Combination of Irinotecan, Oxaliplatin and 5-Fluorouracil as a Rechallenge Regimen for Heavily Pretreated Metastatic Colorectal Cancer Patients

Abstract

Purpose

Our objective was to evaluate the benefit of re-exposing patients with refractory metastatic colorectal cancer (mCRC) to a combination of oxaliplatin, irinotecan and 5-fluorouracil treatment.

Methods

We retrospectively analysed patients with mCRC who received a combination of oxaliplatin, irinotecan and fluorouracil as a rechallenge regimen after progressing on the same drugs. Both FOLFOXIRI and FOLFIRINOX were used. Toxicity was evaluated for each treatment cycle, and survival analysis was performed using the Kaplan-Meier method.

Results

A total of 21 patients who were treated between January 2011 and December 2013 were selected for this study. Most of the patients (95.2%) had an ECOG status of 0–1. The median age at diagnosis was 52.1 years (range 36–77 years), and 14 (66.6%) patients had wild-type KRAS. Thirteen patients received FOLFIRINOX, and eight received FOLFOXIRI. Most patients had previously received at least three regimens, with 80% receiving anti-VEGF and 66% anti-EGFR antibodies. The response rate was 38%, and 24% patients had stable disease. The median time to disease progression was 4.0 months (range 1.0–9.1 months), and the median overall survival duration was 8.6 months (range 6.3–11.5 months). Most patients required dose adjustment and treatment delays. One patient experienced grade 5 neutropenic sepsis.

Conclusions

Both FOLFIRINOX and FOLFOXIRI are active and potentially feasible rechallenge treatment options for heavily pretreated patients with good performance status. With dose reduction and close monitoring for toxicity, the risk of serious adverse events can be minimised.

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AN-7, a butyric acid prodrug, sensitizes cutaneous T-cell lymphoma cell lines to doxorubicin via inhibition of DNA double strand breaks repair

Summary

We previously found that the novel histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) had greater selectivity against cutaneous T-cell lymphoma (CTCL) than SAHA. AN-7 synergizes with doxorubicin (Dox), an anthracycline antibiotic that induces DNA breaks. This study aimed to elucidate the mechanism underlying the effect of AN-7 on Dox-induced double-strand DNA breaks (DSBs) in CTCL, MyLa and Hut78 cell lines. The following markers/assays were employed: comet assay; western blot of γH2AX and p-KAP1; immunofluorescence of γH2AX nuclear foci; Western blot of repair protein; quantification of DSBs-repair through homologous recombination. DSB induction by Dox was evidenced by an increase in DSB markers, and DSBs-repair, by their subsequent decrease. The addition of AN-7 slightly increased Dox induction of DSBs in MyLa cells with no effect in Hut78 cells. AN-7 inhibited the repair of Dox-induced DSBs, with a more robust effect in Hut78. Treatment with AN-7 followed by Dox reduced the expression of DSB-repair proteins, with direct interference of AN-7 with the homologous recombination repair. AN-7 sensitizes CTCL cell lines to Dox, and when combined with Dox, sustains unrepaired DSBs by suppressing repair protein expression. Our data provide a mechanistic rationale for combining AN-7 with Dox or other DSB inducers as a therapeutic modality in CTCL.

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CD155T/TIGIT Signaling Regulates CD8+ T Cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

The T cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer (GC). We show that the percentage of CD8 T cells that are TIGIT+ was increased in GC patients compared to healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production and metabolism, all of which were rescued by glucose. In addition, GC tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-GC cell co-culture system, GC cells deprived CD8 T cells of glucose and impaired CD8 T cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In GC tumor cells, CD155 silencing increased T cell metabolism and IFNγ production, whereas CD155 overexpression inhibited T cell metabolism and IFNγ production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T cell reaction and improved survival in tumor bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T cell activation and improved survival in tumor bearing mice. Our results suggest that GC cells inhibit CD8 T cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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FSTL1 promotes metastasis and chemoresistance in esophageal squamous cell carcinoma through NF{kappa}B-BMP signaling crosstalk

Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis and molecular markers to improve early detection and predict outcomes are greatly needed. Here we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q where it is located occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Elevating FSTL1 levels by various means was sufficient to drive ESCC cell proliferation, clonogenicity, migration, invasion, self-renewal and cisplatin resistance in vitro and tumorigenicity and distant metastasis in vivo. Conversely, FSTL1 attenution by shRNA or neutralizing antibody elicited the opposite effects in ESCC cells. mRNA profiling analyses suggested that FSTL1 drives ESCC oncogenesis and metastasis through various pathways with deregulation of NF-κB and BMP signaling figuring prominently. Crosstalk between the NF-κB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NF-κB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinate NF-κB and BMP pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and a candidate therapeutic target in this disease setting.

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Discovery of human-similar gene fusions in canine cancers

Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathological features as well as oncogenic events including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human-dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine.

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Genetic dissociation of glycolysis and the TCA cycle affects neither normal nor neoplastic proliferation

Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas (HB) was only modestly slowed in the face of 80-90% reductions in AcCoA and significant alterations in the levels of key TCA cycle intermediates and amino acids. Overall, oxphos activity in KO livers and HB was comparable to that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances.

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KDM4 inhibition targets breast cancer stem-like cells

Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the anti-tumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSC regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation and xenograft tumor formation. QC6352 also abrogated expression of EGFR which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer.

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Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma

The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell intrinsic and extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host.

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Transplantation of iPS-derived tumor cells with a homozygous MHC haplotype induces GRP94 antibody production in MHC-matched macaques

Immune surveillance is a critical component of the anti-tumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo. We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro. These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance.

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miR-193b-regulated signaling networks serve as tumor suppressors in liposarcoma and promote adipogenesis in adipose-derived stem cells

Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared to normal fat. Re-introduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated ROS signaling by targeting the antioxidant methionine sulfoxide reductase A (MSRA) to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma, but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration.

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Blood monocytes sample MelanA/MART1 antigen for long-lasting cross-presentation to CD8+ T cells after differentiation into dendritic cells

Abstract

Human blood monocytes are very potent to take up antigens. Like macrophages in tissue, they efficiently degrade exogenous protein and are less efficient than dendritic cells at cross-presenting antigens to CD8⁺ T cells. Although it is generally accepted that dendritic cells take up tissue antigens and then migrate to lymph nodes to prime T cells, the mechanisms of presentation of antigens taken up by monocytes are poorly documented so far. In the present work, we show that monocytes loaded in vitro with MelanA long peptides retain the capacity to stimulate antigen-specific CD8⁺ T cell clones after 5 days of differentiation into monocytes-derived dendritic cells (MoDC). Tagged-long peptides can be visualized in electron-dense endocytic compartments distinct from lysosomes, suggesting that antigens can be protected from degradation for extended periods of time. To address the pathophysiological relevance of these findings, we screened blood monocytes from eighteen metastatic melanoma patients and found that CD14⁺ monocytes from 2 patients effectively activate a MelanA-specific CD8 T cell clone after in vitro differentiation into MoDC. This in vivo sampling of tumor antigen by circulating monocytes might alter the tumor-specific immune response and should be taken into account for cancer immunotherapy. This article is protected by copyright. All rights reserved.

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Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival and the influence of prognostic factors in 129,692 patients

Abstract

This large population-based study compared breast-conserving surgery with radiation therapy (BCT) with mastectomy on (long-term) breast cancer-specific (BCSS) and overall survival (OS), and investigated the influence of several prognostic factors.

Patients with primary T1-2N0-2M0 breast cancer, diagnosed between 1999-2012, were selected from the Netherlands Cancer Registry. We investigated the 1999-2005 (long-term outcome) and the 2006-2012 cohort (contemporary adjuvant systemic therapy). Cause of death was derived from the Statistics Netherlands (CBS). Multivariable analyses, per time cohort, were performed in T1-2N0-2, and separately in T1-2N0-1 and T1-2N2 stages. The T1-2N0-1 stages were further stratified for age, hormonal receptor and HER2 status, adjuvant systemic therapy and comorbidity.

In total, 129,692 patients were included. In the 1999-2005 cohort, better BCSS and OS for BCT than mastectomy was seen in all subgroups, except in patients <40 years with T1-2N0-1 stage. In the 2006-2012 cohort, superior BCSS and OS were found for T1-2N0-1, but not for T1-2N2. Subgroup analyses for T1-2N0-1 showed superior BCSS and OS for BCT in patients >50 years, not treated with chemotherapy and with comorbidity. Both treatments led to similar BCSS in patients <50 years, without comorbidity and those treated with chemotherapy.

