Non-small cell lung cancers (NSCLC) marked by EGFR mutations tend to develop resistance to therapeutic EGFR inhibitors, often due to secondary mutation EGFRT790M but also other mechanisms. Here we report support for a rationale to target IKBKE, an IκB kinase family member which activates the AKT and NF-κB pathways, as one strategy to address NSCLC resistant to EGFR inhibitors. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. The unphosphorylatable mutant IKBKE-Y153F/Y179-F which lost kinase activity failed to activate AKT and inhibited EGFR signaling. In clinical specimens of NSCLC with activating mutations of EGFR, we observed elevated levels of phospho-Y153 IKBKE. IKBKE ablation with shRNA or small molecule inhibitor amlexanox selectively inhibited the viability of NSCLC cells with EGFR mutations in vitro. In parallel, we found that these treatments activated the MAPK pathway due to attenuation of an IKBKE feedback mechanism. In vivo studies revealed that combining amlexanox with MEK inhibitor AZD6244 significantly inhibited the xenograft tumor growth of NSCLC cells harboring activating EGFR mutations, including EGFRT790M. Overall, our findings define IKBKE as a direct effector target of EGFR and provide a therapeutic rationale to target IKBKE as a strategy to eradicate EGFR-TKI resistant NSCLC cells.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 10 Ιουνίου 2016
IKBKE in NSCLCs with EGFR mutation
Pomalidomide in the management of relapsed multiple myeloma
Future Oncology Ahead of Print.
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Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases
Background: Germline mutations in CDKN2A have been associated with increased risk of melanoma and tobacco-related cancers in respiratory and upper digestive tissues. In CDKN2A wild-type (wt) melanoma families, other known high-risk, melanoma-predisposing mutations are rare, and no increased risk has been observed for nonskin cancers in this group. This study is the first to compare survival in germline CDKN2A mutated (mut) and nonmutated melanoma cases.
Methods: Melanoma-prone families participating in this study were identified through a nationwide predictive program starting in 1987. Information on cancer diagnoses (types, stages, and dates) and deaths (causes and dates) were obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan Meier and Cox proportional hazards regression models were used to assess survival in CDKN2Amut (n = 96) and CDKN2Awt (n = 377) familial melanoma cases and in matched sporadic melanoma cases (n = 1042). All statistical tests were two-sided.
Results: When comparing CDKN2Amut and CDKN2Awt melanoma cases, after adjusting for age, sex, and T classification, CDKN2Amut had worse survival than melanoma (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.49 to 4.21) and than nonmelanoma cancers (HR = 7.77, 95% CI = 3.65 to 16.51). Compared with matched sporadic cases, CDKN2Amut cases had statistically significantly worse survival from both melanoma and nonmelanoma cancers while no differences in survival were seen in CDKN2Awt compared with sporadic cases.
Conclusions: CDKN2Amut cases had statistically significantly worse survival than nonmelanoma cancers and, intriguingly, also from melanoma, compared with melanoma cases with no CDKN2A mutations. Further studies are required to elucidate possible mechanisms behind increased carcinogen susceptibility and the more aggressive melanoma phenotype in CDKN2A mutation carriers.
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Pomalidomide in the management of relapsed multiple myeloma
Future Oncology Ahead of Print.
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Total body irradiation—an attachment free sweeping beam technique
A sweeping beam technique for total body irradiation in standard treatment rooms and for standard linear accelerators (linacs) is introduced, which does not require any accessory attached to the linac. Lung sh...
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Stepped Care Targeting Psychological Distress in Head and Neck Cancer and Lung Cancer Patients: a Randomized Controlled Trial
Among head and neck cancer patients and lung cancer patients with untreated psychological distress, stepped care including watchful waiting, guided self-help, problem solving therapy, and specialized psychological interventions or medication, is effective and speeds up recovery of distress. Stepped care is especially effective for cancer patients with a depressive or anxiety disorder.
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A Phase II Study (ARCHER 1042) to Evaluate Prophylactic Treatment of Dacomitinib-induced Dermatologic and Gastrointestinal Adverse Events in Advanced Non-Small-Cell Lung Cancer
The randomized phase II study ARCHER 1042 explored the impact of prophylactic treatment on select dermatologic and gastrointestinal adverse events (AE) of interest and patient-reported outcomes. Doxycycline reduced the incidence of grade ≥2 select dermatologic AEs of interest by 50% (p=0.016). Both doxycycline and alclometasone reduced the negative impact in patient-reported dermatologic AEs.
