Prediction of genetic subgroups in adult supra tentorial gliomas by pre- and intraoperative parameters

Abstract

Recent progress in neuro-oncology has validated the significance of genetic diagnosis in gliomas. We previously investigated IDH1/2 and TP53 mutations via Sanger sequencing for adult supratentorial gliomas and reported that PCR-based sequence analysis classified gliomas into three genetic subgroups that have a strong association with patient prognosis: IDH mutant gliomas without TP53 mutations, IDH and TP53 mutant gliomas, and IDH wild-type gliomas. Furthermore, this analysis had a strong association with patient prognosis. To predict genetic subgroups prior to initial surgery, we retrospectively investigated preoperative radiological data using CT and MRI, including MR spectroscopy (MRS), and evaluated positive 5-aminolevulinic acid (5-ALA) fluorescence as an intraoperative factor. We subsequently compared these factors to differentiate each genetic subgroup. Multiple factors such as age at diagnosis, tumor location, gadolinium enhancement, 5-ALA fluorescence, and several tumor metabolites according to MRS, such as myo-inositol (myo-inositol/total choline) or lipid20, were statistically significant factors for differentiating IDH mutant and wild-type, suggesting that these two subtypes have totally distinct characteristics. In contrast, only calcification, laterality, and lipid13 (lipid13/total Choline) were statistically significant parameters for differentiating TP53 wild-type and mutant in IDH mutant gliomas. In this study, we detected several pre- and intraoperative factors that enabled us to predict genetic subgroups for adult supratentorial gliomas and clarified that lipid13 quantified by MRS is the key tumor metabolite that differentiates TP53 wild-type and mutant in IDH mutant gliomas. These results suggested that each genetic subtype in gliomas selects the distinct lipid synthesis pathways in the process of tumorigenesis.

http://ift.tt/2fr8M6Y

Rare urological manifestation of Henoch-Schönlein purpura: testicular torsion

The Henoch-Schönlein purpura (HSP) is a systemic vasculitis that mostly occurs in children. Besides the most common clinical manifestations such as palpable purpura, arthralgia, abdominal pain and renal disease, it can have urological manifestations. We report a rare case of a 2-year-old boy with the HSP who developed a testicular torsion under corticosteroid treatment.

http://casereports.bmj.com/cgi/content/short/2016/nov11_1/bcr2016217531?rss=1

Acanthosis nigricans in insulinoma: before and after successful surgical enucleation

Description

A 14-year-old girl without diabetes presented with recurrent attacks of generalised tonic–clonic seizures for the past 3 years which had partially been controlled with phenytoin and not with sodium valproate or levetiracetam. A detailed history revealed that each of those episodes was probably related to recurrent spontaneous hypoglycaemia. She was severely obese (body mass index: 36.54 kg/m²) with acanthosis nigricans (AN), facial acne and hirsutism (figure 1). During her hospital stay she developed spontaneous hypoglycaemia (plasma glucose: 25 mg/dL) and biochemical evaluation of the critical sample documented hyperinsulinaemic hypoglycaemia (serum insulin: 16.8 (>3 µIU/mL); C peptide: 3.46 (>0.6 ng/mL); β-hydroxybutyrate: 0.01 (<2.7 mmol/L)). The triphasic CT scan of abdomen revealed a 31x29 mm mass in the neck of the pancreas (figure 2). Screening for other components of multiple endocrine neoplasia type 1 (MEN-1) syndrome was negative. She underwent enucleation of the pancreatic mass and the histopathology was consistent with insulinoma....

http://ift.tt/2fIpUoo

Electromyography needle breaks within the perineum: a rare complication of urodynamics not reported earlier and lesson learnt

The urodynamic study (UDS) is nowadays frequently used by the urologist worldwide to aid in the diagnosis of various urological disorders and electromyography (EMG) is an integral part of it. EMG is performed either by using surface electrodes or concentric needle electrodes. We report an unusual case in which the concentric EMG needle was accidentally broken within the perineum of a man aged 60 years undergoing urodynamics. The needle was removed urgently in a minimally invasive manner under the C-arm guidance without any associated morbidity. This case report highlights the need of urgent intervention in such rare scenarios to help prevent any associated infectious complications. Also, vigilant behaviour during the procedure (and after) to detect such incidents along with detailed patient counselling should be included in the patient management protocol of patients undergoing UDS.

http://ift.tt/2fqHjT4

Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies

Even though significant improvements in the treatment of colorectal cancer (CRC) have been made in recent years, survival rates for metastatic colorectal cancer (mCRC) are poor. Effective treatment options for metastatic colorectal cancer remain limited, and new therapeutic strategies are desperately needed. Several tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) that target angiogenesis, a critical process for facilitating tumor cell growth, invasion, and metastasis, are either approved or in clinical development for the treatment of mCRC. Many of these agents have shown efficacy in mCRC, both as single agents and in combination with standard chemotherapy regimens. However, there is a need for predictive markers of response to identify those patients most likely to benefit from antiangiogenic therapy, and, to date, no markers of this type have been validated in patients. Additionally, because antiangiogenic agents typically cause cytostatic as opposed to cytotoxic antitumor effects, it is important to determine the best strategies for evaluating therapeutic response in mCRC to ensure maximum clinical benefit. In this review, we summarize the efficacy and tolerability of approved and investigational antiangiogenic agents for the treatment of mCRC. We also discuss potential markers of response to antiangiogenic agents and how these markers, along with appropriate endpoint selection, can improve clinical trial design.