Although confounding by severity and residual confounding cannot be excluded, this study showed better long-term BCSS for BCT than mastectomy. Even with more contemporary diagnostics and therapies we identified several subgroups that may benefit from BCT. Our results support the hypothesis that BCT might be preferred in most breast cancer patients when both treatments are suitable. This article is protected by copyright. All rights reserved.

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Transcriptional repression of Aurora-A gene by wild-type p53 through directly binding to its promoter with histone deacetylase 1 and mSin3a

Abstract

In this study, we firstly showed that p53 transcriptionally represses Aurora-A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay indicated that p53 physically bound to the Aurora-A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora-A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides -360 to -354 (CCTGCCC), upstream of the Aurora-A transcriptional start site, was responsible for the p53-mediated repression. Mutation within this site disrupted its interaction with p53, mSin3a and HDAC1, as well as attenuated the repressive effect of p53 on Aurora-A promoter activity. Treatment with trichostatin A (TSA), a HDAC1 inhibitor, disrupted the interaction of p53-HDAC1-mSin3a complex with the nucleotides -365∼-345 region, and enhanced the Aurora-A promoter activity and gene expression. Additionally, knockdown of p53 or mSin3a also drastically blocked the formation of p53-HDAC1-mSin3a repressive complex onto this promoter region and elevated the Aurora-A promoter activity and gene expression. Moreover, the p53-HDAC1-mSin3a repressive complex also involved in the inhibition of Aurora-A gene expression upon cisplatin treatment. Finally, the clinical investigation showed that Aurora-A and p53 exhibited an inverse correlation in both the expression level and prognostic status and the low p53/high Aurora-A showed the poorest prognosis of NSCLC patients. Our findings showed novel regulatory mechanisms of p53 in regulating Aurora-A gene expression in NSCLC cells.

Many types of cancer feature a boost in production of the kinase Aurora-A, and several studies have implicated the protein in transformation and tumorigenesis. Some evidence suggests that p53 affects Aurora-A expression, and in this study, the authors set out to describe that relationship. They found that p53 binds directly to the Aurora-A promoter, repressing transcription. Next, they showed that treatment with trichostatin A thwarts this repression, allowing Aurora-A transcription to proceed. Clinical investigation revealed that lung cancer patients with low p53 and high Aurora-A expression had the worst prognosis. This article is protected by copyright. All rights reserved.

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Recognition by Natural Killer cells of N6-isopentenyladenosine-treated human glioma cell lines

Abstract

Cancer cell stress induced by cytotoxic agents promote antitumor immune response. Here we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of NKG2D ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1µM) control the selective upregulation of ULBP2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for natural killer (NK) cell mediated recognition through a NKG2D restricted mechanism. p53 siRNA mediated knock-down and pharmacological inhibition (pifithrin-α), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest.

Collectively, our results indicate that behind the well established cytotoxic and anti-angiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in anti-glioma research. This article is protected by copyright. All rights reserved.

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Introducing nerve-sparing approach during minimally invasive radical hysterectomy for locally-advanced cervical cancer: a multi-institutional experience

Publication date: Available online 7 September 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Francesco Raspagliesi, Giorgio Bogani, Arsenio Spinillo, Antonino Ditto, Stefano Bogliolo, Jvan Casarin, Umberto Leone Roberti Maggiore, Fabio Martinelli, Mauro Signorelli, Barbara Gardella, Valentina Chiappa, Cono Scaffa, Simone Ferrero, Antonella Cromi, Domenica Lorusso, Fabio Ghezzi
ObjectiveTo evaluate the impact of nerve-sparing (NS) approach on outcomes of patients undergoing minimally invasive radical hysterectomy (MRH) for locally advanced stage cervical cancer (LACC).MethodsData of consecutive patients undergoing minimally invasive surgery for LACC were retrospectively retrieved in a multi-institutional setting from 2009 to 2016. All patients included had minimally invasive class III radical hysterectomy (MRH or NS-MRH). Propensity matching algorithm was used to decrease possible allocation bias when comparing outcomes between groups.ResultsOverall, 83 patients were included. The prevalence of patients undergoing NS approach increased aver the study period (from 7% in the year 2009-2010 to 97% in the year 2015-2016; p-for-trend<.001). NS-MRH and MRH were performed in 47 (57%) and 36 (43%) patients, respectively. After the application the propensity-matching algorithm, we compared 35 patients' pair (total 70 patients). Postoperative complications rate was similar between groups. Patients undergoing NS-LRH experienced shorter hospital stay than patients undergoing LRH (3.6 vs. 5.0 days). 60-day pelvic floor dysfunction rates, including voiding, fecal and sexual alterations, were lower in the NS group in comparison to control group (p=.02). Five-year disease-free (p=.77) and overall (p=.36) survivals were similar comparing NS-MRH with MRH.ConclusionsThe implementation of NS approach in the setting of LACC improves patients' outcomes, minimizing pelvic dysfunction rates. NS approach has not detrimental effects on survival outcomes.



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Perioperative Therapies – Enhancing the Impact of Cancer Surgery with Repurposed Drugs

Publication date: Available online 7 September 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Pan Pantziarka, Gauthier Bouche, Richard Sullivan, André M. Ilbawi, Anna J. Dare, Lydie Meheus
Surgical resection remains the major modality for modern curative treatment for solid tumours. However, post-surgical recurrence, even following clear-margin resection and adjuvant treatment, remains common in many types of cancer. Reducing recurrence rates, therefore, offers the potential to increase cure rates and increase overall survival. Perioperative therapies, simple interventions during the perioperative period, are designed to address some of the factors which influence post-surgical recurrence. A range of perioperative therapies are introduced and the rationale for further clinical investigation outlined.



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Frequency and Prognostic Significance of Incidental Prostate Cancer at Radical Cystectomy: Results from an international retrospective study

Publication date: Available online 7 September 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Rieken Malte, Luis A. Kluth, Dharam Kaushik, Stephen A. Boorjian, Mohammad Abufaraj, Beat Foerster, Michael Rink, Kilian Gust, Florian Roghmann, Joachim Noldus, Dimitri Vordos, Masayuki Hagiwara, Eiji Kikuchi, Masaomi Ikeda, Kazumasa Matsumoto, Pierre I. Karakiewicz, Morgan Rouprêt, Alberto Briganti, Douglas S. Scherr, Shahrokh F. Shariat, Veronika Seebacher
ObjectivesTo analyze the frequency of incidental prostate cancer (PC) at radical cystoprostatectomy (RC) for urothelial carcinoma of the bladder (UCB) and its association with survival outcomes in an international cohort.Patients and MethodsIn this retrospective study, we included 2114 who underwent RC and lymphadenectomy for UCB between 1976 and 2012 male patients from seven institutions. Univariable and multivariable Cox regression models addressed the association of incidental PC with cancer-specific mortality and overall mortality after RC.ResultsOverall, incidental PC was found in 513 (24.3%) patients with the lowest frequency in a Japanese center (23/164, 11.2%) and the highest frequency in a North American center (122/325, 37.5%), respectively (p<0.001). Within a median follow up of 27 months (IQR: 50 months), 20 patients (3.9%) were diagnosed with biochemical recurrence (BCR) and none of the patients died of PC. PC pathological tumor stage was more advanced in patients experiencing BCR (p<0.001). In multivariable Cox regression analyses adjusted for standard clinicopathologic features, incidental PC was not associated with cancer-specific (HR: 1.11, 95% CI: 0.91-1.35, p=0.30) or overall mortality (HR: 1.06, 95% CI: 0.83-1.35, p=0.65).ConclusionsIncidental PC at RC for UCB is a frequent event. However, the majority of PC cases are well-differentiated and organ-confined. Presence of incidental PC shows significant geographic differences. The risk of BCR after incidental PC is low and incidental PC is not associated with survival in UCB patients treated with RC.



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Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma

Abstract

Background

We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL).

Patients and methods

From June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15–36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20–45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6–57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5–92 months).

Results

The 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date.

Conclusion

Consolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.

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A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer

Abstract

Background

The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach.

Patients and methods

Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0–1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out.

