Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population

Abstract

IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35–0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99–1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10–1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45–0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development.

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Inhibitory effects of Arhgap6 on cervical carcinoma cells

Abstract

Ras homology GTPase activation protein 6 (Arhgap6), as a member of the rhoGAP family of proteins, performs vital functions on the regulation of actin polymerization at the plasma membrane during several cellular processes. The role of Arhgap6 in the progression and development of cancer remains nearly unknown. This study aimed at exploring the effects of Arhgap6 on cervical carcinoma. Human cervical cancer cells HeLa and SiHa were transduced with a lentivirus targeting Arhgap6 (Arhgap6+), while CaSki and C4-1 cells were transfected with miRNA. Cell proliferation was identified by Cell Counting Kit-8 (CCK-8). Cell cycle distribution and cell apoptosis were identified by flow cytometry. The capacity of cell migration, invasion, and adhesion were detected by Transwell assay. Further, quantitative real-time PCR (qRT-PCR) and western blot were used to analyze the expression levels of Arhgap6 and several tumor-related genes. Co-immunoprecipitation assay was performed to validate the interaction between Arhgap6 and Rac3 (Ras-related C3 botulinum toxin substrate 3). Results showed that Arhgap6 inhibited cell proliferation, migration, invasion, and adhesion of cervical carcinoma, induced cell apoptosis, and caused cell cycle arrest in the G0/G1 phase (n = 3, p < 0.05). Expression of the tumor suppressor genes and oncogenes were up- and down-regulated respectively by Arhgap6, and Rac3 was proved to be the target of Arhgap6. Besides, in in vivo assays, tumor size and weight were destructed in Arhgap6+ athymic nude mouse. This study indicated that Arhgap6 may play a role in the treatment of cervical cancer as a tumor supressor.

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Assessing cancer-related distress in cancer patients and caregivers receiving outpatient psycho-oncological counseling

Abstract

Purpose

The diagnosis of cancer, the symptoms of the illness and its treatment have an influence on how patients and their caregivers experience distress. However, data focusing on caregivers and their cancer-related distress in the outpatient setting is sparse. This study aimed to compare cancer-related distress of caregivers and patients and to derive implications for the system of outpatient psycho-oncological care.

Methods

One hundred thirty-eight patients and 102 caregivers receiving psycho-oncological counseling completed a standardized interview based on a self-assessment questionnaire (Questionnaire on Stress in Cancer Patients, FBK).

Results

Group comparisons for cancer-related distress revealed one statistically significant difference for the subscale ‘Fear’ of the FBK, Z = 2.308, p = .021, and d = .44. Caregivers showed higher cancer-related fear (M = 2.76, SD = 1.14) than patients (M = 2.41, SD = 1.29). There were no differences in ‘psychosomatic complaints’, ‘information deficit’, ‘restrictions in everyday life’, ‘social strains’, or the total score of the FBK.

Conclusions

Caregivers seem to experience cancer-related distress equal to or even more severely than patients themselves. Results suggest that there is a need for more low-threshold offers of outpatient psycho-oncological counseling for caregivers.

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Developing and implementing a complex Complementary and Alternative (CAM) nursing intervention for breast and gynecologic cancer patients undergoing chemotherapy—report from the CONGO (complementary nursing in gynecologic oncology) study

Abstract

Purpose/objectives

The purpose of this study was to develop a complex nursing intervention including complementary and alternative medicine (CAM) for breast and gynecologic cancer patients during chemotherapy to improve quality of life.

Methods

Data sources Theoretical framework and concepts, practical nursing knowledge, and evidence-based studies were compiled in interprofessional meetings.

Data synthesis The final complex intervention consists of three autonomous, but interacting components: (1) CAM nursing package, (2) resource-oriented counseling, and (3) evidence-based information material on CAM. CAM interventions include acupressure, aromatherapy, compress, and massage, targeting 14 clinically relevant symptoms during chemotherapy. Participants receive these interventions during chemotherapy with instructions for self care. During a counseling interview, the patient’s needs and preferences are assessed by trained nurses. Furthermore, participants are equipped with evidence-based information material (booklet and DVD). Prior to study start, nurses attended training modules for administering CAM therapies and for communicating and counseling within the salutogenic approach.

Conclusions

It was possible to design a multimodal CAM nursing intervention based on a theoretical concept, evidence-based studies, and practical nursing experience targeting the prevention or relief of side-effects women suffer during chemotherapy. The systematic analysis of the CONGO study will contribute to evidence-based CAM nursing care within supportive cancer care.