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Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome
Ewing sarcoma is the second most frequent primary malignant bone tumor diagnosed in children and adolescents, after osteosarcoma; 30%-40% of patients with a localized primary tumor and 60%-80% of patients with disseminated disease experience relapse locally and/or distantly. In this study we report, and replicate in an independent cohort, associations between germline variants in three pharmacokinetic genes and overall survival. This is the first study to apply an integrated pathway-based approach to investigate the pharmacogenetics of this disease, and the results could be used to develop clinical strategies to improve early therapeutic decisions for these patients.
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Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial
Exploratory analyses of time to platinum resistance suggest a better prognosis in bevacizumab-treated patients with secondary vs primary platinum resistance. Progression-free and overall survival benefit from bevacizumab was enhanced in secondary-resistant disease. Our findings should be considered when selecting stratification factors in future trials of anti-angiogenic therapy in this setting.
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Adjuvant treatment with pegylated interferon alpha-2a versus low-dose interferon alpha-2a in patients with high-risk melanoma. A randomized phase III DeCOG trial
Pegylated-Interferon-alpha did not improve the outcome over low dose Interferon-alpha in the adjuvant treatment of intermediate and high risk melanoma patients. A higher percentage of patients under Pegylated-Interferon-alpha discontinued treatment due to toxicity.
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Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I-IIa clinical trial
The combination of the campothecan-containing nanoparticle–drug conjugate, CRLX101 and bevacizumab is well tolerated, safe, and active in a heavily pretreated population of patients with metastatic renal cell carcinoma of clear and non-clear cell histology.
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Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model
Abstract
Malignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than one-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this pre-clinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma. This article is protected by copyright. All rights reserved.
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Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study
Abstract
Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m2 daily or etoposide 50 mg/m2/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9–24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk–benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients.
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Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study
Abstract
Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m2 daily or etoposide 50 mg/m2/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9–24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk–benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients.
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Atrial natriuretic peptide protects against cisplatin-induced granulocytopenia
Abstract
Purpose
Granulocytopenia is the major toxicity associated with cisplatin treatment. Atrial natriuretic peptide (ANP) is a cardiac hormone used clinically for the treatment of acute heart failure in Japan. ANP exerts a wide range of protective effects on various organs, including the heart, blood vessels, lungs, and kidneys. This study's objective was to investigate the protective effects of ANP on cisplatin-induced granulocytopenia in mice.
Methods
The mice were divided into two groups: cisplatin with vehicle and cisplatin with ANP. ANP (1.5 μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started 1 day before cisplatin injection until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), the white blood cell, red blood cell, and platelet counts were measured in the peripheral blood in both groups. The numbers of total and live cells and colony-forming unit-granulocyte–macrophage (CFU-GM) colonies in the bone marrow of the mice were also examined. In addition, at 0, 0.5, 1, and 2 days after cisplatin injection, serum granulocyte colony-stimulating factor (G-CSF) levels were measured.
Results
ANP significantly attenuated the white blood cell count decrease in the peripheral blood 2 and 4 days after cisplatin injection. ANP also attenuated the decrease in the number of live cells and CFU-GM colonies in bone marrow 2, 4, and 8 days after cisplatin injection. ANP significantly increased serum G-CSF levels 1 day after cisplatin injection.
Conclusions
ANP has protective effects in cisplatin-induced granulocytopenia, with increased G-CSF production.
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Effect of renal function on pemetrexed-induced haematotoxicity
Abstract
Purpose
Pemetrexed (PEM) is an anticancer agent used for the treatment of non-small cell lung cancer, malignant pleural mesothelioma and thymoma. Reportedly, PEM has higher efficacy and safety when used in combination with platinum-based agents. However, there are only few reports on the safety of PEM in patients with an eGFR of ≤45 mL/min. We examined the effect of renal function on the safety of regimens containing PEM.
Methods
We retrospectively reviewed 221 patients with lung cancer, malignant pleural mesothelioma or thymoma who received treatment with a PEM-containing regimen between 2009 and 2014. Subgroup analyses were performed on the basis of pre-treatment renal function: group A [creatinine clearance (CLcr), <45 mL/min]; group B (CLcr, 45–80 mL/min); and group C (CLcr, ≥80 mL/min). For the purpose of this analysis, the lowest documented blood cell counts and haemoglobin levels, the highest levels of serum creatinine, aspartate aminotransferase, alanine aminotransferase and CLcr from the time of initial administration up to prior to the start of second administration were considered.
Results
Groups A, B and C had 8, 123 and 90 patients, respectively. The incidence of grade 2 thrombocytopaenia was significantly higher in group A as compared to that in groups B (P < 0.01) and C (P < 0.05). On multivariate analysis, only a CLcr of <45 mL/min was an independent risk factor for thrombocytopaenia of ≥grade 2.