Results

Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1–20; 5-FU/cisplatin: 1–30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination.

Conclusions

These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met.

ClinicalTrial.gov registration number

NCT01285557.

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Maintenance therapy in advanced colorectal cancer, yes or no? Ask the laboratory

In oncology, the concept of maintenance therapy is dependent upon two conditions: the availability of an effective induction treatment preventing a rapid progression and a certain degree of toxicity that does not allow indefinite continuation of therapy. When FU was the only active agent against advanced colorectal cancer we knew that continuing FU chemotherapy beyond 3–5 months (the time to response and maximum response to this agent) was not efficacious [1]. When FOLFOX and FOLFIRI became standard practice (prolongation of median OS beyond 18 months, but added toxicity), investigating less intense ways of prolonging the first line treatment became necessary. Consequently, the on–off FOLFIRI strategy [2] and the intermittent use of oxaliplatin [3] were demonstrated to be equivalent or better than continuing the doublet until progression. This produced the new concept of 'first line strategy' as opposed to the 'first line treatment' concept.

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Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

Abstract

Background

Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation.

Design and methods

We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling.

Results

Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72–1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69–1.84) who are less likely to develop chemotherapy-induced amenorrhea.

Conclusion

Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.

Clinicaltrials.gov

NCT00066690 and NCT00066703.

http://ift.tt/2wLLZxE

The Italian Collaborative Group sets a standard for the treatment of locally advanced head and neck cancer

The role of induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head/neck (LA-SCCHN) continues to be a controversial. While randomized trials have established that cisplatin/5-FU (PF) IC is equivalent to surgery followed by radiation therapy and may improve survival compared with chemoradiotherapy (CRT) for organ preservation, a definitive answer in locally advanced disease, outside of organ preservation, has been elusive [1–3]. The DeCIDE and Paradigm trials are considered to be negative IC trials exploring taxotere/cisplatin/5-FU (TPF) as IC, however both trials were inconclusive. They accrued poorly and failed to meet planned enrollment goals. Hence, the studies were underpowered and the results indeterminate [4, 5]. The GSTTC Italian Collaborative Group study in this issue of the Annals of Oncology is the first well-designed, multi-institutional, randomized phase III study comparing overall survival (OS) between a sequential approach of IC followed by concurrent CRT versus CRT alone, which fully completed. This trial is noteworthy of its innovation, management, robust analysis and adequate follow-up. The improvements in OS (HR 0.74, P <0.031), progression-free survival (PFS) (HR 0.72, P <0.013) and local regional control (LRC) (HR 0.74, P <0.036) were significant and consistently favored sequential treatment over CRT. It is notable that an improvement in LRC accounted for a great deal of the survival advantage and confirms the results of the Tax 324 study of TPF sequential therapy where the experimental TPF IC improved LRC compared with the PF control arm [6].

http://ift.tt/2wcukvj

An antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages

Abstract

Background

The transforming growth factor (TGF)-β pathway is a well-described inducer of immunosuppression and can act as an oncogenic factor in advanced tumors. Several preclinical and clinical studies show that the TGF-β pathway can be considered a promising molecular target for cancer therapy. The human genome has three TGF-β isoforms and not much is known about the oncogenic response to each of the isoforms. Here, we studied the antitumor response to ISTH0047, a recently developed locked nucleic acid-modified antisense oligonucleotide targeting TGF-β2.

Materials and methods

We have studied the anticancer response to ISTH0047 using gymnotic delivery in tumor cell cultures and in in vivo preclinical orthotopic mouse models for primary tumors (breast and kidney tumors) and lung metastasis.

Results

We observed that ISTH0047 is able to significantly reduce TGF-β2 mRNA and protein levels without altering the levels of TGF-β1 and TGF-β3. ISTH0047 prevented lung metastasis in syngeneic orthotopic renal cell carcinoma (RENCA) and breast cancer (4T1) tumor models. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-β2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86.

Conclusion

Overall, our data point to TGF-β2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages.

http://ift.tt/2wLAx4V

Do not throw the baby out with the bathwater: SELECT a personalized, de-escalated lenvatinib schedule allows response in locally advanced DTC while controlling major drug-related bleeding

Lenvatinib has proved to be an effective but quite toxic therapeutic tool for differentiated thyroid carcinomas (DTCs), with two third of pts needing dose reduction and 14.2% discontinuing treatment in the SELECT trial [1]. Severe bleeding has been reported as one of the main cause of death in DTC pts treated with multi-target TKI [2].

http://ift.tt/2wcKXr2

Rituximab for nivolumab plus ipilimumab-induced encephalitis in a small-cell lung cancer patient

Immune checkpoint inhibitors (ICIs) have shown antitumor activity against several malignancies. Nivolumab plus ipilimumab has shown promising efficacy in patients with melanoma and small-cell lung cancer (SCLC) [1–4]. ICI-induced encephalitis is an extremely rare immune-related adverse event and little is known about its clinical course and management [1–4]. We report a case of encephalitis induced by nivolumab plus ipilimumab in an SCLC patient, who showed remarkable improvement upon treatment with rituximab.

http://ift.tt/2wLAuWN

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions

Abstract

Background

In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

Patients and methods

Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected.

Results

Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%.

Conclusions

Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

http://ift.tt/2wLxQ3n

Survival advantage for etoposide/cisplatin over paclitaxel/carboplatin concurrent chemoradiation in patients with inoperable stage III NSCLC: a subgroup analysis for ECOG 2 patients would be of great interest

The phase III trial of Liang et al. [1] on the optimal chemotherapy regimen for concurrent chemoradiation in patients with inoperable stage III NSCLC is of interest as it contradicts, in part, previously published data. Surprisingly, the study revealed a survival advantage for etoposide/cisplatin (EP) (administered every 4 weeks) over paclitaxel/carboplatin (PC) weekly concurrent chemoradiation and did not confirm results from the previous Veterans Affairs Central Cancer Registry analysis [2]. Despite a relatively high rate of stage IIIB disease and low rate of complete remission, favorable 2- and 3-year overall survival was achieved.

http://ift.tt/2wcZcMf

The ‘critical mass’ survey of palliative care programme at ESMO designated centres of integrated oncology and palliative care

Abstract

Background

The ESMO Designated Centres (ESMO-DCs) of Integrated Oncology and Palliative Care (PC) Incentive Programme has grown steadily. We aimed to characterise the level of PC clinical services, education and research at ESMO-DCs.

Methods

We sent all 184 ESMO-DCs an electronic survey consisting of 78 questions examining the DC characteristics, palliative care clinical programme (structure, processes, and outcomes), primary PC delivery by oncologists, education, research and attitudes and beliefs towards the ESMO-DC programme.

Results

The response rate was 83% (152/184). 115 (76%) ESMO-DCs were from Europe, 87 (57%) were tertiary care centres. 136 (90%) had inpatient consultation teams, 135 (89%) had outpatient PC clinics, 107 (71%) had dedicated acute care beds, and 75 (50%) offered community-based PC. An estimated 70% (interquartile range [IQR] 28–80%) of patients with advanced cancer had a PC consultation before death, occurring 90 days before death (median, IQR 40–150 days) for outpatients and 21 days (IQR 14–45 days) for inpatients. 59 (39%) offered PC fellowship programme; 47 (32%) had mandatory PC rotations for oncology fellows. Ninety-nine (65%) had double-boarded palliative oncologists. 118 (78%) of the ESMO-DCs reported that routine symptom screening was offered in the oncology clinic and 30% of patients had documented end-of-life discussions by their oncologists. Most centres (>80%) perceived the ESMO-DC programme to increase their status.

Conclusions

The ESMO-DCs had a high level of PC infrastructure and provided access to a large proportion of patients with advanced cancer. The survey supports that the 13 criteria required for ESMO designation set a robust framework for integration, stimulated investment of resources into some palliative care programmes prior to accreditation, and raised the interest about palliative care among clinicians, trainees and patients.

http://ift.tt/2wMouVb

Borderline resectable pancreatic cancer: an evolving concept

We read with interest the article entitled 'Borderline resectable pancreatic cancer: conceptual evolution and current approach to image-based classification' published in the Annals of Oncology, in April 2017, by Gilbert et al. [1]. The review extensively discusses the major controversies concerning borderline resectable pancreatic cancer (BRPC): lack of universally agreed definition, variance in institution-by-institution practice, and lack of solid evidence concerning management of these patients. We congratulate the authors for the excellent work and would like to solicit authors' expert opinion about some points.

http://ift.tt/2wdq8M0

A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician’s choice in patients with advanced non-small cell lung cancer

Abstract

Background

Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician's choice (TPC).