Implications for integrative cancer care

Oncology nurses play an important role in supportive CAM care of breast and gynecologic cancer patients in daily clinical practice. Within oncology outpatient services, the implementation of evidence-based CAM nursing interventions and counseling may contribute to understand the impact of nursing on patient quality of life and symptom relief. This can lead to a new understanding of the nurse’s professional role.

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Penfluridol: An antipsychotic agent suppresses metastatic tumor growth in triple negative breast cancer by inhibiting integrin signaling axis

Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anti-cancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the anti-metastatic potential of penfluridol (PF), an antipsychotic drug frequently prescribed for schizophrenia with anti-cancer activity. We show that PF induced apoptosis and reduced the survival of several metastatic triple negative breast cancer (TNBC) cell lines. Additionally, PF treatment significantly reduced the expression of integrinα6, integrin β4, Fak, Paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of PF in three different in vivo tumor models. We demonstrate that PF administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, PF treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. PF-treated tumors from all three models exhibited reduced integrinβ4 and increased apoptosis. Moreover, chronic administration of PF failed to elicit significant toxic or behavioral side effects in mice. Taken together, our result indicate that PF effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing PF for the treatment of metastatic TNBC.

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The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia

Translocations of the mixed lineage leukemia (MLL) gene occur in 60-80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDACs), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate protumorigenic gene expression programs. We conducted a small molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven AML. We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the pro-survival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies, and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

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Melphalan, Antimelanoma Immunity, and Inflammation—Letter

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Dependence Receptor and Cancer

Data accumulating over the last 20 years support the notion that some transmembrane receptors are activated not only by their respective ligands but also, differentially, by the withdrawal or absence of these same ligands. In this latter setting, these receptors actively trigger apoptosis. They have been dubbed dependence receptors because their expression confers a state of ligand dependence for survival on the expressing cells. Twenty of these receptors have been identified to date, and several have been shown to inhibit tumor progression by inducing apoptosis. As a corollary, these receptors, or their transduced death signals, are frequently silenced in cancer cells as a selective mechanism to prevent cell death, allowing invasion and metastasis. Drugs aimed at inducing programmed cell death in neoplastic cells by re-engaging the proapoptotic activity induced by unliganded dependence receptors are in late-stage preclinical tests, poised for clinical evaluation. This approach may offer novel opportunities for patient treatments. In this review, we discuss the implications of dependence receptors in limiting cancer progression and address the therapeutic perspectives brought to light by this paradigm. Cancer Res; 75(24); 1–5. ©2015 AACR.

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Cancer Education

Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine. Cancer Res; 75(24); 1–4. ©2015 AACR.

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Druggable Mutations in Childhood Cancer

Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies. Cancer Res; 75(24); 1–11. ©2015 AACR.

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Comprehensive Phenotyping of Rare PIK3CA Variants

Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal “driver” mutations that promote tumor progression along with many more pathologically neutral “passenger” events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. Although PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07% to 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of mitogen-activated protein kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. Cancer Res; 75(24); 1–14. ©2015 AACR.

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IL15 in T-cell Therapy of Cancer

Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8+ memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell–based immunotherapy of cancer. Cancer Res; 75(24); 1–7. ©2015 AACR.

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Genomic Profiling of Merkel Cell Carcinomas

Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 1–7. ©2015 AACR.

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Melphalan, Antimelanoma Immunity, and Inflammation—Response

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Amphiregulin is a critical downstream effector of estrogen signaling in ERAlpha-positive breast cancer

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERAlpha)-positive breast cancer. Many ERAlpha target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the EGF eceptor ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERAlpha-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Further, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the amphiregulin response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERAlpha-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response.

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uPAR Promotes Skin Tumor Formation

The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development. Cancer Res; 75(22); 1–15. ©2015 AACR.

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Evolution and Cancer Treatment

The dynamic cancer ecosystem, with its rich temporal and spatial diversity in environmental conditions and heritable cell phenotypes, is remarkably robust to therapeutic perturbations. Even when response to therapy is clinically complete, adaptive tumor strategies almost inevitably emerge and the tumor returns. Although evolution of resistance remains the proximate cause of death in most cancer patients, a recent analysis found that evolutionary terms were included in less than 1% of articles on the cancer treatment outcomes, and this has not changed in 30 years. Here, we review treatment methods that attempt to understand and exploit intratumoral evolution to prolong response to therapy. In general, we find that treating metastatic (i.e., noncurable) cancers using the traditional strategy aimed at killing the maximum number of tumor cells is evolutionarily unsound because, by eliminating all treatment-sensitive cells, it enables rapid proliferation of resistant populations—a well-known evolutionary phenomenon termed “competitive release.” Alternative strategies, such as adaptive therapy, “ersatzdroges,” and double-bind treatments, shift focus from eliminating tumor cells to evolution-based methods that suppress growth of resistant populations to maintain long-term control. Cancer Res; 75(22); 1–6. ©2015 AACR.