Conclusion
When administering a PEM-containing regimen, thrombocytopaenia of ≥grade 2 is more likely to develop in patients with a CLcr of <45 mL/min.
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Do Corticosteroids Still Have a Role in the Management of Third Molar Surgery?
Abstract
Introduction
The use of corticosteroids to reduce the post-operative sequelae of lower third molar surgery, namely pain, swelling and trismus, has been well studied by many researchers over the past 6 decades. This study reviewed the reported outcome of corticosteroids used in controlling the above sequalae after third molar surgery.
Materials and Methods
A PubMed, Medline, EMBASE and Google search was undertaken of all controlled clinical trials on the effects of corticosteroids on pain, swelling and trismus after lower third molar surgery. The review was limited to studies published over the last 10 years (2006–2015).
Results
Of the 46 initially retrieved articles, 34 were finally included. Eleven studies compared the effect of 2 similar (but different dose) or different group of corticosteroids. Thirty-one studies reported the effects of corticosteroids on all sequale, 2 reported the outcome on swelling and trismus and another 1 on swelling and pain only. In 16 of the studies, corticosteroid use resulted in significant reductions in pain after third molar removal. Twenty-two out of 29 studies reported reduced swelling against negative control while 18 out of 25 studies reported improved mouth opening. Fourteen studies reported the benefit of corticosteroids on all 3 sequelae, with 71.4% resulted from the use of methylprednisolone.
Conclusion
Although there are some conflicting effects, the results of this analysis shows in general the benefits derived from short-term use of corticosteroids in relation to pain, swelling and trismus following third molar surgical extraction, with no side effects observed.
Funding
This work was supported by the University of Malaya's High Impact Research grant UM.C/625/1/HIR/MOHE/05.
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Characteristics of the Novel Potassium-Competitive Acid Blocker Vonoprazan Fumarate (TAK-438)
Abstract
Proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases, such as peptic ulcers and gastro-esophageal reflux disease, and for the eradication of Helicobacter pylori. However, the therapeutic efficacy of conventional PPIs is considered limited because: (1) they are unstable under acidic conditions and require an enteric-coated formulation in clinical use; (2) they show high interindividual variability in pharmacokinetics due to genetic polymorphisms of cytochrome P450 (CYP) 2C19 metabolism; (3) they have a relatively slow onset of pharmacological action and may require several doses to achieve optimal acid suppression and symptom relief; and (4) they often do not provide stable suppression of gastric acid secretion over 24 h. Vonoprazan fumarate (TAK-438, hereinafter referred to as "vonoprazan") is a new potassium-competitive acid blocker (P-CAB) developed to resolve the above limitations of conventional PPIs. Various physicochemical data have shown that vonoprazan has a high solubility and stability over a broad pH range in aqueous conditions. In addition, vonoprazan has a more potent and longer-lasting acid suppression effect than the conventional PPI, lansoprazole. Preclinical pharmacokinetic studies have shown that vonoprazan is accumulated and retained in the stomach for more than 24 h, even after it is eliminated from the plasma. From these findings, we propose that vonoprazan, which possesses a novel mode of action, can improve on the outcomes seen with conventional PPI-based treatments for acid-related diseases.
Funding
This review project, including the publication of this article, was funded by Takeda Pharmaceutical Company Limited.
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Management of Pemphigus Vulgaris
Abstract
Introduction
Pemphigus vulgaris (PV) is a chronic, autoimmune, vesiculobullous disease. As a result of the relative rarity of PV, published randomized controlled trials (RCTs) are limited, which makes it difficult to evaluate the efficacy of different treatment regimens in this disease. This also precludes conduct of a meta-analysis.
Methods
English-language publications describing treatment outcomes of patients with PV were identified by searches of electronic databases through May 2015, and additionally by review of the bibliography of these publications. A total of 89 papers, which included 21 case reports, 47 case series, 8 RCTs, and 13 observational studies, were identified. The findings from these publications, including information on disease course and prognosis, medications used, treatment responses, and side effects, are summarized in the tables and text of this review.
Results
Prior to availability of corticosteroid therapy, PV had a high fatality rate. Early publications from the 1970s reported high-dose, prolonged corticosteroid use and significant associated side effects. Later reports described use of corticosteroids along with steroid-sparing adjuvants, which allows a reduction in the total dose of corticosteroids and a reduction in observed mortality and morbidity. For the majority of patients in these reports, a long-term course on medications lasting about 5–10 years was observed; however, subgroups of patients requiring shorter courses or needing longer-term therapy have also been described. Early diagnosis of PV and early initiation of treatment were prognostic factors. In recent publications, commonly used initial regimens include corticosteroids in combination with mycophenolate or azathioprine; whereas, for patients with inadequate response to these regimens, adjuvants such as intravenous immunoglobulin (IVIg) or rituximab are used.