Patients and methods

Patients with advanced NSCLC who had received ≥2 prior therapies, including platinum-based doublet and epidermal growth factor receptor tyrosine kinase inhibitor, were randomly assigned to receive eribulin or TPC (gemcitabine, pemetrexed, vinorelbine, docetaxel). The primary endpoint was OS. Secondary endpoints were progression-free survival and objective response rate.

Results

Five hundred and forty patients were randomized to either eribulin (n = 270) or TPC (n = 270). Median OS for eribulin and TPC was the same: 9.5 months [hazard ratio (HR): 1.16; 95% confidence interval: 0.95–1.41; P = 0.13]. Progression-free survival for eribulin and TPC was 3.0 and 2.8 months, respectively (HR: 1.09; 95% confidence interval: 0.90–1.32; P = 0.39). The objective response rate was 12% for eribulin and 15% for TPC. Clinical benefit rate (eribulin, 57%; TPC, 55%) and disease control rate (eribulin, 63%; TPC, 58%) were similar between treatment arms. The most common adverse event was neutropenia, which occurred in 57% of eribulin patients and 49% of TPC patients at all grades. Other non-hematologic side-effects were manageable and similar in both groups except for peripheral sensory neuropathy (all grades; eribulin, 16%; TPC, 9%).

Conclusion

This phase 3 study did not demonstrate superiority of eribulin over TPC with regard to overall survival. However, eribulin does show activity in the third-line setting for NSCLC.

Trial registration ID

http://ift.tt/PmpYKN; NCT01454934.

http://ift.tt/2wcNzFn

Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis

Abstract

Background

Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution.

Patients and methods

We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors.

Results

CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes.

Conclusions

In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.

http://ift.tt/2wcAewB

Revival of PI3K inhibitors in non-Hodgkin’s lymphoma

The phosphoinositide 3-kinase (PI3K) family is classified into three distinct classes (I, II and III). Class I is most relevant to cell growth and survival and has been the target for drug development of cancer. The class I PI3K pathway includes four isoforms: α, β, δ, and γ [1]. PI3Kδ and -γ expression is largely limited to leukocytes, while PI3K-α and -β are ubiquitously expressed [2]. PI3Kα mutations and amplifications have been identified across multiple cancer subtypes and both overexpression of PI3Kα and gain of function PI3Kα mutations were found to be oncogenic [3–6]. PI3Kα is also the primary isoform required for insulin signaling [7]. PI3Kβ isoform has roles in regulating formation and stability of integrin which is required for platelet activation [8]. PI3Kδ and -γ regulate leukocyte trafficking and cell proliferation [9–12]. Mice with functionally deficient PI3Kδ have impaired immune systems with abnormal antibody development and inflammatory bowel disease [12]. However, dissecting the individual function of class I PI3K isoforms have been complicated by the heterodimeric nature of the proteins as altering expression of one subunit affects the expression profile of others.

http://ift.tt/2wL9h6z

Proton therapy in mediastinal Hodgkin lymphoma: moving from dosimetric prediction to clinical evidence

Combined modality therapy with chemotherapy followed by consolidation radiotherapy is now considered the standard of care in early-stage Hodgkin lymphoma (HL); in advanced stage disease with bulky sites, radiotherapy may also be used to locally consolidate response after more intensive chemotherapy [1]. As most early-stage HL patients achieve durable complete remission and become long-term survivors, it is important to reduce the risk of treatment-induced late effects [2]. This is especially relevant for patients with mediastinal involvement as their disease is in close proximity to critical healthy tissues (heart, lungs, breasts). The effort to reduce treatment-related toxicity—mainly cardiovascular disease and secondary malignancies—is the main driver behind the recent improvements in the radiation therapy (RT) delivery for patients with HL.

http://ift.tt/2wLKOya

Chemotherapy-induced toxicity—a secondary effect caused by released DNA?

The use of chemotherapy treatment is often limited by toxic side-effects caused to healthy cells. In general, most chemotherapy treatments cause DNA damage or stop cells in mitosis, targeting both dividing cancer and dividing healthy cells (e.g. gut epithelium, bone marrow, hair follicle). Clearly, DNA damaging chemotherapy treatments may cause damage to both cancer and healthy cells to generate toxic side-effects (Figure 1A). In a new study presented in this issue of Annals of Oncology, Mittra et al. challenge this concept and suggest that released cell-free chromatin (cfCh) may itself cause inflammation and DNA damage as a secondary event [1] (Figure 1B). The authors also demonstrate that treatment with DNAse I or the DNA-degrading agent Resveratrol-Cu may suppress some chemotherapy-induced neutropenia, inflammation and DNA damage markers in multiple organs and in peripheral blood mononuclear cells. The authors demonstrated suppressed toxicity by all five different chemotherapy treatments used, i.e. adriamycin, cyclophosphamide, cisplatin, methotrexate and paclitaxel. Although caution should be taken when interpreting the results since this is a small limited animal study, the implication could be that DNA neutralizing agents may prevent chemotherapy-induced toxicities.

http://ift.tt/2wclBJN

Treating cancer cachexia: an evolving landscape

Currently, there is no licensed treatment and no standard of care for cancer cachexia. Putting this in the context of a condition which impairs the delivery of anti-cancer therapy (through increased side-effects, treatment delays, dose reductions) [1], causes marked distress to patients and their families and is associated with reduced survival, there remains an urgency to progress the research agenda in cancer cachexia [2].

http://ift.tt/2wLDZNa

Stromal inflammation, necrosis and HER2 overexpression in ductal carcinoma in situ of the breast: another causality dilemma?

We read with interest the manuscript of Pruneri et al. [1] concerning tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS). TILs were retrospectively studied in an extensive cohort of 1488 patients. DCIS studies are often underpowered due to limited patient numbers, and robust statistical analysis is frequently hampered by low recurrence rates. Therefore, Pruneri et al. [1] provide truly valuable information for the scientific and oncologic community. However, we do have some remarks regarding the conclusions of this study.

http://ift.tt/2xSJIPM

Metastasis of cancer: when and how?

Despite encouraging advances in both local and systemic treatment over the past two decades, cancer remains the leading cause of death worldwide. Metastasis, a process of cancer cells spreading from the primary tumor to surrounding tissues and to distant organs is the primary cause of cancer mortality. It is estimated that metastasis is responsible for ∼90% of cancer deaths [1]. This has not changed much in the past half century [2]. Understanding metastases is critical to improving cancer patient outcomes. Although metastasis equates to late stage cancer clinically, when the process begins and how metastasis occurs is largely unknown.

http://ift.tt/2xStupO

The TREX1 Dinosaur Bites the Brain through the LINE

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): José Luis García Pérez, Marta E. Alarcón-Riquelme
In this issue of Cell Stem Cell, Thomas et al. (2017) define the nature of accumulated ssDNA present in the neuron and astrocyte cytoplasm of TREX1 mutated stem cell-derived organoids. Accumulated ssDNAs are derived from LINE-1 endogenous retroelements, providing new clues as to the development of Aicardi-Goutières syndrome in the neural system.

Teaser

In this issue of Cell Stem Cell, Thomas et al. (2017) define the nature of accumulated ssDNA present in the neuron and astrocyte cytoplasm of TREX1 mutated stem cell-derived organoids. Accumulated ssDNAs are derived from LINE-1 endogenous retroelements, providing new clues as to the development of Aicardi-Goutières syndrome in the neural system.


http://ift.tt/2ePVfut

Putting Two Heads Together to Build a Better Brain

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): John K. Mich, Jennie L. Close, Boaz P. Levi
3D organoids enable in vitro human brain development models, but they have not yet recapitulated some essential features of brain circuit formation. Recently, several studies appearing in Nature, Nature Methods, and Cell Stem Cell generated fused organoid models of inhibitory and excitatory neuron development, which can now achieve functional circuit integration.