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Nrf2 and Skin Cancer

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 1–13. ©2015 AACR.

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Tumor Microenvironment Confers De Novo Therapy Resistance

Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a “resistance niche” adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed “osteocrines”) found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer. Cancer Res; 75(22); 1–11. ©2015 AACR.

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MUC16 and Cancer Therapeutics

CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. Cancer Res; 75(22); 1–6. ©2015 AACR.

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A p16 Missense SNP Underlying ALL Risk

Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case–control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10−9) and Hispanic children (OR, 2.77; P = 3.78 × 10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors. Cancer Res; 75(22); 1–11. ©2015 AACR.

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Cutaneous T cell Lymphoma: an Update on Pathogenesis and Systemic Therapy

Abstract

Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are malignancies of skin-homing T cells that comprise the majority of cutaneous T cell lymphomas (CTCL). Treatment of CTCL is limited and can be approached by skin-directed therapy or systemic therapy. Recent investigations into the pathogenesis of MF and SS have broadened the therapeutic targets; here, we review emerging concepts in the pathogenesis of MF and SS as well as novel and traditional systemic therapies for MF and SS. These include histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, and belinostat), monoclonal antibodies (alemtuzumab, brentuximab vedotin, and mogamulizumab) and single-agent cytotoxic chemotherapeutic agents (e.g., pralatrexate, doxorubicin, bendamustine, and forodesine), as well as multi-agent chemotherapy regimens.

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EOV Editorial Board.

EOV Editorial Board.

Nutr Cancer. 2015 Nov-Dec;67(8):ebi

Authors:

PMID: 26620636 [PubMed - in process]

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Acknowledgment to Reviewers.

Acknowledgment to Reviewers.

Nutr Cancer. 2015 Nov-Dec;67(8):1359-64

Authors:

PMID: 26620635 [PubMed - in process]

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Evaluation of 18 F-FDG uptake for detecting lymph node metastasis of gastric cancer: a prospective pilot study for one-to-one comparison of radiation dose and pathological findings

Abstract

Background

Gastric cancer exhibits various degrees of fluorine F-18 fluorodeoxyglucose (¹⁸F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). We evaluated the relationship between ¹⁸F-FDG uptake and the presence/absence of metastasis in individual lymph nodes (LN) on a one-to-one basis.

Methods

We analyzed 21 patients with gastric cancer. We injected ¹⁸F-FDG intravenously in the morning, and gastrectomy with LN dissection was performed in the afternoon of the same day. Radiation doses were measured at each LN using a well-type counter, and we then compared ¹⁸F-FDG uptake, the shortest diameter, and pathological examination results for each LN.

Results

In our study, 906 LNs were analyzed, including 115 metastatic LNs. Metastatic LNs showed significantly higher ¹⁸F-FDG uptake (P < 0.0001), and were significantly enlarged (P < 0.0001). The receiver operating characteristics (ROC) curve had a larger area under the curve (0.71) for ¹⁸F-FDG uptake than for the shortest LN diameter (0.60). Considering histology, the ROC curve for intestinal type adenocarcinoma had a larger area under the curve than that for diffuse type (0.75 vs 0.61).

Conclusions

F-FDG uptake is potentially a more useful variable than LN diameter for discriminating between LN with and without metastasis, especially in intestinal type gastric cancer cases.

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PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells

Abstract

TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53-null and p53-mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo-like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up-regulated by cisplatin. PLK2-phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up-regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73-enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.

We found that PLK2 does bind to and phosphorylate TAp73 when TAp73 is up-regulated by the drug cisplatin and that inhibition of PLK2 up-regulates p21 and puma mRNA expression in the presence of cisplatin. PLK2 inhibition also led to reduced cell proliferation and invasion and increased apoptosis and G1 arrest, but only in the presence of TAp73, in osteosarcoma cells.

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Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer

Abstract

Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy—we performed RIT of experimental cervical cancer with Rhenium-188 (¹⁸⁸Re) and Lutetium-177 (¹⁷⁷Lu)-labeled mAb C1P5 to E6. The biodistribution of ¹⁸⁸Re- and ¹⁷⁷Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either ¹⁸⁸Re-C1P5 or ¹⁷⁷Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of ¹⁸⁸Re- and ¹⁷⁷Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both ¹⁷⁷Lu-C1P5 and ¹⁸⁸Re-C1P5. The dose to the liver was five times higher for ¹⁷⁷Lu-C1P5. The doses to the tumor were 259 and 181 cGy for ¹⁷⁷Lu-C1P5 and ¹⁸⁸Re-C1P5, respectively. RIT with either ¹⁷⁷Lu-C1P5 or ¹⁸⁸Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in ¹⁷⁷Lu-C1P5 group only and on day 10 it was observed in both ¹⁷⁷Lu-C1P5 and ¹⁸⁸Re-C1P5 groups. ¹⁸⁸Re- and ¹⁷⁷Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer.