Conclusion
The review findings emphasize the importance of early diagnosis, early initiation of treatment, and use of steroid-sparing adjuvants to allow a reduced total dose and duration on corticosteroids. Also highlighted is the need for more RCTs.
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Utility of sedation for young children undergoing dimercaptosuccinic acid renal scans
Abstract
Background
No studies have examined whether use of sedation during a Tc-99 m dimercaptosuccinic acid (DMSA) renal scan reduces patient discomfort.
Objective
To compare discomfort level during a DMSA scan to the discomfort level during other frequently performed uroradiologic tests, and to determine whether use of sedation during a DMSA scan modifies the level of discomfort.
Materials and methods
We examined the discomfort level in 798 children enrolled in the Randomized Intervention for children with Vesicoureteral Reflux (RIVUR) and Careful Urinary Tract Infection Evaluation (CUTIE) studies by asking parents to rate their child's discomfort level with each procedure on a scale from 0 to 10. We compared discomfort during the DMSA scan and the DMSA image quality between centers in which sedation was used >90% of the time (sedation centers), centers in which sedation was used <10% of the time (non-sedation centers), and centers in which sedation was used on a case-by-case basis (selective centers).
Results
Mean discomfort level was highest for voiding cystourethrogram (6.4), followed by DMSA (4.0), followed by ultrasound (2.4; P<0.0001). Mean discomfort level during the DMSA scan was significantly higher at non-sedation centers than at selective centers (P<0.001). No difference was apparent in discomfort level during the DMSA scan between sedation centers and selective centers (P=0.12), or between the sedation centers and non-sedation centers (P=0.80). There were no differences in the proportion with uninterpretable DMSA scans according to sedation use.
Conclusion
Selective use of sedation in children 12–36 months of age can reduce the discomfort level experienced during a DMSA scan.
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Total body irradiation—an attachment free sweeping beam technique
Abstract
Introduction
A sweeping beam technique for total body irradiation in standard treatment rooms and for standard linear accelerators (linacs) is introduced, which does not require any accessory attached to the linac. Lung shielding is facilitated to reduce the risk of pulmonary toxicity. Additionally, the applicability of a commercial radiotherapy planning system (RTPS) is examined.
Material and Methods
The patient is positioned on a low couch on the floor, the longitudinal axis of the body in the rotational plane of the linac. Eight arc fields and five additional fixed beams are applied to the patient in supine and prone position respectively. The dose distributions were measured in a solid water phantom and in an Alderson phantom. Diode detectors were calibrated for in-vivo dosimetry. The RTPS Oncentra was employed for calculations of the dose distribution.
Results
For the cranial 120 cm the longitudinal dose profile in a slab phantom measured with ionization chamber varies between 94 and 107 % of the prescription dose. These values were confirmed by film measurements and RTPS calculations. The transmittance of the lung shields has been determined as a function of the thickness of the absorber material. Measurements in an Alderson phantom and in-vivo dosimetry of the first patients match the calculated dose.
Discussion and conclusion
A treatment technique with clinically good dose distributions has been introduced, which can be applied with each standard linac and in standard treatment rooms. Dose calculations were performed with a commercial RTPS and should enable individual dose optimization.
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Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials
Abstract
Purpose
Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction has been identified as an important but manageable adverse effect of targeted therapy. Several studies have suggested that patients who develop hypothyroidism respond better to TKIs, but this relationship is not well elucidated. We evaluated the relationship between new-onset hypothyroidism and clinical response in patients with advanced cancers treated with TKIs at our institution.
Methods
We retrospectively reviewed records for patients from four clinical trials that included at least one TKI therapy between January 2006 and December 2011. Patients with preexisting thyroid disease, including thyroid cancer, hypothyroidism, or hyperthyroidism, were excluded. Analysis of 197 patients was performed. Response was determined using RECIST 1.0. Clinical benefit was described as complete response, partial response, or stable disease greater than 4 months. Multivariable logistic regression analysis was performed to correlate patient characteristics with clinical response.