http://ift.tt/2fIwFYD

Dietary Acrylamide and the Risk of Pancreatic Cancer in the International Pancreatic Cancer Case-Control Consortium (PanC4)

In a combined set of 1975 cases of pancreatic cancer and 4239 controls enrolled in six studies of the Pancreatic Cancer Case-Control Consortium (PanC4), there was no association between dietary acrylamide and pancreatic cancer.

http://ift.tt/2fDwFsQ

Sunitinib in Pancreatic Neuroendocrine Tumors: Updated Progression-Free Survival and Final Overall Survival From a Phase III Randomized Study

Blinded independent central review analysis showed a 6.8-month improvement in median progression-free survival with sunitinib versus placebo in patients with pancreatic neuroendocrine tumors. The 5-year overall survival (OS) results continued to favor sunitinib, although not statistically significant. Adjustment for treatment crossover in the placebo arm confirmed OS benefit of sunitinib therapy.

http://ift.tt/2fDAvBT

Should rectal cancer located 10-15cm from the anal verge be defined as colon cancer

http://ift.tt/2fIv4Cf

Dietary Acrylamide and the Risk of Pancreatic Cancer in the International Pancreatic Cancer Case-Control Consortium (PanC4)

In a combined set of 1975 cases of pancreatic cancer and 4239 controls enrolled in six studies of the Pancreatic Cancer Case-Control Consortium (PanC4), there was no association between dietary acrylamide and pancreatic cancer.

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Sunitinib in Pancreatic Neuroendocrine Tumors: Updated Progression-Free Survival and Final Overall Survival From a Phase III Randomized Study

Blinded independent central review analysis showed a 6.8-month improvement in median progression-free survival with sunitinib versus placebo in patients with pancreatic neuroendocrine tumors. The 5-year overall survival (OS) results continued to favor sunitinib, although not statistically significant. Adjustment for treatment crossover in the placebo arm confirmed OS benefit of sunitinib therapy.

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Should rectal cancer located 10-15cm from the anal verge be defined as colon cancer

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Neoadjuvant epigenetic priming for upper GI adenocarcinoma

Purpose: Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pre-treatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally-advanced esophageal/gastric adenocarcinoma (EGC). Experimental Design: Eligible patients had untreated, locally-advanced, resectable EGC, ECOG 0-2 and adequate organ function. 5-azacitidine (V, 75mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E 50 mg/m2, O 130 mg/m2, X 625 mg/m2 BIDx21 d). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and five had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days.

http://ift.tt/2fqtzHP

Sipuleucel-T and ADT in Biochemically-Recurrent Prostate Ca

Background: STAND, a randomized, phase II, open-label trial (NCT01431391) assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC) patients at high risk for metastasis. Methods: Men with BRPC following prostatectomy and/or radiotherapy, a prostate-specific antigen (PSA) doubling time (PSADT)less than or equal to 12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T cell response (Enzyme-Linked ImmunoSPOT [ELISPOT]) over time. Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T->ADT versus ADT->sipuleucel-T (P=0.013). PA2024-specific T cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T->ADT versus ADT->sipuleucel-T (P equals 0.001). PA2024-specific cellular and humoral responses, and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P less than 0.001), and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P=0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (hazard ratio 0.22, 95% CI 0.08 to 0.67; P=0.007). Sipuleucel-T with ADT was generally well-tolerated. Conclusions: Sipuleucel-T->ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine if this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation.

http://ift.tt/2fDpuAL

Opportunities for Immunotherapy in Pediatric Solid tumors

Pediatric brain and extracranial solid tumors are a diverse group of malignancies that represent almost half of pediatric cancers. Standard therapy includes various combinations of surgery, cytotoxic chemotherapy and radiation, which can be very harmful to a developing child, and survivors carry a substantial burden of long term morbidities. While these therapies have improved survival rates for children with solid tumors, outcomes still remain extremely poor for subsets of patients. Recently, immunosuppressive checkpoint molecules that negatively regulate immune cell function have been described. When found on malignant cells or in the tumor microenvironment, they contribute to immune evasion and tumor escape. Agents designed to inhibit these proteins have demonstrated significant efficacy in human adult solid tumor studies. However, there is limited research focusing on immune checkpoint molecules and inhibitors in pediatric solid tumors. In this review, we examine the current knowledge on immune checkpoint proteins with an emphasis on Cytotoxic T Lymphocyte Antigen-4 (CTLA-4); Programmed cell Death protein-1 (PD-1) and Programmed Death Ligand 1 (PD-L1); OX-2 membrane glycoprotein (CD200); and Indoleamine 2,3-dioxygenase (IDO). We review T cell signaling, the mechanisms of action of these checkpoint molecules, pediatric preclinical studies on checkpoint proteins and checkpoint blockade, pediatric checkpoint inhibitor clinical trials conducted to date, and future immunotherapy opportunities for childhood cancers.