Our group has been developing an approach of targeting human papilloma virus (HPV) antigens with the radiolabeled antibodies on cancers of viral etiology. We have demonstrated that such approach is specific, effective and safe in several experimental models of cervical and head and neck cancers. In all our previously published studies we have utilized 188Rhenium, a strong beta emitter with a short half-life. In this study, we investigated the influence of different radionuclides on the radioimmunotherapy efficacy by performing side by side comparison of the efficacy and mechanisms of action of the 188Rhenium versus 177Lutetium-labeled antibodies to HPV-16/18 viral oncoprotein E6. This study demonstrated equal efficacy of these two radionuclides for therapy of experimental cervical cancer which makes these radionuclides candidates for clinical translation.

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Recent decline in prostate cancer incidence in the United States, by age, stage, and Gleason score

Abstract

Prostate cancer incidence is sensitive to screening practices, however the impact of recent screening recommendations from the United States Preventative Services Task Force on prostate cancer incidence by age, stage, race, and Gleason score is unknown. This study described the timing and magnitude of changes in prostate cancer incidence trends in the United States by month of diagnosis, and evaluated trends by age, Gleason score, and stage at diagnosis. We analyzed prostate cancer incidence trends using Surveillance, Epidemiology, and End Results (SEER) program data for men diagnosed with invasive prostate cancer from 2007 through 2012. JoinPoint analysis was used to detect changes in the rate of annual percent change (APC) in prostate cancer incidence for all diagnoses and by age, Gleason score, race, and stage. Prostate cancer incidence declined at an estimated −19.6% APC beginning May 2011. This decline was observed in all age groups. Low-grade tumors (Gleason score ≤6) showed a steeper decline (−29.1% APC) than high-grade tumors (Gleason score 8–10: −10.8% APC). Only stage I/II and stage III tumors saw declines (−24.2% and −16.7% APC, respectively). A sharp decline in prostate cancer incidence began before release of the United States Preventative Services Task Force October 2011 draft and May 2012 final screening recommendation. The greatest change occurred with incidence of low-grade tumors, although there is concern that some high-grade tumors may now go undetected.

Prostate cancer incidence is sensitive to screening practices, however, the impact of recent screening recommendations from the United States Preventative Services Task Force on prostate cancer incidence by age, stage, and Gleason score is unknown. A trend of −19.6% annual percent change in incidence began in May 2011 and was seen in men of all ages, with more effect on incidence of low-grade tumors than high-grade tumors.

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Impact of body fat distribution on neoadjuvant chemotherapy outcomes in advanced breast cancer patients

Abstract

Obesity is known to decrease the efficacy of neoadjuvant chemotherapy (NAC) against breast cancer; however, the relationship between actual body composition and NAC outcomes remains unknown. Therefore, we determined the effect of body composition on NAC outcomes. A total of 172 advanced breast cancer patients who underwent surgery after NAC were retrospectively analyzed. Body composition parameters including abdominal circumference (AC), subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle area (SMA) were calculated using computed tomography volume-analyzing software. VFA/SFA ratio was used to evaluate visceral obesity. The associations of body composition parameters with pathological complete remission (pCR) and survival were analyzed. AC, SFA, and VFA were significantly correlated with body mass index (BMI) (all P < 0.05; r = 0.82, r = 0.71, and r = 0.78, respectively). AC, SFA, and VFA increased significantly and SMA decreased significantly after menopause (all P < 0.05). VFA/SFA ratio increased significantly after menopause, even though BMI remained unchanged. Body composition parameters were not associated with pCR. Distant disease-free survival (DDFS) was significantly worse in the high VFA group than in the low VFA group (P < 0.05). Furthermore, in the high VFA group, postmenopausal patients had significantly shorter DDFS than premenopausal patients (P < 0.05). VFA was independently associated with DDFS in the multivariate analysis (P < 0.05). High visceral fat is associated with worse NAC outcomes in breast cancer patients, especially postmenopausal patients. Interventions targeting visceral fat accumulation will likely improve NAC outcomes.

Increased visceral fat amount worsens survival outcome after neoadjuvant chemotherapy for breast cancer patients.