Results
The median age for the 197 patients was 58 years (range, 13–85 years), and 56 % were female. Of the 197 patients, 52 (26 %) developed hypothyroidism after therapy. Clinical benefit rates were 50 % in patients with new-onset hypothyroidism versus 34 % in patients without hypothyroidism. In the univariate model, the odds ratio (OR) for new-onset hypothyroidism was 1.9 [95 % confidence interval (CI) (1.0, 3.6) and p = 0.05]. We grouped tumor types into six categories (breast, colorectal carcinoma, melanoma, non-small cell lung cancer, pancreas, and other). When adjusted for tumor type, age (>50 years) and sex, the OR was 2.9 [95 % CI (1.3, 6.5) and p = 0.012] for new-onset hypothyroidism.
Conclusion
New-onset hypothyroidism was associated with favorable clinical response in patients who received TKI treatment.
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Pharmacokinetics, safety, and efficacy of lenalidomide plus dexamethasone in patients with multiple myeloma and renal impairment
Abstract
Purpose
Renal impairment (RI) is a common comorbidity in multiple myeloma (MM). Current dose adjustments recommended for renally excreted lenalidomide are based on data from noncancer patients. This study evaluated the pharmacokinetics, safety, efficacy, and exposure–response for lenalidomide plus dexamethasone in patients with relapsed/refractory MM and stable RI using the recommended dose adjustments.
Methods
This phase 2 multicenter, open-label study stratified patients into 5 groups based on creatinine clearance (CrCl) calculated by Cockcroft–Gault equation: normal renal function (CrCl > 80 mL/min), mild RI (50 ≤ CrCl ≤ 80 mL/min), moderate RI (30 ≤ CrCl < 50 mL/min), severe RI (CrCl < 30 mL/min), and end-stage renal disease requiring hemodialysis. Dosing was based on the lenalidomide label.
Results
Among 38 patients, the median age was 68 (range 62–74) years, and poorer renal function was associated with older age, more advanced disease, and more lines of prior therapy. Lenalidomide clearance declined with decreased CrCl. Mean lenalidomide area under plasma concentration–time curve (AUC) was within ±25 % of the target AUC in each group. Overall response was 76 %, and safety profiles were similar across groups, with no exposure-dependent trend in efficacy or toxicity. Estimated glomerular filtration rates calculated using the simplified Modification of Diet in Renal Disease equation highly correlated with lenalidomide clearance and, in 87 % of patients, would lead to assigning the same starting dose of lenalidomide as CrCl.
Conclusions
In patients with stable renal function, the recommended dose adjustments achieved proper plasma exposure and similar safety and efficacy across renal groups.
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Expression level and methylation status of three tumor suppressor genes, DLEC1 , ITGA9 and MLH1 , in non-small cell lung cancer
Abstract
Despite therapeutic advances, lung cancer remains one of the most common causes of cancer-related death in the world. There is a need to develop biomarkers of diagnostic and/or prognostic value and to translate findings in basic science research to clinical application. Tumor suppressor genes (TSGs) represent potential useful markers for disease detection, progression and treatment target. We tried to elucidate the role of three 3p21.3 TSGs: DLEC1, ITGA9 and MLH1, in non-small cell lung cancer (NSCLC). We assessed their expression pattern by qPCR in 59 NSCLC tissues and in the matched macroscopically unchanged lung tissues. Additionally, we analyzed gene promoter methylation status by methylation-specific PCR in NSCLC samples. We did not find significant correlations between gene expression and methylation. In case of DLEC1 and ITGA9, expression levels were decreased in 71–78 % of tumor samples and significantly different between tumor and normal tissues (P = 0.0001). It could point to their diagnostic value. ITGA9 could also be regarded as a diagnostic marker differentiating NSCLC subtypes, as its expression level was significantly lower in squamous cell carcinoma (P = 0.001). The simultaneous down-regulation of DLEC1 and ITGA9 was observed in 52.5 % of NSCLCs. MSPs revealed high frequencies of gene promoter methylation in NSCLCs: 84 % for DLEC1 and MLH1 and 57 % for ITGA9. Methylation indexes reflected moderate gene methylation levels: 34 % for ITGA9, 27 % for MLH1 and 26 % for DLEC1. However, frequent simultaneous methylation of the studied genes in more than 50 % of NSCLCs suggests the possibility of consider them as a panel of epigenetic markers.
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Using natural products to promote caspase-8-dependent cancer cell death
Abstract
The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.
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Using natural products to promote caspase-8-dependent cancer cell death
Abstract
The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.
