients(23.3%) had clinical complete response; 44 patients(60.3%) had a clinical partial response; 12 patients(16.4%) had no response or progression, and an overall response rate was 83.6%(65/73). On final surgical pathology, 14 patients(19.2%) had pathological complete response; 59 patients(80.8%) had histological incomplete response(residual tumor). Univariate analysis showed that the tumor size(P< 0.05), cervical lymphatic metastasis(P< 0.05),clinical stage(P< 0.05), the different clinical remissions(P< 0.05), had or not pathological complete remission(P< 0.05) were risk factors affecting prognosis(P< 0.05).Multivariate analysis indicated that cervical lymphatic metastasis cervical lymphatic metastasis(P< 0.05), the different clinical remissions (P< 0.05), had or not pathological complete remission(P< 0.05) were independent factors for prognosis. Five-year OS of clinical effective of IC was 62.5%, apparently higher than the invalid effect 41.7% (P< 0.05). Five-year OS of pCR was 92.9%, while have no pCR was 47.9%(P< 0.05). A significant difference between the two groups was also found. During whole follow-up time, 22 patients developed recurrence. Five-year OS was 59.8%, local control rate were 69.9%.Conclusion:IC plus surgery with or without postoperative radiotherapy was a treatment modality that was tolerated with encouraging activity and survival outcome in patients with advanced resectable SCCOT. Response rate with this IC regimen was limited, but the responders were associated with excellent prognosis.

Reinventing HCV Treatment: Past and Future Perspectives

This review paper summarizes the epidemiology of hepatitis C virus (HCV) and chronic HCV infection, including HCV virology and treatment regimens. Specifically, we focus on the evolution of past, current, and future HCV treatment options, the reasons for treatment failure, and the impact of resistance-associated variants on treatment success.

Non‐surgical retreatment of teeth with persisting apical periodontitis following apicoectomy: decision making, treatment strategies and problems, and case reports

In the endodontic literature, only a few studies and case reports can be found demonstrating and further discussing non‐surgical treatment of failed apicoectomies. As a second apicoectomy has a limited success rate, non‐surgical retreatment should be discussed as an additional treatment option before extraction is considered. Depending on the reason for treatment failure or for persistence or development of apical periodontitis, and depending on the presence or absence and the type of retrofilling, treatment strategies need to be adapted to the specific clinical scenario. It is the aim of this review to describe a strategy for non‐surgical orthograde retreatment of previously apicected teeth with persisting apical periodontitis, to review the literature that may be helpful to discuss such cases, to develop an individual treatment plan, to discuss several specific aspects of treatment, and to present different clinical cases.