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The effects of attachment and outness on illness adjustment among gay men with prostate cancer

Abstract

Objective

Previous research has suggested that gay men facing prostate cancer may be particularly vulnerable to poor illness adjustment. Moreover, although attachment and greater disclosure of sexual orientation have been associated with health outcomes, their associations in this population have been largely unexamined. The purpose of the present study was to investigate whether greater outness about one's sexual orientation significantly mediated the associations between anxious and avoidant attachment and illness intrusiveness among gay men with prostate cancer.

Methods

Ninety-two gay and bisexual men who had received a diagnosis of prostate cancer in the past 4 years were recruited for the present study. Self-report questionnaires assessed demographic and medical variables, attachment, outness level and comfort, and illness intrusiveness. Bootstrapping procedures were used to assess for mediation.

Results

Results suggested significant associations between anxious attachment, outness comfort, and illness intrusiveness. Less comfort with outness significantly mediated the association between greater anxious attachment and more illness intrusiveness. Avoidant attachment was not significantly associated with illness intrusiveness.

Conclusions

Findings support the mediating role of the subjective experience of being an out gay man in the association between anxious attachment and illness intrusiveness. These results suggest that facilitating greater comfort with outness would be beneficial for illness adjustment among gay men with prostate cancer whom have more anxious attachment styles. Copyright © 2015 John Wiley & Sons, Ltd.

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Cancer and Employment Issues: Perspectives from Cancer Patient Navigators

Abstract

Among individuals diagnosed with cancer, 40 % are working-age adults who will face numerous challenges in returning to work, yet oncology providers report limited guidance and uncoordinated communication processes in addressing patients’ work-related issues. Cancer patient navigators are uniquely positioned to fill this care and communication gap due to their focus on both practical matters and clinical care. This cross-sectional study utilized survey methodology to collect quantitative and qualitative data from 58 cancer patient navigators to (1) identify patients’ cancer and employment issues that commonly challenge navigators and (2) identify the necessary training navigators felt would allow them to more effectively help patients deal with cancer and employment issues. Participants from the southeast USA were invited to complete a paper survey while in attendance at a statewide cancer patient navigator conference or online via the state comprehensive cancer coalition’s cancer patient navigator listserv. Results suggest financial burdens, work and treatment conflicts, taking unpaid leave for cancer care, and working through treatment were common concerns among their patients. Navigators also identified employment, legal, government programs, and financial resources as important training and education topics that would help them address their clients’ employment and cancer conflicts. Given the fact that employment issues remain one of the most common unmet need of survivors and the increasing presence of navigators across the USA, it is important to address the role of navigators in meeting patients’ needs regarding cancer and employment and ensure they are provide with adequate training and resources.

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Prostate Cancer Ambassadors: Enhancing a Theory-Informed Training Program for Informed Decision-Making

Abstract

Despite the high burden of prostate cancer in African American communities, there is a paucity of knowledge about prostate health. This paper describes the enhancement of a curriculum for training lay health advisors, called prostate cancer ambassadors, on informed decision-making for prostate cancer screening. Adult learning theory informed the structuring of the training sessions to be interactive, self-directed, and engaging. Trainings were developed in a manner that made the material relevant to the learners and encouraged co-learning. The research team developed strategies, such as using discussions and interactive activities, to help community members weigh the pros and cons of prostate-specific antigen (PSA) screening and to make an informed decision about screening. Furthermore, activities were developed to bolster four social cognitive theory constructs: observational learning, self-efficacy for presenting information to the community and for making an informed decision themselves, collective efficacy for presenting information to the community, and outcome expectations from those presentations. Games, discussions, and debates were included to make learning fun and encourage discovery. Practice sessions and team-building activities were designed to build self-efficacy for sharing information about informed decision-making. Topics added to the original curriculum included updates on prostate cancer screening, informed decision-making for screening, skills for being a lay health advisor, and ethics. This dynamic model and approach to lay health advisor (ambassador) training is flexible: while it was tailored for use with prostate cancer education, it can be adjusted for use with other types of cancer and even other diseases.

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Considerations in the Diagnosis and Management of Pediatric Patients With Favorable Histology Wilms Tumor Who Present With Only Pulmonary Nodules

More than 70% of children with stage IV, favorable histology (FH) Wilms tumor will be relapse-free survivors 16 years after diagnosis. Successful treatment generally includes whole lung radiation therapy and doxorubicin. Such therapy is associated with adverse, long-term effects, including impaired pulmonary function, congestive heart failure, and second malignant neoplasms, especially breast cancer. Cooperative groups have adopted a risk-based approach to the treatment of these patients. It is important to recall the good overall prognosis for this group before recommendations for intensification are made based on preliminary data and in the absence of histological confirmation of persistent malignant disease.

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Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium.