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Dosimetric and Clinical Outcomes with Intensity-modulated Radiation Therapy after Chemotherapy for Patients with Early-stage Diffuse Large B-cell Lymphoma of Waldeyer’s Ring
Publication date: Available online 8 June 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yong-Gang Xu, Shu-Nan Qi, Shu-Lian Wang, Yue-Ping Liu, Wei-Hu Wang, Jing Jin, Yong-Wen Song, Hua Ren, Hui Fang, Xiao-Hui He, Mei Dong, Bo Chen, Ning-Ning Lu, Ning Li, Yuan Tang, Yu Tang, Jian-Rong Dai, Ye-Xiong Li
PurposeTo assess the dosimetric benefit, prognosis and toxicity of intensity-modulated radiation therapy (IMRT) for early-stage, diffuse large B-cell lymphoma of Waldeyer's ring (WR-DLBCL).Methods and MaterialsSixty-one patients with early-stage WR-DLBCL who received chemotherapy followed by IMRT were retrospectively reviewed. Dosimetric parameters for the target volume and critical normal structures were evaluated and survival calculated. Linear regression analysis was used to assess the effect of the mean dose (Dmean) to the parotid glands upon xerostomia.ResultsThe median Conformity Index (CI) and Homogeneity Index (HI) of the planning target volume (PTV) were 0.83 and 0.90, respectively, demonstrating very good coverage of the target volume. Mean dose to the parotid glands was 24.9 Gy. Five-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were 94.7%, 93.1%, and 98.3%, respectively. Early and late toxicities were mild, and no patient developed late toxicities of grade ≥3. Dmean to the parotid glands had a linear correlation with late xerostomia of grade ≥2.ConclusionsIMRT after chemotherapy can provide excellent dose conformity and achieve favorable survival and LRC with mild toxicities in patients with early-stage WR-DLBCL. Dose constraints for the parotid glands should be limited to <24 Gy for early-stage WR-DLBCL.
Teaser
The dosimetric benefit, efficacy and toxicity of intensity-modulated radiation therapy (IMRT) for early-stage diffuse large B-cell lymphoma of Waldeyer's ring have not been addressed specifically. We demonstrated that IMRT elicits excellent target volume coverage and sparing of the parotid glands, and achieves favorable survival with mild toxicity. Dose constraints for the parotid glands should be <24 Gy in such patients.from Cancer via ola Kala on Inoreader http://ift.tt/1thk0km
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Optimal patient positioning (prone versus supine) for VMAT in gynecological cancer: a dosimetric study on the effect of different margins
Publication date: Available online 8 June 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): S.T. Heijkoop, G.H. Westerveld, N. Bijker, R. Feije, A.W. Sharfo, N. van Wieringen, J.W.M. Mens, L.J.A. Stalpers, M.S. Hoogeman
Purpose/ objectiveIt is unknown whether the historically found dosimetric advantages of treating gynecological cancer in prone position using a small-bowel displacement device (bellyboard) remain when using VMAT and if they depend on the needed CTV-to-PTV margin. The aim is to determine the best patient position (prone or supine) in terms of OAR sparing for various CTV-to-PTV margins and VMAT dose delivery.Material and MethodsIn an IRB approved study, 26 patients with gynecological cancer scheduled for primary (9) or postoperative (17) radiotherapy were scanned in prone position on a bellyboard and in supine position at the same day. The primary tumor Clinical Target Volume (CTV), nodal-CTV, bladder, bowel and rectum were delineated on both scans. Planning Target Volumes (PTVs) were created each with a different margin for the primary tumor- and nodal CTV. VMAT plans were generated using our in-house system for automated treatment planning. For all margin combinations supine and prone plans were compared considering all OAR dose-volume parameters, but giving highest priority to bowel cavity V45Gy (cm3).ResultsFor both groups, prone position reduced the bowel cavity V45Gy, in particular for nodal margins ≥10 mm (ΔV45Gy=23.9±10.6 cm3). However, for smaller margins the advantage was much less pronounced (ΔV45Gy=6.5±3.0 cm3) and did not reach statistical significance. The rectum Dmean was significantly lower (ΔDmean=2.5±0.3 Gy) in prone position for both patient groups and for all margins, while the bladder Dmean was significantly lower in supine (ΔDmean=2.6±0.4 Gy), only for the postoperative group. The advantage for prone was not present if prone needs a larger margin than supine position.ConclusionFor patients with gynecological cancer the historically found dosimetric advantages for prone position remain for modern dose delivery techniques if large margins are needed. However, the advantage is lost for small margins and if prone position needs a larger margin than supine.