http://ift.tt/2fqpraY

Understanding and Targeting Mutant Spliceosomal Proteins

Splicing of precursor messenger RNA is a critical step in regulating gene expression and major advances are being made in understanding the composition and structure of the enzymatic complex which performs splicing, termed the spliceosome. In parallel, there has been increased appreciation for diverse mechanisms by which alterations in splicing contribute to cancer pathogenesis. Key among these includes change-of-function mutations in genes encoding spliceosomal proteins. Such mutations are amongst the most common genetic alterations in myeloid and lymphoid leukemias, making efforts to therapeutically target cells bearing these mutations critical. To this end, recent studies have clarified that pharmacologic modulation of splicing may be preferentially lethal for cells bearing spliceosomal mutations and also may have role in the therapy of MYC-driven cancers. This has culminated in the initiation of a clinical trial of a novel oral spliceosome modulatory compound targeting the SF3B complex and several novel alternative approaches to target splicing are in development as reviewed here. There is therefore now a great need to understand the mechanistic basis of altered spliceosomal function in cancers and to study the effects of spliceosomal modulatory compounds in pre-clinical settings and in well-designed clinical trials.

http://ift.tt/2fI7P9Z

Combining molecularly targeted agents: is more always better

The concurrent targeting of critical nodes along key signaling pathways with molecularly targeted agents is a rational antitumor strategy, which has had varying degrees of success. Combinatorial challenges include overcoming synergistic toxicities and establishing if combinations are truly active, to make "go, no-go" decisions to proceed to later phase trials.

http://ift.tt/2fqnkE8

Neoadjuvant epigenetic priming for upper GI adenocarcinoma

Purpose: Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pre-treatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally-advanced esophageal/gastric adenocarcinoma (EGC). Experimental Design: Eligible patients had untreated, locally-advanced, resectable EGC, ECOG 0-2 and adequate organ function. 5-azacitidine (V, 75mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E 50 mg/m2, O 130 mg/m2, X 625 mg/m2 BIDx21 d). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and five had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days.

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Sipuleucel-T and ADT in Biochemically-Recurrent Prostate Ca

Background: STAND, a randomized, phase II, open-label trial (NCT01431391) assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC) patients at high risk for metastasis. Methods: Men with BRPC following prostatectomy and/or radiotherapy, a prostate-specific antigen (PSA) doubling time (PSADT)less than or equal to 12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T cell response (Enzyme-Linked ImmunoSPOT [ELISPOT]) over time. Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T->ADT versus ADT->sipuleucel-T (P=0.013). PA2024-specific T cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T->ADT versus ADT->sipuleucel-T (P equals 0.001). PA2024-specific cellular and humoral responses, and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P less than 0.001), and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P=0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (hazard ratio 0.22, 95% CI 0.08 to 0.67; P=0.007). Sipuleucel-T with ADT was generally well-tolerated. Conclusions: Sipuleucel-T->ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine if this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation.

from Cancer via ola Kala on Inoreader http://ift.tt/2fDpuAL
via IFTTT

Opportunities for Immunotherapy in Pediatric Solid tumors

Pediatric brain and extracranial solid tumors are a diverse group of malignancies that represent almost half of pediatric cancers. Standard therapy includes various combinations of surgery, cytotoxic chemotherapy and radiation, which can be very harmful to a developing child, and survivors carry a substantial burden of long term morbidities. While these therapies have improved survival rates for children with solid tumors, outcomes still remain extremely poor for subsets of patients. Recently, immunosuppressive checkpoint molecules that negatively regulate immune cell function have been described. When found on malignant cells or in the tumor microenvironment, they contribute to immune evasion and tumor escape. Agents designed to inhibit these proteins have demonstrated significant efficacy in human adult solid tumor studies. However, there is limited research focusing on immune checkpoint molecules and inhibitors in pediatric solid tumors. In this review, we examine the current knowledge on immune checkpoint proteins with an emphasis on Cytotoxic T Lymphocyte Antigen-4 (CTLA-4); Programmed cell Death protein-1 (PD-1) and Programmed Death Ligand 1 (PD-L1); OX-2 membrane glycoprotein (CD200); and Indoleamine 2,3-dioxygenase (IDO). We review T cell signaling, the mechanisms of action of these checkpoint molecules, pediatric preclinical studies on checkpoint proteins and checkpoint blockade, pediatric checkpoint inhibitor clinical trials conducted to date, and future immunotherapy opportunities for childhood cancers.

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via IFTTT

Understanding and Targeting Mutant Spliceosomal Proteins

Splicing of precursor messenger RNA is a critical step in regulating gene expression and major advances are being made in understanding the composition and structure of the enzymatic complex which performs splicing, termed the spliceosome. In parallel, there has been increased appreciation for diverse mechanisms by which alterations in splicing contribute to cancer pathogenesis. Key among these includes change-of-function mutations in genes encoding spliceosomal proteins. Such mutations are amongst the most common genetic alterations in myeloid and lymphoid leukemias, making efforts to therapeutically target cells bearing these mutations critical. To this end, recent studies have clarified that pharmacologic modulation of splicing may be preferentially lethal for cells bearing spliceosomal mutations and also may have role in the therapy of MYC-driven cancers. This has culminated in the initiation of a clinical trial of a novel oral spliceosome modulatory compound targeting the SF3B complex and several novel alternative approaches to target splicing are in development as reviewed here. There is therefore now a great need to understand the mechanistic basis of altered spliceosomal function in cancers and to study the effects of spliceosomal modulatory compounds in pre-clinical settings and in well-designed clinical trials.