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Intraoperative electron radiation therapy combined with external beam radiation therapy and limb sparing surgery in extremity soft tissue sarcoma: a retrospective single center analysis of 183 cases

To report our experience with limb-sparing surgery, IOERT and EBRT in extremity STS.

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The role of preoperative breast magnetic resonance (MR) imaging for surgical decision in patients with triple-negative breast cancer

Background

Several reliable randomized studies do not recommend routine preoperative breast MR imaging for patients with breast cancer. However, because the principle of MR imaging is based on the dynamics of contrast enhancement, a specific biologic subgroup of tumors should sensitively respond to the imaging process.

Methods

From 2008 to 2013, 918 eligible patients with breast cancer underwent breast surgery and were divided into two groups based on preoperative breast MR findings: patients in whom the surgical plan was changed and those in whom the surgical plan remained unchanged. We investigated the changing patterns of breast surgery based on routine mammography, ultrasound, and preoperative breast magnetic resonance (MR) findings and analyzed the association between additional suspicious lesions on breast MR imaging and clinicopathologic factors.

Results

Additional suspicious breast lesions were detected on preoperative MR imaging in 104 cases (11.3%), and the surgical strategy was changed as the final decision in 97 cases (10.6%). There was no difference between oncologic results between two groups. However, the triple-negative breast cancer (TNBC) was significantly associated with changing of the surgical strategy based on breast MR findings (P = 0.048).

Conclusions

Additional preoperative breast MR imaging may be helpful in surgical decision for patients with TNBC. J. Surg. Oncol. 2015;9999:1–5. © 2015 Wiley Periodicals, Inc.

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Stage II differentiated thyroid cancer: A mixed bag

Background and Objectives

AJCC-TNM Stage II well-differentiated thyroid cancer (WDTC) comprises T2N0M0 tumors in patients ≥45 years of age or metastatic WDTC in patients younger than 45 years. The objectives of this study were to assess the oncological outcome of stage II WDTC and to compare the oncological outcome of metastatic WDTC in patient younger (stage II) and older (stage IVC) than 45 years.

Methods

This study involved review of clinical presentation and oncological outcome of population cohort of 2,128 consecutive WDTC, diagnosed during 1970–2010 that includes 215 Stage II WDTC and 61 metastatic WDTC. Cox proportional hazard model was used to assess independent impact of prognostic factors on disease-specific survival (DSS) and disease-free survival (DFS) as calculated by Kaplan–Meier method.

Results

Metastatic and non-metastatic stage II WDTC had a 15-year DSS of 41.7% and 96.7%, respectively (P < 0.001). Multivariable analysis showed a 52 times higher risk of death in metastatic stage II WDTC and the DSS of metastatic stage II WDTC was not statistically different from that of stage IVC WDTC.

Conclusion

Metastatic stage II WDTC is very different from non-metastatic stage II WDTC with oncological outcome similar to stage IVC WDTC. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.

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Oncologic outcomes after nipple-sparing mastectomy: A single-institution experience

Introduction

Long-term oncologic outcomes in nipple-sparing mastectomy (NSM) continue to be defined. Rates of locoregional recurrence for skin-sparing mastectomy (SSM) and NSM in the literature range from 0% to 14.3%. We investigated the outcomes of NSM at our institution.

Methods

Patients undergoing NSM at our institution from 2006 to 2014 were identified and outcomes were analyzed.

Results

From 2006 to 2014, 319 patients (555 breasts) underwent NSM. One-hundered and fourty-one patients (237 breasts) had long-term follow-up available. Average patient age and BMI were 47.78 and 24.63. Eighty-four percent of patients underwent mastectomy primarily for a therapeutic indication. Average tumor size was 1.50 cm with the most common histologic type being invasive ductal carcinoma (62.7%) followed by DCIS (23.7%). Average patient follow-up was 30.73 months. There was one (0.8%) incidence of ipsilateral chest-wall recurrence. There were 0.37 complications per patient.

Conclusions

We examined our institutional outcomes with NSM and found a locoregional recurrence rate of 0.8% with no nipple-areolar complex recurrence. This rate is lower than published rates for both NSM and SSM. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.

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Mutated pathways as a guide to adjuvant therapy treatments for breast cancer

Adjuvant therapy following breast cancer surgery generally consists of either a course of chemotherapy if the cancer lacks hormone receptors, or a course of hormonal therapy, otherwise. Here we report a correlation between adjuvant strategy, and mutated pathway patterns. In particular we find that for breast cancer patients, pathways enriched in non-synonymous mutations in the chemotherapy group, are distinct from those of the hormonal therapy group. We apply a recently developed method that identifies collaborative pathway groups for hormone and chemotherapy patients. A collaborative group of pathways is one in which each member is altered in the same--generally large--number of samples. In particular we find the following: (i) A chemotherapy group consisting of 3 pathways and a hormone therapy group consisting of 20, the members of the two groups being mutually exclusive. (ii) Each group is highly enriched in breast cancer drivers. (iii) The pathway groups are correlates of subtype-based therapeutic recommendations. These results suggest that patient profiling using these pathway groups can potentially enable the development of personalized treatment plans that may be more accurate and specific than those currently available.