Teaser

3D organoids enable in vitro human brain development models, but they have not yet recapitulated some essential features of brain circuit formation. Recently, several studies appearing in Nature, Nature Methods, and Cell Stem Cell generated fused organoid models of inhibitory and excitatory neuron development, which can now achieve functional circuit integration.


http://ift.tt/2j80TcA

Survival of the Fittest: Darwinian Selection Underpins Chemotherapy Resistance in AML

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Laura MacPherson, Mark A. Dawson
Intratumor heterogeneity driving therapeutic resistance is a major challenge in cancer management. Recently in Nature, Shlush et al. (2017) provide a tour de force of genomics coupled to functional assays to demonstrate that resistance emerges from a pre-existing subpopulation of acute myeloid leukemia (AML) cells with a stem cell transcription program.

Teaser

Intratumor heterogeneity driving therapeutic resistance is a major challenge in cancer management. Recently in Nature, Shlush et al. (2017) provide a tour de force of genomics coupled to functional assays to demonstrate that resistance emerges from a pre-existing subpopulation of acute myeloid leukemia (AML) cells with a stem cell transcription program.


http://ift.tt/2ePV1n7

Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Julia P. Andreotti, Luiza Lousado, Luiz Alexandre V. Magno, Alexander Birbrair
Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation.

Teaser

Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation.


http://ift.tt/2j8ohXB

CRISPR: Established Editor of Human Embryos?

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Xiao-Jiang Li, Zhuchi Tu, Weili Yang, Shihua Li
Off-target effects and mosaicism are major concerns for applying CRISPR-Cas9 to correct genetic mutations. A recent article in Nature by Ma et al. (2017) uses an elegant CRISPR-Cas9 approach that repairs a genetic mutation in human embryos with negligible mosaicism and no off-target effects, bringing this editing tool closer to clinical application.

Teaser

Off-target effects and mosaicism are major concerns for applying CRISPR-Cas9 to correct genetic mutations. A recent article in Nature by Ma et al. (2017) uses an elegant CRISPR-Cas9 approach that repairs a genetic mutation in human embryos with negligible mosaicism and no off-target effects, bringing this editing tool closer to clinical application.


http://ift.tt/2ePK1WE

Open Sesame: Open Chromatin Regions Shed Light onto Non-coding Risk Variants

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Kun Yang, Akira Sawa
Human genetics and stem cell biology have advanced neurobiology for neurodevelopmental psychiatric disorders. In this issue of Cell Stem Cell, Forrest et al. (2017) demonstrate that studying the landscape of open chromatin regions in stem cell-derived neurons helps functional interpretation of non-coding genetic variants associated with these diseases.

Teaser

Human genetics and stem cell biology have advanced neurobiology for neurodevelopmental psychiatric disorders. In this issue of Cell Stem Cell, Forrest et al. (2017) demonstrate that studying the landscape of open chromatin regions in stem cell-derived neurons helps functional interpretation of non-coding genetic variants associated with these diseases.


http://ift.tt/2j80A1q

Synergistic Engineering: Organoids Meet Organs-on-a-Chip

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Takanori Takebe, Boyang Zhang, Milica Radisic
Organoid technology and organ-on-a-chip engineering have emerged as two distinct approaches for stem cell-derived 3D tissue preparation. Their strategic integration can address each approach's limitations and provide a path toward a superior, synergistic strategy of constructing tissues that will truly deliver on the promise of regenerative and precision medicine.

Teaser

Organoid technology and organ-on-a-chip engineering have emerged as two distinct approaches for stem cell-derived 3D tissue preparation. Their strategic integration can address each approach's limitations and provide a path toward a superior, synergistic strategy of constructing tissues that will truly deliver on the promise of regenerative and precision medicine.


http://ift.tt/2ePotK0

Mitochondrial Replacement Techniques: Remaining Ethical Challenges

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Annelien L. Bredenoord, John B. Appleby
Recent developments in the field of mitochondrial replacement technique (MRT) research and clinical practice have raised ethical concerns worldwide. We argue that the future use of MRTs requires a concerted effort among the global research and clinical community to implement and enforce responsible innovation and governance.

Teaser

Recent developments in the field of mitochondrial replacement technique (MRT) research and clinical practice have raised ethical concerns worldwide. We argue that the future use of MRTs requires a concerted effort among the global research and clinical community to implement and enforce responsible innovation and governance.


http://ift.tt/2j824J3

MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Daniel G. Abernathy, Woo Kyung Kim, Matthew J. McCoy, Allison M. Lake, Rebecca Ouwenga, Seong Won Lee, Xiaoyun Xing, Daofeng Li, Hyung Joo Lee, Robert O. Heuckeroth, Joseph D. Dougherty, Ting Wang, Andrew S. Yoo
Directed reprogramming of human fibroblasts into fully differentiated neurons requires massive changes in epigenetic and transcriptional states. Induction of a chromatin environment permissive for acquiring neuronal subtype identity is therefore a major barrier to fate conversion. Here we show that the brain-enriched miRNAs miR-9/9^∗ and miR-124 (miR-9/9^∗-124) trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9^∗-124-induced neurons (miNs) are functionally excitable and uncommitted toward specific subtypes but possess open chromatin at neuronal subtype-specific loci, suggesting that such identity can be imparted by additional lineage-specific transcription factors. Consistently, we show that ISL1 and LHX3 selectively drive conversion to a highly homogeneous population of human spinal cord motor neurons. This study shows that modular synergism between miRNAs and neuronal subtype-specific transcription factors can drive lineage-specific neuronal reprogramming, providing a general platform for high-efficiency generation of distinct subtypes of human neurons.

Graphical abstract

Teaser

Abernathy et al. show that widespread epigenetic changes underlie miRNA-mediated direct reprogramming of primary adult human fibroblasts into neurons, revealing modular synergism between miRNAs and transcription factors to allow lineage-specific neuronal reprogramming. This work provides a platform for generating distinct subtypes of human neurons from patients.


http://ift.tt/2ePZu9f

A Modular Platform for Differentiation of Human PSCs into All Major Ectodermal Lineages

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Jason Tchieu, Bastian Zimmer, Faranak Fattahi, Sadaf Amin, Nadja Zeltner, Shuibing Chen, Lorenz Studer
Directing the fate of human pluripotent stem cells (hPSCs) into different lineages requires variable starting conditions and components with undefined activities, introducing inconsistencies that confound reproducibility and assessment of specific perturbations. Here we introduce a simple, modular protocol for deriving the four main ectodermal lineages from hPSCs. By precisely varying FGF, BMP, WNT, and TGFβ pathway activity in a minimal, chemically defined medium, we show parallel, robust, and reproducible derivation of neuroectoderm, neural crest (NC), cranial placode (CP), and non-neural ectoderm in multiple hPSC lines, on different substrates independently of cell density. We highlight the utility of this system by interrogating the role of TFAP2 transcription factors in ectodermal differentiation, revealing the importance of TFAP2A in NC and CP specification, and performing a small-molecule screen that identified compounds that further enhance CP differentiation. This platform provides a simple stage for systematic derivation of the entire range of ectodermal cell types.

Graphical abstract

Teaser

Tchieu et al. develop a chemically defined culture platform that allows parallel derivation of human PSCs into all major ectodermal lineages. The utility of this platform is shown through genetic dissection of the roles of TFAP transcription factors in ectoderm and a chemical screen that identified compounds promoting cranial placode differentiation.


http://ift.tt/2ePJqnS

ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells

Publication date: 7 September 2017
Source:Cell Stem Cell, Volume 21, Issue 3
Author(s): Nicole I. Park, Paul Guilhamon, Kinjal Desai, Rochelle F. McAdam, Ellen Langille, Madlen O'Connor, Xiaoyang Lan, Heather Whetstone, Fiona J. Coutinho, Robert J. Vanner, Erick Ling, Panagiotis Prinos, Lilian Lee, Hayden Selvadurai, Gurnit Atwal, Michelle Kushida, Ian D. Clarke, Veronique Voisin, Michael D. Cusimano, Mark Bernstein, Sunit Das, Gary Bader, Cheryl H. Arrowsmith, Stephane Angers, Xi Huang, Mathieu Lupien, Peter B. Dirks




http://ift.tt/2ePFu6y

Proceedings of the International Cancer Imaging Society (ICIS) 17th Annual Teaching Course

http://ift.tt/2ePJJPD

New chemotherapies in gastric adenocarcinoma

Summary

Chemotherapy is still the most important component of systemic therapy in gastric cancer. It is not replaced by targeted agents so far. Novel chemotherapies like 5‑fluorouracil (5FU) prodrugs are applied. Agents such as nanoliposomal irinotecan or nanoparticle albumin-bound paclitaxel are still under investigation. In patients overexpressing the epithelial growth factor receptor 2 (HER2), the addition of trastuzumab to classical chemotherapy improves overall survival (OS) substantially and in second line setting the monoclonal antibody ramucirumab shows single agent activity as well as activity in combination with paclitaxel.