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via IFTTT

Combining molecularly targeted agents: is more always better

The concurrent targeting of critical nodes along key signaling pathways with molecularly targeted agents is a rational antitumor strategy, which has had varying degrees of success. Combinatorial challenges include overcoming synergistic toxicities and establishing if combinations are truly active, to make "go, no-go" decisions to proceed to later phase trials.

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S100A4 and MMPs in Drosophila and human breast cancer

Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9 and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes.

http://ift.tt/2fI4n0n

TIFA supports NF-{kappa}B survival pathway in AML

Aurora A-dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia and other cancers, but the functional basis underlying this association is unclear. Here we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in de novo AML patients relative to healthy individuals, and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of pro-survival factors Bcl-2 and Bcl-XL that support NF-κB-dependent anti-apoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments.

http://ift.tt/2fqgUVB

S100A4 and MMPs in Drosophila and human breast cancer

Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9 and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes.

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TIFA supports NF-{kappa}B survival pathway in AML

Aurora A-dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia and other cancers, but the functional basis underlying this association is unclear. Here we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in de novo AML patients relative to healthy individuals, and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of pro-survival factors Bcl-2 and Bcl-XL that support NF-κB-dependent anti-apoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments.

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TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Related Articles

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Cancer Biol Ther. 2016 Nov 10;:0

Authors: Nguyen JQ, Irby RB

Abstract
The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.

PMID: 27830973 [PubMed - as supplied by publisher]

http://ift.tt/2fHCDJk

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Related Articles

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Cancer Biol Ther. 2016 Nov 10;:0

Authors: Nguyen JQ, Irby RB

Abstract
The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.

PMID: 27830973 [PubMed - as supplied by publisher]

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Vitamin E ({alpha}-Tocopherol) Exhibits Antitumour Activity on Oral Squamous Carcinoma Cells ORL-48

Cancers involving the oral cavity, head, and neck regions are often treated with cisplatin. In cancer therapy, the main target is to eliminate unwanted cancerous cells. However, reports on the nonselective nature of this drug have raised few concerns. Incorrect nutritional habits and lifestyle practices have been directly linked to cancer incidence. Nutrients with antioxidant activity inhibit cancer cells development, destroying them through oxidative stress and apoptosis. α-tocopherol, the potent antioxidant form of vitamin E is a known scavenger of free radicals. In vitro study exhibited effective antitumor activity of α-tocopherol on ORL-48 at 2.5 ± 0.42 µg/mL. Cisplatin exhibited stronger activity at 1.0 ± 0.15 µg/mL, but unlike α-tocopherol it exhibited cytotoxicity on normal human epidermal keratinocytes at very low concentration (<0.1 µg/mL). Despite the lower potency of α-tocopherol, signs of apoptosis such as the shrinkage of cells and appearance of apoptotic bodies were observed much earlier than cisplatin in time lapse microscopy. No apoptotic vesicles were formed with cisplatin, instead an increased population of cells in the holoclone form which may suggest different induction mechanisms between both agents. High accumulation of cells in the G0/G1 phase were observed through TUNEL and annexin V-biotin assays, while the exhibition of ultrastructural changes of the cellular structures verified the apoptotic mode of cell death by both agents. Both cisplatin and α-tocopherol displayed cell cycle arrest at the Sub G0 phase. α-tocopherol thus, showed potential as an antitumour agent for the treatment of oral cancer and merits further research.

http://ift.tt/2fHWB74

Danggui Buxue Decoction, a Classical Formula of Traditional Chinese Medicine, Fails to Prevent Myelosuppression in Breast Cancer Patients Treated With Adjuvant Chemotherapy: A Prospective Study

Danggui Buxue Decoction (DBD), a classical formula of traditional Chinese medicine (TCM), has an impact on promoting hematopoiesis. The aim of our study was to determine whether DBD can prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. We conducted a phase II randomized prospective controlled clinical study. From December 2013 to February 2015, 106 patients were enrolled and randomly assigned (1:1) to the TCM group and control group. The primary end point was incidence of grade 3-4 neutropenia. The secondary end points included incidence of grade 3-4 neutropenia in each cycle, incidence of anemia, and incidence of thrombopenia during 4 cycles. Seventeen patients withdrew from this study, and 89 patients were included in the final analysis. Incidences of grade 3-4 neutropenia during 4 cycles were 57.1% in the TCM group and 59.6% in the control group, and there was no significant difference (P = .816). Similarly, no significant differences were observed between the 2 groups for incidence of grade 3-4 neutropenia in each cycle. While incidences of anemia were 54.8% and 66.6% for the TCM group and control group, respectively (P = .280), incidences of thrombopenia were 11.9% for the TCM group and 4.3% for the control group (P = .248). No significant differences were observed for the incidence of other nonhematological toxicities between the 2 groups. DBD failed to prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. Further studies are warranted to validate the efficacy of DBD in selected patients.

http://ift.tt/2fq7idm

Vitamin E ({alpha}-Tocopherol) Exhibits Antitumour Activity on Oral Squamous Carcinoma Cells ORL-48