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Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Photodynamic therapy (PDT) is a minimally invasive antitumor therapy that eradicates tumor cells through a photosensitizer-mediated cytotoxic effect upon light irradiation. However, systemic administration of photosensitizer often makes it difficult to avoid a photosensitive adverse effect. A red fluorescent protein KillerRed generates reactive oxygen species (ROS) upon green light irradiation. Here we show the therapeutic potential of a novel tumor-specific replicating photodynamic viral agent (TelomeKiller) constructed by using the human telomerase reverse transcriptase (hTERT) promoter. We investigated the light-induced antitumor effect of TelomeKiller in several types of human cancer cell lines. Relative cell viability was investigated using an XTT assay. The in vivo antitumor effect was assessed using subcutaneous xenografted tumor and lymph node metastasis models. KillerRed accumulation resulted in ROS generation and apoptosis in light-irradiated cancer cells. Intratumoral injection of TelomeKiller efficiently delivered the KillerRed protein throughout the tumors and exhibited a long-lasting antitumor effect with repeated administration and light irradiation in mice. Moreover, intratumorally injected TelomeKiller could spread into the regional lymph node area and eliminate micrometastasis with limited-field laser irradiation. Our results suggest that KillerRed has great potential as a novel photosensitizer if delivered with a tumor-specific virus-mediated delivery system. TelomeKiller-based PDT is a promising antitumor strategy to efficiently eradicate tumor cells.

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Experiences of Parents and General Practitioners with End-of-Life Care in Adolescents and Young Adults with Cancer

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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In memoriam Prof. Dr. Hans-Jürgen Eichhorn

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Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients with Unresectable Pancreatic Cancer

Publication date: Available online 1 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Aaron T. Wild, Joseph M. Herman, Avani S. Dholakia, Shalini Moningi, Yao Lu, Lauren M. Rosati, Amy Hacker-Prietz, Ryan K. Assadi, Ali M. Saeed, Timothy M. Pawlik, Elizabeth M. Jaffee, Daniel A. Laheru, Phuoc T. Tran, Matthew J. Weiss, Christopher L. Wolfgang, Eric Ford, Stuart A. Grossman, Xiaobu Ye, Susannah G. Ellsworth
PurposeRadiation-induced lymphopenia (RIL) is associated with inferior survival in glioblastoma, lung cancer, and pancreatic cancer. We studied whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation (CRT) in locally advanced pancreatic cancer (LAPC).Methods/MaterialsSerial total lymphocyte counts (TLCs) from patients enrolled on a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy×5). CRT patients received median 50.4 Gy (1.8 Gy×28) with concurrent 5-fluorouracil (77%) or gemcitabine (23%). Uni- and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival.ResultsThirty-two patients received SBRT and 101 CRT. Median planning target volume (PTV) was smaller in SBRT (88.7cc) versus CRT (344.6cc; p<0.001); median tumor diameter was larger for SBRT (4.6cm) versus CRT (3.6cm; p=0.01). SBRT and CRT groups had similar median baseline TLC. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia, i.e., TLC<500 cells/mm³ versus 13.8% of SBRT patients (p<0.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic versus 13.6% of SBRT patients (p=0.007). MVA demonstrated that treatment technique and baseline TLC were significantly associated with post-treatment TLC at one but not two months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (HR for death 2.059 (1.310 – 3.237), p = 0.002).ConclusionsSBRT is associated with significantly less severe RIL than CRT at one month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

Teaser

This study compared post-treatment total lymphocyte counts (TLC) in patients treated with SBRT vs. conventional chemoradiation; multivariate analysis demonstrated that treatment technique and baseline TLC were significantly associated with post-treatment TLC at one but not two months post-treatment, providing preliminary support of a model predicting that fraction number and field size are associated with post-treatment TLC. Additionally, severe radiation-induced lymphopenia was associated with inferior survival regardless of treatment technique.


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Subdural hematoma in a patient taking imatinib for GIST: a case report and discussion of risk with other chemotherapeutics.