Teaser
Institutes treat gynecological cancer patients in prone position using a small-bowel displacement device justified by historically found dosimetric advantages in 3DCRT and IMRT using large CTV-to-PTV margins. In this treatment planning study we compared dose to OARs in prone and supine position for various CTV-to-PTV margins and using VMAT-dose delivery. We found a significant advantage for prone setup in terms of small-bowel sparing if large margins are required, but the advantage was lost for smaller margins.from Cancer via ola Kala on Inoreader http://ift.tt/25Pw6my
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Palsy of the recurrent laryngeal nerves in association with an ultrasonic activated device during thoracoscopic esophagectomy with three-field lymphadenectomy
Abstract
Background
Ultrasonic activated devices (USADs) may produce inadvertent injuries due to heat or shock waves. However, thermal injury and shock waves are considered to be avoidable if these devices are used appropriately.
Methods
Utilizing a porcine model, we examined the relationship between the occurrence of tissue damage around the iliac artery and sciatic nerve and the usage of an USAD. Thereafter, we prospectively determined the clinical outcomes following the usage of the USAD during dissection along the recurrent laryngeal nerves (RLN) in 114 consecutive patients who underwent thoracoscopic esophageal surgery.
Results
The temperatures measured in the pig iliac artery and sciatic nerve more than 2 mm from the activating blade (at a power setting of 70 %, within 2 s) did not increase to 42 °C. In a subsequent clinical series using the short activating technique according to the findings of in vivo experiments, scheduled laryngoscopic studies showed the rate of vocal cord palsy after esophagectomy to be 39 %, which was more sensitive than the substantial presence of hoarseness (28 %).
Conclusions
Adverse effects by using the USAD on the nerves may be avoidable if the activation of the current using an USAD is conducted within 2 s at positions more than 2 mm from the nerves. This short activation technique using the USAD is therefore considered to be safe and feasible for lymph node dissection along the RLNs during thoracoscopic esophagectomy, although the apparent reasons for postoperative dysfunction in the vocal cords remain unclear.
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Clinical mutational profiling of bone metastases of lung and colon carcinoma and malignant melanoma using next-generation sequencing
BACKGROUND
Bone is a common metastatic site for solid tumors and is often the only source for molecular testing. Current routine decalcification protocols for the processing of bone specimens damage nucleic acids, leading to a high failure rate.
METHODS
In this retrospective quality-assessment analysis, preanalytic factors that contributed to the failure of mutational profiling in metastatic bone specimens were evaluated using a next-generation sequencing assay.
RESULTS
Mutational profiling was conducted in 33 formalin-fixed, paraffin-embedded bone lesions that were submitted to a clinical laboratory. Adequate depth of coverage was obtained in 21 specimens, of which, 16 had mutations detected. "No results" were reported in 12 specimens because the NGS assay failed. There was a significantly higher failure rate in bone specimens compared with nonbone specimens (36% vs 2.3%, respectively). Although nonbone specimens had a higher failure rate in biopsy/fine-needle aspiration (FNA) specimens, in-house bone biopsy/FNA specimens with or without short-duration surface decalcification had a lower failure rate than resected bone specimens (11% vs 60%, respectively). The high failure rate in resected metastatic bone specimens was associated with regular decalcification but not with low DNA input.
CONCLUSIONS
Next-generation sequencing assays demonstrated clinical utility in metastatic bone specimens. FNA (smear and cell block) and core-biopsy specimens provided adequate resources of nucleic acids for molecular profiling of metastatic bone lesions. The current findings suggest the need for developing specific tissue procurement and processing protocols for bone metastases and greater use of small biopsy and FNA specimens. Cancer Cytopathol 2016. © 2016 American Cancer Society.
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Combination of the novel histone deacetylase inhibitor YCW1 and radiation induces autophagic cell death through the downregulation of BNIP3 in triple-negative breast cancer cells in vitro and in an orthotopic mouse model
Abstract
Background
Triple-negative breast cancer (TNBC) is the most aggressive and invasive of the breast cancer subtypes. TNBC is a challenging disease that lacks targets for treatment. Histone deacetylase inhibitors (HDACi) are a group of targeted anticancer agents that enhance radiosensitivity. Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a member of the Bcl-2 subfamily. BNIP3 is not found in normal breast tissue but is up-regulated in breast cancer. In the present study, we investigated the anti-cancer effects of a newly developed HDACi, YCW1, combined with ionizing radiation (IR) in TNBC in vitro and in an orthotopic mouse model. Furthermore, we examined the relationship between autophagy and BNIP3.
Methods
Trypan blue exclusion was used to investigate the viability of 4 T1 (a mouse TNBC cell line) and MDA-MB-231 cells (a human TNBC cell line) following combined YCW1 and IR treatment. Flow cytometry was used to determine apoptosis and autophagy. The expression levels of BNIP3, endoplasmic reticulum (ER) stress- and autophagic-related proteins were measured using western blot analysis. An orthotopic mouse model was used to investigate the in vivo effects of YCW1 and IR alone and in combination. Tumor volumes were monitored using a bioluminescence-based IVIS Imaging System 200.