Cancers involving the oral cavity, head, and neck regions are often treated with cisplatin. In cancer therapy, the main target is to eliminate unwanted cancerous cells. However, reports on the nonselective nature of this drug have raised few concerns. Incorrect nutritional habits and lifestyle practices have been directly linked to cancer incidence. Nutrients with antioxidant activity inhibit cancer cells development, destroying them through oxidative stress and apoptosis. α-tocopherol, the potent antioxidant form of vitamin E is a known scavenger of free radicals. In vitro study exhibited effective antitumor activity of α-tocopherol on ORL-48 at 2.5 ± 0.42 µg/mL. Cisplatin exhibited stronger activity at 1.0 ± 0.15 µg/mL, but unlike α-tocopherol it exhibited cytotoxicity on normal human epidermal keratinocytes at very low concentration (<0.1 µg/mL). Despite the lower potency of α-tocopherol, signs of apoptosis such as the shrinkage of cells and appearance of apoptotic bodies were observed much earlier than cisplatin in time lapse microscopy. No apoptotic vesicles were formed with cisplatin, instead an increased population of cells in the holoclone form which may suggest different induction mechanisms between both agents. High accumulation of cells in the G0/G1 phase were observed through TUNEL and annexin V-biotin assays, while the exhibition of ultrastructural changes of the cellular structures verified the apoptotic mode of cell death by both agents. Both cisplatin and α-tocopherol displayed cell cycle arrest at the Sub G0 phase. α-tocopherol thus, showed potential as an antitumour agent for the treatment of oral cancer and merits further research.

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Danggui Buxue Decoction, a Classical Formula of Traditional Chinese Medicine, Fails to Prevent Myelosuppression in Breast Cancer Patients Treated With Adjuvant Chemotherapy: A Prospective Study

Danggui Buxue Decoction (DBD), a classical formula of traditional Chinese medicine (TCM), has an impact on promoting hematopoiesis. The aim of our study was to determine whether DBD can prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. We conducted a phase II randomized prospective controlled clinical study. From December 2013 to February 2015, 106 patients were enrolled and randomly assigned (1:1) to the TCM group and control group. The primary end point was incidence of grade 3-4 neutropenia. The secondary end points included incidence of grade 3-4 neutropenia in each cycle, incidence of anemia, and incidence of thrombopenia during 4 cycles. Seventeen patients withdrew from this study, and 89 patients were included in the final analysis. Incidences of grade 3-4 neutropenia during 4 cycles were 57.1% in the TCM group and 59.6% in the control group, and there was no significant difference (P = .816). Similarly, no significant differences were observed between the 2 groups for incidence of grade 3-4 neutropenia in each cycle. While incidences of anemia were 54.8% and 66.6% for the TCM group and control group, respectively (P = .280), incidences of thrombopenia were 11.9% for the TCM group and 4.3% for the control group (P = .248). No significant differences were observed for the incidence of other nonhematological toxicities between the 2 groups. DBD failed to prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. Further studies are warranted to validate the efficacy of DBD in selected patients.

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Escalating and de-escalating treatment in HER2-positive early breast cancer

Publication date: Available online 10 November 2016
Source:Cancer Treatment Reviews
Author(s): Heikki Joensuu
The current standard adjuvant systemic treatment of early HER2-positive breast cancer consists of chemotherapy plus 12 months of trastuzumab, with or without endocrine therapy. Several trials have investigated modifications of the standard treatment that are shorter and less resource-demanding (de-escalation) or regimens that aim at dual HER2 inhibition or include longer than 12 months of HER2-targeted treatment (escalation). Seven randomized trials investigate shorter than 12 months of trastuzumab treatment duration. The shorter durations were not statistically inferior to the 1-year duration in the 3 trials with survival results available, but 2 of the trials were small and 1 had a relatively short follow-up time of the patients at the time of reporting. The pathological complete response (pCR) rates were numerically higher in all 9 randomized trials that compared chemotherapy plus dual HER2 inhibition consisting of trastuzumab plus either lapatinib, neratinib, or pertuzumab with chemotherapy plus trastuzumab as neoadjuvant treatments, but the superiority of chemotherapy plus dual HER2-inhibition over chemotherapy plus trastuzumab remains to be demonstrated in the adjuvant setting. One year of adjuvant trastuzumab was as effective as 2 years of trastuzumab in the HERA trial, and was associated with fewer side-effects. Extending 1-year adjuvant trastuzumab treatment with 1 year of neratinib improved disease-free survival in the ExteNET trial, but the patient follow-up times are still short, and no overall survival benefit was reported. Several important trials are expected to report results in the near future and may modify the current standard.



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The expanding role of stereotactic body radiation therapy in oligometastatic solid tumors: what do we know and where are we going?

Publication date: Available online 10 November 2016
Source:Cancer Treatment Reviews
Author(s): Julian C. Hong, Joseph K. Salama
The spectrum hypothesis posits that there are distinct clinical states of metastatic progression. Early data suggest that aggressive treatment of more biologically indolent metastatic disease, characterized by metastases limited in number and destination organ, may offer an opportunity to alter the disease course, potentially allowing for longer survival, delay of systemic therapy, or even cure. The development of stereotactic body radiation therapy (SBRT) has opened new avenues for the treatment of oligometastatic disease. Early data support the use of SBRT for treating oligometastases in a number of organs, with promising rates of treated metastasis control and overall survival. Ongoing investigation is required to definitively establish benefit, determine the appropriate treatment regimen, refine patient selection, and incorporate SBRT with systemic therapies.