http://ift.tt/2wLisnM

Pre-treatment carcinoembryonic antigen and outcome of patients with rectal cancer receiving neo-adjuvant chemo-radiation and surgical resection: a systematic review and meta-analysis

Abstract

Neo-adjuvant chemo-radiation is the standard of care for patients with locally advanced rectal carcinoma. The aim of the present paper is to evaluate the relationship of the baseline serologic concentration of the carcinoembryonic antigen with the outcome. Data sources included MEDLINE and Web of Science databases. A systematic search of the databases by a predefined criterion has been conducted. Chemo-radiation followed by surgical resection of rectal tumors was the intervention of interest. From selected studies, the relationships between carcinoembryonic antigen and pathologic complete response, disease-free survival and overall survival were assessed. Carcinoembryonic antigen correlated significantly and inversely with the rate of pathologic complete responses (OR 2.00). Similar to this relationship, a low baseline carcinoembryonic antigen concentration was associated with a better disease-free survival (OR 1.88) and a better overall survival (OR 1.85). Heterogeneity of studies and publication bias were considerable in evaluating the relationship of baseline carcinoembryonic antigen and pathologic complete response. Baseline carcinoembryonic antigen should be regarded as a predictor of outcome of patients undergoing neo-adjuvant chemo-radiation. A calibration of the cutoff value from 5 to 3 ng/ml appears more appropriate to this patient population and should be evaluated in prospective trials.

http://ift.tt/2wLknsr

Clinical Predictors of Malignancy in Patients with Pheochromocytoma and Paraganglioma

Abstract

Background and Purpose

Factors associated with malignancy in patients with pheochromocytoma (adrenal tumors, Pheo) and paraganglioma (extra-adrenal, PGL) are not well-defined and all patients require lifelong surveillance. The primary aim of our study was to determine genetic and clinical variables associated with malignancy in patients with Pheo/PGL.

Methods

Single institution retrospective review was performed of all patients who underwent surgery (1/95–1/15) for Pheo/PGL. Malignancy was defined as histology-confirmed distant metastasis, lymph nodal involvement, or tumor bed recurrence.

Results

A total of 157 Pheo/PGL patients (44 malignant, 113 benign) with mean follow-up of 87 months were included. Compared with patients with benign Pheo/PGL, patients with malignant Pheo/PGL were younger (median 42 vs 50 years, p = 0.014), had larger tumors (median 6.5 vs 4 cm, p < 0.001) and had PGL (63.6 vs 4.4%, p < 0.001). Genetic testing was performed in 60 patients and was positive in 38 (63%). Although positive genetic results were equally likely in malignant vs benign Pheo/PGL (76 vs 54%, p = 0.1), all 11 patients with germline SDHB mutations had malignant disease. In multivariable analysis, younger age, larger tumor size, and PGL were associated with malignancy (p < 0.05). Pheo patients with negative genetic testing and negative family history who developed metachronous metastases all had primary tumors ≥4 cm in size.

Conclusions

Patients who are young, have larger tumors, positive genetic testing (especially SDHB) or have PGL require long-term follow-up. Patients with negative genetic testing or family history and Pheo <4 cm have a lower risk of malignancy, and de-escalated long-term surveillance may be appropriate follow-up.

http://ift.tt/2wLL68h

IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas

Abstract

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P < 0.001, P = 0.02, and P < 0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P < 0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.

http://ift.tt/2wcb94I

Radiation-induced acute dysphagia

Abstract

Purpose

Acute toxicity in head and neck (H&N) cancer patients treated with definitive radiotherapy (RT) has a crucial role in compliance to treatments. The aim of this study was to correlate doses to swallowing-associated structures and acute dysphagia.

Methods

We prospectively analyzed 42 H&N cancer patients treated with RT. Dysphagia (grade ≥ 3) and indication for percutaneous endoscopic gastrostomy (PEG) insertion were classified as acute toxicity. Ten swallowing-related structures were considered for the dosimetric analysis. The correlation between clinical information and the dose absorbed by the contoured structures was analyzed. Multivariate logistic regression method using resampling methods (bootstrapping) was applied to select model order and parameters for normal tissue complication probability (NTCP) modelling.

Results

A strong multiple correlation between dosimetric parameters was found. A two-variable model was suggested as the optimal order by bootstrap method. The optimal model (Rs = 0.452, p < 0.001) includes V₄₅ of the cervical esophagus (odds ratio [OR] = 1.016) and D_mean of the cricopharyngeal muscle (OR = 1.057). The model area under the curve was 0.82 (95% confidence interval 0.69–0.95).

Conclusion

Our results suggested that the absorbed dose to the cricopharyngeal muscle and cervical esophagus might play a relevant role in the development of acute RT-related dysphagia.

http://ift.tt/2vPDyTb

Orbital recurrence of iris melanoma 21 years after enucleation

We present the case of a 56-year-old man who developed a neoplasm of epithelioid histology in his anophthalmic left orbit 21 years after he underwent enucleation for a spindle cell iris melanoma. The recurrent tumour was managed by orbital exenteration. Neither further recurrence nor metastasis was diagnosed over a 5-year follow-up period. This case, along with five other similar cases in the literature,^1–3 emphasises the importance of long-term follow-up after treatment of iris melanoma.

http://ift.tt/2wLhUfL

Medical expenditure for esophageal cancer in China: a 10-year multicenter retrospective survey (2002–2011)

Esophageal cancer is associated with substantial disease burden in China, and data on the economic burden are fundamental for setting priorities in cancer interventions. The medical expenditure for the diagnos...

http://ift.tt/2wKoe8Y

Medical expenditure for esophageal cancer in China: a 10-year multicenter retrospective survey (2002–2011)

Abstract

Background

Esophageal cancer is associated with substantial disease burden in China, and data on the economic burden are fundamental for setting priorities in cancer interventions. The medical expenditure for the diagnosis and treatment of esophageal cancer in China has not been fully quantified. This study aimed to examine the medical expenditure of Chinese patients with esophageal cancer and the associated trends.

Methods

From 2012 to 2014, a hospital-based multicenter retrospective survey was conducted in 37 hospitals in 13 provinces/municipalities across China as a part of the Cancer Screening Program of Urban China. For each esophageal cancer patient diagnosed between 2002 and 2011, clinical information and expense data were extracted by using structured questionnaires. All expense data were reported in Chinese Yuan (CNY; 1 CNY = 0.155 USD) based on the 2011 value and inflated using the year-specific health care consumer price index for China.

Results

A total of 14,967 esophageal cancer patients were included in the analysis. It was estimated that the overall average expenditure per patient was 38,666 CNY, and an average annual increase of 6.27% was observed from 2002 (25,111 CNY) to 2011 (46,124 CNY). The average expenditures were 34,460 CNY for stage I, 39,302 CNY for stage II, 40,353 CNY for stage III, and 37,432 CNY for stage IV diseases (P < 0.01). The expenditure also differed by the therapy type, which was 38,492 CNY for surgery, 27,933 CNY for radiotherapy, and 27,805 CNY for chemotherapy (P < 0.05). Drugs contributed to 45.02% of the overall expenditure.

Conclusions

These conservative estimates suggested that medical expenditures for esophageal cancer in China substantially increased in the last 10 years, treatment for early-stage esophageal cancer costs less than that for advanced cases, and spending on drugs continued to account for a considerable proportion of the overall expenditure.

http://ift.tt/2wLvno1

Nadir PSA is a strong predictor of treatment outcome in intermediate and high risk localized prostate cancer patients treated by definitive external beam radiotherapy and androgen deprivation

The aim of this study is to investigate the effect of tumor characteristics and parameters of treatment response in predicting biochemical disease-free survival (BFS) for patients with intermediate or high ris...

http://ift.tt/2eNX6Qi

Radiation-induced acute dysphagia

Abstract

Purpose

Acute toxicity in head and neck (H&N) cancer patients treated with definitive radiotherapy (RT) has a crucial role in compliance to treatments. The aim of this study was to correlate doses to swallowing-associated structures and acute dysphagia.