Although anticancer drugs have existed for over 50 years, targeted drugs have only recently been marketed, and their side effects may not be completely understood. The patient is a 56-year-old woman with a gastrointestinal stromal tumor who presented with headache, nausea, and vomiting lasting 2 weeks. An MRI to rule out brain metastasis found a large right-hemispheric subdural hematoma without metastases. She denied trauma, seizures, or alcohol abuse. Laboratory test results were normal. Eight months prior, she had begun a dose escalation of imatinib, which became the suspected cause of her hemorrhage. The literature was reviewed for reports of intracranial hemorrhage with targeted chemotherapeutics excluding metastases, anticoagulation, and trauma. Multiple events have been documented but only one for imatinib with gastrointestinal stromal tumor. Imatinib is believed to cause platelet dysfunction (missed by standard testing), leading to intracranial hemorrhage. Intracranial hemorrhage risk may be under-reported and neurosurgical consultation for immediate treatment and oncology for reinitiation of chemotherapy are recommended. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Severe post-treatment leukopenia associated with the development of encephalopathy following ifosfamide infusion.

Ifosfamide has been shown to be associated with encephalopathy in 10-40% of patients. Although it is a well-documented toxicity associated with ifosfamide therapy, an anecdotal upsurge in its occurrence at our institution prompted us to review ifosfamide usage. A 1-year single-center retrospective study was performed to assess the incidence of and potential risk factors for ifosfamide-induced encephalopathy (IIE). A total of 28 inpatients received ifosfamide-based chemotherapy over 47 separate treatment sessions. During those treatment sessions, seven cases of IIE (14.9%) were observed, which presented a significant increase compared with historical data from our institution (

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Performance of the Breast Cancer Risk Assessment Tool Among Women Age 75 Years and Older

Background:

The Breast Cancer Risk Assessment Tool (BCRAT, "Gail model") is commonly used for breast cancer prediction; however, it has not been validated for women age 75 years and older.

Methods:

We used Nurses’ Health Study (NHS) data beginning in 2004 and Women’s Health Initiative (WHI) data beginning in 2005 to compare BCRAT’s performance among women age 75 years and older with that in women age 55 to 74 years in predicting five-year breast cancer incidence. BCRAT risk factors include: age, race/ethnicity, age at menarche, age at first birth, family history, history of benign breast biopsy, and atypia. We examined BCRAT’s calibration by age by comparing expected/observed (E/O) ratios of breast cancer incidence. We examined discrimination by computing c-statistics for the model by age. All statistical tests were two-sided.

Results:

Seventy-three thousand seventy-two NHS and 97 081 WHI women participated. NHS participants were more likely to be non-Hispanic white (96.2% vs 84.7% in WHI, P < .001) and were less likely to develop breast cancer (1.8% vs 2.0%, P = .02). E/O ratios by age in NHS were 1.16 (95% confidence interval [CI] = 1.09 to 1.23, age 57–74 years) and 1.31 (95% CI = 1.18 to 1.45, age ≥ 75 years, P = .02), and in WHI 1.03 (95% CI = 0.97 to 1.09, age 55–74 years) and 1.10 (95% CI = 1.00 to 1.21, age ≥ 75 years, P = .21). E/O ratio 95% confidence intervals crossed one among women age 75 years and older when samples were limited to women who underwent mammography and were without significant illness. C-statistics ranged between 0.56 and 0.58 in both cohorts regardless of age.

Conclusions:

BCRAT accurately predicted breast cancer for women age 75 years and older who underwent mammography and were without significant illness but had modest discrimination. Models that consider individual competing risks of non–breast cancer death may improve breast cancer risk prediction for older women.

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MRI Screening in Women With a Personal History of Breast cancer

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Hepatitis-Associated Liver Cancer: Gaps and Opportunities to Improve Care

The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches.

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ASCO 2015: highlights in colorectal cancer

Abstract

Two “first-in” studies of colorectal liver metastases were highlighted at the 2015 ASCO Annual Meeting: the first prospective randomized trial to evaluate radiofrequency ablation plus chemotherapy [J Clin Oncol 33] and the first large randomized phase III trial to study liver-directed selective internal radiation therapy [J Clin Oncol 33]. Radiofrequency ablation plus chemotherapy appeared to have clear benefit in this setting, whereas the results for selective internal radiotherapy in first-line therapy are currently less conclusive. Colorectal tumors that lacked the ability to repair DNA—or mismatch repair-deficient tumors—were found to be highly responsive to checkpoint blockade with the anti-programmed death 1 (PD-1) drug pembrolizumab, according to data from a phase II study [J Clin Onco 33]. Taregetd therapy with dual blockade of HER2/Neu with Trastuzumab and Lapatinib proved successful in in previously treated patients with HER2/Neu-positive tumors [J Clin Oncol 33].

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Biomarkers—hope and hype

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