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ESR1 mutations: moving towards guiding treatment decision-making in metastatic breast cancer patients

Publication date: Available online 10 November 2016
Source:Cancer Treatment Reviews
Author(s): Lindsay Angus, Nick Beije, Agnes Jager, John W. M. Martens, Stefan Sleijfer
Mutations in the gene coding for the estrogen receptor (ER), ESR1, have been associated with acquired endocrine resistance in patients with ER-positive metastatic breast cancer (MBC). Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of its ligand estrogen, conferring resistance against several endocrine agents. While recent clinical studies reported that the occurrence of ESR1 mutations is rare in primary breast cancer tumors, these mutations are more frequently observed in metastatic tissue and circulating cell-free DNA of MBC patients pretreated with endocrine therapy. Given the assumed impact that the presence of ESR1 mutations has on outcome to endocrine therapy, assessing ESR1 mutations in MBC patients is likely to be of significant interest to further individualize treatment for MBC patients. Here, ESR1 mutation detection methods and the most relevant pre-clinical and clinical studies on ESR1 mutations regarding endocrine resistance are reviewed, with particular interest in the ultimate goal of guiding treatment decision-making based on ESR1 mutations.



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Incidence of hypophosphatemia in advanced cancer patients: a recent report from a single institution

Abstract

Background

Recent approval of molecular-targeted agents has contributed to improving the therapeutic outcomes of advanced cancer patients. However, they result in unusual adverse events that rarely occur with cytotoxic agents, such as hypertension, hypomagnesemia, and an acne-like rash. Although hypophosphatemia can be induced by various agents, some kinds of molecular-targeted agents are known to induce it. In addition, cancer survivors may be at a risk of hypophosphatemia.

Methods

One hundred and seventy patients, who visited the Department of Clinical Oncology at Akita University from 1 April 2014 to 31 August 2016 were enrolled in this study after providing informed consent. Serum inorganic phosphorus levels were examined along with other routine clinical examinations. Correlation between the serum inorganic phosphorus level and other clinical data were also analyzed.

Results

Grade ≥2 severe hypophosphatemia (<2.5 mg/dL of phosphorus) was detected in 49.4% of patients, and grade ≥3 (<2.0 mg/dL of phosphorus) was observed in 22.9% patients. These results indicated that the presence of bone metastasis (p < 0.001), history of bone-modifying agents (p < 0.001) and molecular-targeted drugs (p = 0.001), and time from the date of the first visit to the date of minimum serum phosphorus level (p < 0.001) might correlate with hypophosphatemia. Multivariate logistic regression analysis showed that disease duration might be a risk factor (p = 0.0466).

Conclusion

As hypophosphatemia can be induced by various factors in advanced cancer patients, the serum phosphorus level of cancer patients at risk should be cautiously examined.

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Association between UGT1A1 *28*28 genotype and lung cancer in the Japanese population

Abstract

Background

Lung cancer is the leading cause of cancer death and is closely linked to tobacco smoking. Genetic polymorphisms in genes that encode enzymes involved in metabolizing tobacco carcinogens could affect an individual's risk for lung cancer. While polymorphism of UDP-glucuronosyltransferase1A1 (UGT1A1) is involved in detoxification of benzo(a)pyrene-7,8-dihydrodiol(–), a major tobacco carcinogen, the association between UGT1A1 genotype and lung cancer has not been examined.

Methods

We retrieved the clinical data of 5,285 patients who underwent systemic chemotherapy at Kyoto University Hospital. A total of 765 patients (194 lung cancer patients and 671 patients with other malignancies) with UGT1A1 genotyping data were included in this analysis. We used logistic regression with recessive, dominant, and additive models to identify differences in genotype frequencies between lung cancer and other malignancies.

Results

In the recessive model, UGT1A1*28*28 genotype was significantly associated with lung cancer compared to other malignancies (odds ratio 5.3, P = 0.0083). Among lung cancer patients with a smoking history, squamous cell carcinoma was significantly predominant in patients with UGT1A1*28*28 compared to those with other UGT1A1 genotypes (P = 0.024).

Conclusion

This is the first study to demonstrate a significant association between the homozygous UGT1A1*28 genotype and lung cancer.

http://ift.tt/2eYOC3F

Incidence of hypophosphatemia in advanced cancer patients: a recent report from a single institution

Abstract

Background

Recent approval of molecular-targeted agents has contributed to improving the therapeutic outcomes of advanced cancer patients. However, they result in unusual adverse events that rarely occur with cytotoxic agents, such as hypertension, hypomagnesemia, and an acne-like rash. Although hypophosphatemia can be induced by various agents, some kinds of molecular-targeted agents are known to induce it. In addition, cancer survivors may be at a risk of hypophosphatemia.

Methods

One hundred and seventy patients, who visited the Department of Clinical Oncology at Akita University from 1 April 2014 to 31 August 2016 were enrolled in this study after providing informed consent. Serum inorganic phosphorus levels were examined along with other routine clinical examinations. Correlation between the serum inorganic phosphorus level and other clinical data were also analyzed.

Results

Grade ≥2 severe hypophosphatemia (<2.5 mg/dL of phosphorus) was detected in 49.4% of patients, and grade ≥3 (<2.0 mg/dL of phosphorus) was observed in 22.9% patients. These results indicated that the presence of bone metastasis (p < 0.001), history of bone-modifying agents (p < 0.001) and molecular-targeted drugs (p = 0.001), and time from the date of the first visit to the date of minimum serum phosphorus level (p < 0.001) might correlate with hypophosphatemia. Multivariate logistic regression analysis showed that disease duration might be a risk factor (p = 0.0466).