Methods

We prospectively analyzed 42 H&N cancer patients treated with RT. Dysphagia (grade ≥ 3) and indication for percutaneous endoscopic gastrostomy (PEG) insertion were classified as acute toxicity. Ten swallowing-related structures were considered for the dosimetric analysis. The correlation between clinical information and the dose absorbed by the contoured structures was analyzed. Multivariate logistic regression method using resampling methods (bootstrapping) was applied to select model order and parameters for normal tissue complication probability (NTCP) modelling.

Results

A strong multiple correlation between dosimetric parameters was found. A two-variable model was suggested as the optimal order by bootstrap method. The optimal model (Rs = 0.452, p < 0.001) includes V₄₅ of the cervical esophagus (odds ratio [OR] = 1.016) and D_mean of the cricopharyngeal muscle (OR = 1.057). The model area under the curve was 0.82 (95% confidence interval 0.69–0.95).

Conclusion

Our results suggested that the absorbed dose to the cricopharyngeal muscle and cervical esophagus might play a relevant role in the development of acute RT-related dysphagia.

http://ift.tt/2vPDyTb

Intrinsic fluorescence of the clinically approved multikinase inhibitor nintedanib reveals lysosomal sequestration as resistance mechanism in FGFR-driven lung cancer

Abstract

Background

Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure.

Methods

3-dimensional fluorescence spectroscopy was conducted to asses cell-free nintedanib fluorescence properties. MTT assay was used to determine the impact of the lysosome-targeting agents bafilomycin A1 and chloroquine combined with nintedanib on lung cancer cell viability. Flow cytometry and live cell as well as confocal microscopy were performed to analyze uptake kinetics as well as subcellular distribution of nintedanib. Western blot was conducted to investigate protein expression. Cryosections of subcutaneous tumor allografts were generated to detect intratumoral nintedanib in mice after oral drug administration.

Results

Here, we report for the first time drug-intrinsic fluorescence properties of nintedanib in living and fixed cancer cells as well as in cryosections derived from allograft tumors of orally treated mice. Using this feature in conjunction with flow cytometry and confocal microscopy allowed to determine cellular drug accumulation levels, impact of the ABCB1 efflux pump and to uncover nintedanib trapping into lysosomes. Lysosomal sequestration - resulting in an organelle-specific and pH-dependent nintedanib fluorescence - was identified as an intrinsic resistance mechanism in FGFR-driven lung cancer cells. Accordingly, combination of nintedanib with agents compromising lysosomal acidification (bafilomycin A1, chloroquine) exerted distinctly synergistic growth inhibitory effects.

Conclusion

Our findings provide a powerful tool to dissect molecular factors impacting organismal and intracellular pharmacokinetics of nintedanib. Regarding clinical application, prevention of lysosomal trapping via lysosome-alkalization might represent a promising strategy to circumvent cancer cell-intrinsic nintedanib resistance.

http://ift.tt/2wcejpk

(S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1

Abstract

Background

Non–small cell lung cancer (NSCLC) accounts for approximately 80–85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. Targeted therapy has produced unprecedented outcomes in patients with NSCLC as a number of oncogenic drivers have been found. Crizotinib, a selective small-molecule inhibitor, has been widely used for the treatment of NSCLC patients with ALK gene rearrangements. A recent study has also shown that (S)-enantiomer of crizotinib exhibits anticancer activity by targeting the protein mutT homologue (MTH1). Since this discovery, contradictory studies have cast a doubt on MTH1 as a therapeutic target of (S)-crizotinib.

Methods

NCI-H460, H1975, and A549 cells and immunodeficient mice were chosen as a model to study the (S)-crizotinib treatment. The changes induced by (S)-crizotinib treatment in cell viability, apoptosis as well as ROS, and endoplasmic reticulum stress pathway in the cells were analyzed by MTT assay, FACSCalibur, Western blotting, ROS imaging and electron microscopy.

Results

Here, we report that MTH1 does not affect survival of NSCLC cells. We found that (S)-crizotinib induces lethal endoplasmic reticulum stress (ER) response in cultured NSCLC cells by increasing intracellular levels of reactive oxygen species (ROS). Blockage of ROS production markedly reversed (S)-crizotinib-induced ER stress and cell apoptosis, independent of MTH1. We confirmed these findings in NSCLC xenograft studies and showed that (S)-crizotinib-induced ER stress and cell apoptosis.

Conclusions

Our results reveal a novel antitumor mechanism of (S)-crizotinib in NSCLC which involves activation of ROS-dependent ER stress apoptotic pathway and is independent of MTH1 inhibition.

http://ift.tt/2wKKrnt

High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods

Abstract

Background

Next generation sequencing (NGS) is being increasingly applied for assisting cancer molecular diagnosis. However, it is still needed to validate NGS accuracy on detection of DNA alternations based on a large number of clinical samples, especially for DNA rearrangements and copy number variations (CNVs). This study is to set up basic parameters of targeted NGS for clinical diagnosis and to understand advantage of targeted NGS in comparison with the conventional methods of molecular diagnosis.

Methods

Genomic DNA from 1000 Genomes Project and DNA from cancer cell lines have been used to establish the basic parameters for targeted NGS. The following confirmation was conducted by clinical samples. The multiple variants tested by amplification-refractory mutation system (ARMS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were evaluated by targeted NGS to determine the sensitivity. Furthermore, the multiple variants detected by targeted NGS were confirmed by current conventional methods to elucidate the specificity.

Results

At sequencing depth of 500×, the maximal sensitivities on detecting single nucletic variances (SNVs) and small insertions/deletions (Indels) can reach 99% and 98.7% respectively, and in 20% of cancer cells, CNV detection can reach to the maximal level. The following confirmation of the sensitivity and specificity was conducted by a large cohort of clinical samples. For SNV and indel detection in clinical samples, targeted NGS can identify all hotspot mutations with 100% sensitivity and specificity. On ALK fusion detection, about 86% IHC-identified cases could be identified by targeted NGS and all ALK fusion detected by targeted NGS were confirmed by IHC. For HER2-amplification, 14 HER2-amplification cases identified by target NGS were all confirmed by FISH and about 93.3% of Her-2 IHC (3+) cases were identified by targeted NGS. Finally, the targeted NGS platform developed here has accurately detected EGFR hotspot mutations in 215 NSCLC patients.

Conclusions

DNA from cancer cell lines is better than standard DNA as a reference to establish basic parameters for targeted NGS. Comparison of the conventional methods using a large cohort of patient samples confirmed the high preformance of targeted NGS on detecting DNA alterations.

http://ift.tt/2wbtqzs

Development of chemotherapeutics in oncology: is there anything new?

http://ift.tt/2wbO2Y8

Cross-over comparison and new chemotherapy regimens in metastatic pancreatic cancer

Summary

Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) is still one of the most lethal malignant diseases with a devastating 5‑year overall survival of only 4–5%. Indeed, long-term survival was not affected by the introduction of new systemic cytotoxic chemotherapies which remain the key cornerstone in the treatment of metastatic PDAC. In the first-line setting, FOLFIRINOX based upon the results of the PRODIGE/ACCORD trial and gemcitabine with albumin-bound paclitaxel (GNP) based upon the MPACT trial have both been approved as therapeutic options for patients with no significant comorbidities and good performance status. As there is no direct comparison between these regimens, the choice in first-line treatment depends on the toxicity profile, patient's preferences and reimbursability. In the second-line setting, the results of the NAPOLI-1 trial have led to the approval of nanoliposomal irinotecan (nal-iri) in combination with 5‑fluorouracil (5-FU) for the treatment of patients with mPDAC progressing under gemcitabine-based chemotherapy and therefore this regimen is the first to be approved for use in second-line therapy.

http://ift.tt/2wKPAw0

Thyroid cancer mortality is higher in Filipinos in the United States: An analysis using National Mortality Records from 2003 through 2012

BACKGROUND

Well-differentiated thyroid carcinoma has a favorable prognosis, but patients with multiple recurrences have drastically lower survival. Filipinos in the United States are known to have high rates of thyroid cancer incidence and disease recurrence. To the authors' knowledge, it is unknown whether Filipinos also have higher thyroid cancer mortality rates.