Conclusion

As hypophosphatemia can be induced by various factors in advanced cancer patients, the serum phosphorus level of cancer patients at risk should be cautiously examined.

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Association between UGT1A1 *28*28 genotype and lung cancer in the Japanese population

Abstract

Background

Lung cancer is the leading cause of cancer death and is closely linked to tobacco smoking. Genetic polymorphisms in genes that encode enzymes involved in metabolizing tobacco carcinogens could affect an individual's risk for lung cancer. While polymorphism of UDP-glucuronosyltransferase1A1 (UGT1A1) is involved in detoxification of benzo(a)pyrene-7,8-dihydrodiol(–), a major tobacco carcinogen, the association between UGT1A1 genotype and lung cancer has not been examined.

Methods

We retrieved the clinical data of 5,285 patients who underwent systemic chemotherapy at Kyoto University Hospital. A total of 765 patients (194 lung cancer patients and 671 patients with other malignancies) with UGT1A1 genotyping data were included in this analysis. We used logistic regression with recessive, dominant, and additive models to identify differences in genotype frequencies between lung cancer and other malignancies.

Results

In the recessive model, UGT1A1*28*28 genotype was significantly associated with lung cancer compared to other malignancies (odds ratio 5.3, P = 0.0083). Among lung cancer patients with a smoking history, squamous cell carcinoma was significantly predominant in patients with UGT1A1*28*28 compared to those with other UGT1A1 genotypes (P = 0.024).

Conclusion

This is the first study to demonstrate a significant association between the homozygous UGT1A1*28 genotype and lung cancer.

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TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Related Articles

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Cancer Biol Ther. 2016 Nov 10;:0

Authors: Nguyen JQ, Irby RB

Abstract
The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.

PMID: 27830973 [PubMed - as supplied by publisher]

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A systematic review examining factors influencing health related quality of life among melanoma cancer survivors

Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Jean-Francois Hamel, Madeline Pe, Corneel Coens, Francesca Martinelli, Alexander M.M. Eggermont, Yvonne Brandberg, Andrew Bottomley
Eighty percent of melanomas are diagnosed at a localised stage, when they are highly curable. Their survival rate induces long follow-up periods, transforming melanoma into a chronic disease and patients' health-related quality of life (HRQoL). Understanding which patient characteristics are associated with poor HRQoL should allow a more personalised management of their HRQoL. Hence, we propose a systematic review for this purpose.Systematic literature searches were performed in three different electronic databases: PubMed, Web of Science and the Cochrane Library. Only studies published in English after 2005 until June 2016 and exploring HRQoL over a period of at least one year were considered.10 articles were identified from seven different studies, representing a total of 4246 patients. All were observational: six were cross-sectional and only one was prospective. Several patient characteristics associated with HRQoL were identified. Women tend to have lower psychological HRQoL than men. Age was generally associated with variations in HRQoL levels, but there was no consistency across studies. Positive associations between marital status or social interactions and psychological subscales were highlighted by a few studies. Finally, the stage related severity of prognosis at initial diagnosis was systematically associated with worse HRQoL levels (either psychological, physical or global).Several patient characteristics could be identified in melanoma studies that were associated with HRQoL levels. However, these relations were not consistent across studies. Such findings highlight the current lack of empirical data available. Further evidence is needed on HRQoL factors in melanoma survivors.



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The Safety and Efficacy of Irreversible Electroporation for Large Hepatocellular Carcinoma

This study aimed to investigate the safety and effectiveness of irreversible electroporation ablation for unresectable large liver cancer. Fourteen patients were enrolled: 8 with large hepatocellular carcinoma (tumor diameter: 5.1-11.5 cm) and 6 with medium hepatocellular carcinoma (tumor diameter: 3.0-4.1 cm). All patients received percutaneous irreversible electroporation ablation. Ablation time and the incidence of complications were assessed by a t test. Post-irreversible electroporation and regular contrast-enhanced computerized tomography scans were performed to investigate the effect of tumor size (large vs medium) on irreversible electroporation treatment efficacy; 4-table data were assessed using a Fisher exact test. The 14 patients completed irreversible electroporation ablation successfully. In the large hepatocellular carcinoma group, no major complications occurred in the perioperative period. Minor complications comprised bloating, hypokalemia, edema, low white blood cells, and blood clotting abnormalities. All complications were mild and improved after symptomatic treatment. The frequency of minor complications was not significantly different (P > .05) compared with the medium hepatocellular carcinoma group. The average follow-up time was 2.8 ± 2.1 months and complete ablation was achieved in 25% (2/8; residual = 75%). For the patients with medium hepatocellular carcinoma, the mean follow-up time was 4.3 ± 3.2 months; the rate of complete ablation was 66.6% (4/6; residual rate = 33.3%). The complete ablation rate was not statistically different between the 2 groups (P > .05). Irreversible electroporation ablation for unresectable large hepatocellular carcinoma is safe, with no major complications. Short-term efficacy is relatively good; however, long-term efficacy remains to be explored.

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TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Related Articles

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.

Cancer Biol Ther. 2016 Nov 10;:0

Authors: Nguyen JQ, Irby RB

Abstract
The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.