METHODS

The authors studied thyroid cancer mortality in Filipino, non-Filipino Asian (NFA), and non-Hispanic white (NHW) adults using US death records (2003-2012) and US Census data. Age-adjusted mortality rates and proportional mortality ratios (PMRs) were calculated. Sex, nativity status, age at death, and educational attainment also were examined.

RESULTS

The authors examined 19,940,952 deaths. The age-adjusted mortality rates due to thyroid cancer were highest in Filipinos (1.72 deaths per 100,000 population; 95% confidence interval [95% CI], 1.51-1.95) compared with NFAs (1.03 per 100,000 population; 95% CI, 0.95-1.12) and NHWs (1.17 per 100,000 population; 95% CI, 1.16-1.18). Compared with NHWs, higher proportionate mortality was observed in Filipino women (3-5 times higher) across all age groups, and among Filipino men, the PMR was 2 to 3 times higher in the subgroup aged >55 years. Filipinos who completed a higher educational level had a notably higher PMR (5.0) compared with their counterparts who had not (3.5).

CONCLUSIONS

Negative prognostic factors for thyroid cancer traditionally include age >45 years and male sex. The results of the current study demonstrate that Filipinos die of thyroid cancer at higher rates than NFA and NHW individuals of similar ages. Highly educated Filipinos and Filipino women may be especially at risk of poor thyroid cancer outcomes. Filipino ethnicity should be factored into clinical decision making in the management of patients with thyroid cancer. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2gKBGR3

Quality of life from the perspective of the patient with acute myeloid leukemia

BACKGROUND

Although outcomes for acute myeloid leukemia (AML) have improved over time, they remain poor overall, and toxicity from both the disease and its treatment can affect quality of life (QOL). One barrier to including QOL endpoints in clinical trials is the lack of a disease-specific QOL instrument that can efficiently capture the major QOL deficits in this population.

METHODS

A cross-sectional study was performed to elicit concepts for inclusion in a new AML-specific QOL instrument called the AML-QOL. Eighty-two patients at various stages of disease were interviewed about sources of support (positive concepts) and problems and symptoms (negative concepts) experienced over the past week, and they were asked to grade how much each affected their QOL. In addition, patients were asked to complete 2 validated instruments: the Functional Assessment of Cancer Therapy with the leukemia and transplant modules and the 29-item Patient-Reported Outcomes Measurement Information System questionnaire.

RESULTS

With data from the open-ended and questionnaire-based portions of the interview, 7 positive concepts and 64 negative concepts were elicited. From these, 5 positive concepts and 21 negative concepts were selected for inclusion in the preliminary AML-QOL on the basis of concept prevalence and the impact on QOL.

CONCLUSIONS

These concepts will form the basis of a new QOL instrument specific to AML. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2f75Gqa

Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil

BACKGROUND

The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes.

METHODS

A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3).

RESULTS

The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT.

CONCLUSIONS

Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2gK6n8U

The Cancer of the Bladder Risk Assessment (COBRA) score: Estimating mortality after radical cystectomy

BACKGROUND

Risk stratification of patients with urothelial carcinoma of the bladder (UCB) after cystectomy has important clinical and research implications. The authors assessed the relative effect of tumor stage and lymph node status on cancer-specific survival (CSS) after cystectomy and developed a simplified risk-assessment tool.

METHODS

In total, 14,828 patients who underwent cystectomy with lymph node dissection for UCB were identified from the Surveillance, Epidemiology, and End Results database (1988-2011). The relative importance of tumor stage and lymph node status with regard to CSS was assessed using stratified Kaplan-Meier and Cox proportional-hazards analyses. The patients were split randomly into development and validation cohorts. Additional validation using overall survival was performed on 19,362 patients from the National Cancer Data Base. The Cancer of Bladder Risk Assessment (COBRA) tool was created using a Cox model incorporating age, tumor stage, and lymph node density. Performance was validated using observed versus expected survival plots and the Harrell concordance index.

RESULTS

Patients with muscle invasive (T2), lymph node-positive disease had a survival curve similar to that in patients with extravesical (T3 and T4), lymph node-negative disease (2-year CSS, 67% and 70%, respectively). Each point increase in the COBRA score (range, 0-7) was associated with a 1.61-fold increase (95% confidence interval, 1.56-fold to 1.65-fold increase) in the risk of bladder cancer death in the development cohort. The model accurately stratified patients across risk levels in the development cohort and the 2 validation cohorts (C-index, 0.712, 0.705, and 0.68, respectively).

CONCLUSIONS

The COBRA score offers a straightforward, validated risk-stratification tool that incorporates the relative contribution of tumor stage and lymph node involvement to patient prognosis after cystectomy for UCB. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2f75zuK

Heterogeneous impact of smoking on major salivary gland cancer according to histopathological subtype: A case-control study

BACKGROUND

Major salivary gland cancers (M-SGCs) are rare, and have distinct heterogeneous histopathological subtypes. To the authors' knowledge, no consistent evidence of an association between cigarette smoking and the risk of M-SGCs has appeared to date. Furthermore, evidence of potential heterogeneity in the impact of smoking on histopathological subtypes is scarce, despite the fact that the histopathological subtypes of M-SGC exhibit different genetic features.

METHODS

The authors conducted a case-control study to investigate the association between smoking and M-SGC by histopathological subtype. Cases were 81 patients with M-SGCs and the controls were 810 age-matched and sex-matched first-visit outpatients without cancer treated at Aichi Cancer Center Hospital from 1988 to 2005. Odds ratios (OR) and 95% confidence intervals (95% CI) were assessed by conditional logistic regression analysis with adjustment for potential confounders.

RESULTS

Smoking was found to be associated with a significantly increased risk of M-SGC overall, with an OR of 3.45 (95% CI, 1.58-7.51; P =.001) for heavy smokers compared with never-smokers. A significant dose-response relationship was observed (P for trend, .001). When stratified by histological subtype, no obvious impact of smoking was observed among patients with mucoepidermoid carcinoma (MEC). In contrast, smoking demonstrated a significantly increased risk of M-SGCs other than MEC, with an OR of 5.15 (95% CI, 2.06-12.87; P<.001) for heavy smokers compared with never-smokers. The authors observed possible heterogeneity with regard to the impact of smoking on risk between MEC and M-SGCs other than MEC (P for heterogeneity, .052).

CONCLUSIONS

The results of the current study demonstrate a significant positive association between cigarette smoking and the risk of M-SGC overall. However, the impact of smoking appeared to be limited to M-SGCs other than MEC. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2gKMC1c

Validation of a pediatric early warning system for hospitalized pediatric oncology patients in a resource-limited setting

BACKGROUND

Pediatric oncology patients are at high risk of clinical deterioration, particularly in hospitals with resource limitations. The performance of pediatric early warning systems (PEWS) to identify deterioration has not been assessed in these settings. This study evaluates the validity of PEWS to predict the need for unplanned transfer to the pediatric intensive care unit (PICU) among pediatric oncology patients in a resource-limited hospital.

METHODS

A retrospective case-control study comparing the highest documented and corrected PEWS score before unplanned PICU transfer in pediatric oncology patients (129 cases) with matched controls (those not requiring PICU care) was performed.

RESULTS

Documented and corrected PEWS scores were found to be highly correlated with the need for PICU transfer (area under the receiver operating characteristic, 0.940 and 0.930, respectively). PEWS scores increased 24 hours prior to unplanned transfer (P = .0006). In cases, organ dysfunction at the time of PICU admission correlated with maximum PEWS score (correlation coefficient, 0.26; P = .003), patients with PEWS results ≥4 had a higher Pediatric Index of Mortality 2 (PIM2) (P = .028), and PEWS results were higher in patients with septic shock (P = .01). The PICU mortality rate was 17.1%; nonsurvivors had higher mean PEWS scores before PICU transfer (P = .0009). A single-point increase in the PEWS score increased the odds of mechanical ventilation or vasopressors within the first 24 hours and during PICU admission (odds ratio 1.3-1.4).

CONCLUSIONS

PEWS accurately predicted the need for unplanned PICU transfer in pediatric oncology patients in this resource-limited setting, with abnormal results beginning 24 hours before PICU admission and higher scores predicting the severity of illness at the time of PICU admission, need for PICU interventions, and mortality. These results demonstrate that PEWS aid in the identification of clinical deterioration in this high-risk population, regardless of a hospital's resource-level. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2f6NWez