PMID: 27830973 [PubMed - as supplied by publisher]

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miR-486-5p suppresses prostate cancer metastasis by targeting Snail and regulating epithelial–mesenchymal transition

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A retrospective analysis of the clinicopathological and molecular characteristics of pulmonary blastoma

https://www.dovepress.com/a-retrospective-analysis-of-the-clinicopathological-and-molecular-char-peer-reviewed-article-OTT

Combination Therapy for Fit (Younger and Older) Newly Diagnosed Multiple Myeloma Patients: Data Support Carfilzomib, Lenalidomide and Dexamethasone Independent of Cytogenetic Risk Status

Publication date: Available online 10 November 2016
Source:Seminars in Oncology
Author(s): Ola Landgren




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Multiple Myeloma Epidemiology and Survival, a Unique Malignancy

Publication date: Available online 10 November 2016
Source:Seminars in Oncology
Author(s): Dickran Kazandjian
Multiple myeloma (MM), although a rare disease, is the second most common hematologic malignancy. It is found in the spectrum of plasma cell dyscrasias which begins with monoclonal gammopathy of unknown significance to overt plasma cell leukemia and extramedullary myeloma. MM is associated with significant morbidity due to its end-organ destruction. It is a disease of the older population and its incidence in the African American population is twice that of the European American population. Improvements in the treatment of MM in the past couple of decades, beginning with the use of autologous stem cell transplantation followed by availability of novel treatments such as immunomodulatory drugs and proteasome inhibitors has transformed the natural history of the disease leading to longer survival times. Advancements in the diagnosis, monitoring, and treatment of MM are of the utmost importance as the general population lives longer due to other improvements in health care. The recent introduction of novel therapies has been paralleled by advancements in the monitoring of MM, namely, by the availability exquisitely sensitive techniques in detecting minimal residual disease. As drug development and technology continues to improve, it will be important to design rationale clinical trials enrolling patient populations which represent the overall population including racial minorities and the elderly so trial results can be appropriately extrapolated. This manuscript reviews the changing epidemiology, the improvements in survival, and the health disparity observed in important subgroups of MM.



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Parkinson’s disease and risk of prostate cancer: A Danish population-based case-control study, 1995–2010

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Christina G. Jespersen, Mette Nørgaard, Michael Borre
IntroductionProstate cancer growth and progression may be linked to neurogenesis and to medical anti- Parkinson treatment, but results are inconclusive. Therefore, we examined the association between Parkinson's disease and risk of prostate cancer in a population based case-control study.MethodsWe identified 45,429 patients diagnosed with incident prostate cancer during 1997–2010 from the National Cancer Registry. Five age-matched population controls (n=227,145) were selected for each case. Odds ratios (ORs) adjusted for age and comorbidity for prostate cancer associated with Parkinson's disease were computed using conditional logistic regression. Analyses were stratified by duration of Parkinson's disease and stage of prostate cancer (localized and advanced).ResultsIn total, 245 patients (0,5%) and 1656 controls (0,7%) had Parkinson's disease. Overall, patients with Parkinson's disease had a 27% lower risk of prostate cancer compared with patients without Parkinson's disease (adjusted OR (ORa) 0.73; 95% confidence interval (CI), 0.63–0.83).Risk of prostate cancer decreased with increasing duration of Parkinson's disease.The odds ratios were slightly lower for advanced prostate cancer (ORa, 0.68; 95% CI, 0.52–0.88) than for localized prostate cancer (ORa 0.76; 95% CI, 0.61–0.93).ConclusionParkinson's disease was associated with a risk reduction overall (27%), which decreased with increasing duration of Parkinson's disease.



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Parkinson’s disease and risk of prostate cancer: A Danish population-based case-control study, 1995–2010

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Christina G. Jespersen, Mette Nørgaard, Michael Borre
IntroductionProstate cancer growth and progression may be linked to neurogenesis and to medical anti- Parkinson treatment, but results are inconclusive. Therefore, we examined the association between Parkinson's disease and risk of prostate cancer in a population based case-control study.MethodsWe identified 45,429 patients diagnosed with incident prostate cancer during 1997–2010 from the National Cancer Registry. Five age-matched population controls (n=227,145) were selected for each case. Odds ratios (ORs) adjusted for age and comorbidity for prostate cancer associated with Parkinson's disease were computed using conditional logistic regression. Analyses were stratified by duration of Parkinson's disease and stage of prostate cancer (localized and advanced).ResultsIn total, 245 patients (0,5%) and 1656 controls (0,7%) had Parkinson's disease. Overall, patients with Parkinson's disease had a 27% lower risk of prostate cancer compared with patients without Parkinson's disease (adjusted OR (ORa) 0.73; 95% confidence interval (CI), 0.63–0.83).Risk of prostate cancer decreased with increasing duration of Parkinson's disease.The odds ratios were slightly lower for advanced prostate cancer (ORa, 0.68; 95% CI, 0.52–0.88) than for localized prostate cancer (ORa 0.76; 95% CI, 0.61–0.93).ConclusionParkinson's disease was associated with a risk reduction overall (27%), which decreased with increasing duration of Parkinson's disease.



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Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Abstract

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson utilized an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1-independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.

This article is protected by copyright. All rights reserved.

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Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Abstract

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson utilized an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1-independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.

This article is protected by copyright. All rights reserved.

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