Results
We found that YCW1 significantly enhanced toxicity in 4 T1 cells compared with suberoylanilide hydroxamic acid (SAHA), which was the first HDACi approved by the Food and Drug Administration for clinical use in cancer patients. The combined treatment of YCW1 and IR enhanced cytotoxicity by inducing ER stress and increasing autophagy induction. Additionally, the combined treatment caused autophagic flux and autophagic cell death. Furthermore, the expression level of BNIP3 was significantly decreased in cells following combined treatment. The downregulation of BNIP3 led to a significant increase in autophagy and cytotoxicity. The combined anti-tumor effects of YCW1 and IR were also observed in an orthotopic mouse model; combination therapy resulted in a significant increase in autophagy and decreased tumor tissue expression of BNIP3 in the tumor tissue.
Conclusions
These data support the possibility of using a combination of HDACi and IR in the treatment of TNBC. Moreover, BNIP3 may be a potential target protein for TNBC treatment.
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MYC and BCL2 overexpression is associated with a higher class of Memorial Sloan-Kettering Cancer Center prognostic model and poor clinical outcome in primary diffuse large B-cell lymphoma of the central nervous system
Abstract
Background
Primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCLs. However, the prognostic significance of MYC and BCL2 in PCNS-DLBCL remains elusive.
Methods
Immunohistochemistry (IHC) of MYC, BCL2 and BCL6 was performed on tumor samples from 114 patients with PCNS-DLBCL. IHC score was assigned based on the proportion of immunostained cells.
Results
MYC, BCL2, and BCL6 IHC scores were 18.16 ± 19.58, 58.86 ± 35.07, and 39.39 ± 37.66 % (mean ± SD), respectively. Twenty-one cases (18.1 %) were designated as MYC-positive with a cutoff score of 40. BCL2 positivity was found in 87 cases (75.0 %) using a cutoff score of 30. MSKCC (Memorial Sloan-Kettering Cancer Center prognostic model) class 2 and 3 had higher rates of MYC and/or BCL2 positivity (MYC, P = 0.012; BCL2, P = 0.008; dual-positive, P = 0.022). Poor KPS (Karnofsky Performance Status score <70), multifocal disease, Nottingham-Barcelona score ≥2, and MSKCC class 2 and 3 were related to shorter progression-free survival (PFS) (P = 0.001, 0.037, 0.001, and 0.008, respectively). Patients with older age (>60 years) showed poorer overall survival (OS) (P = 0.020). MYC positivity was associated with poor PFS (P = 0.027), while patients with BCL2 positivity exhibited a shorter OS (P = 0.010). Concomitant MYC and BCL2 positivity was related to poor PFS (P = 0.041), while the lack of both MYC and BCL2 expression was related to prolonged OS (P = 0.014). MYC and BCL2 expression had no independent prognostic implication by multivariate analysis in overall patients with PCNS-DLBCL. However, among patients treated with combined high-dose methotrexate, vincristine and procarbazine and radiotherapy, dual MYC and BCL2 overexpression (a cutoff score of 60) was an independent poor prognostic indicator (P = 0.010).
Conclusions
Evaluation of MYC and BCL2 expression may be helpful for the determination of PCNS-DLBCL prognosis.
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Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies
BACKGROUND
Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified.
METHODS
DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements.
RESULTS
Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein.
CONCLUSIONS
Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016. © 2016 American Cancer Society.
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Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery
BACKGROUND
Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS).
METHODS
Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment of any single lesion were considered concurrent if SRS was administered within 4 weeks of immunotherapy. The impact of the timing and type of immunotherapy on the lesional response was determined with the Wilcoxon rank-sum test, which was used to compare the median percent lesion volume change 1.5, 3, and 6 months after SRS treatment, with significance determined by P = .0167 according to the Bonferroni correction for multiple comparisons.
RESULTS
Concurrent use of immunotherapy and SRS resulted in a significantly greater median percent reduction in the lesion volume at 1.5 (−63.1% vs −43.2%, P < .0001), 3 (−83.0% vs −52.8%, P < .0001), and 6 months (−94.9% vs −66.2%, P < .0001) in comparison with nonconcurrent therapy. The median percent reduction in the lesion volume was also significantly greater for anti–programmed cell death protein 1 (anti–PD-1) than anti–cytotoxic T-lymphocyte-associated protein 4 (anti–CTLA-4) at 1.5 (−71.1% vs −48.2%, P < .0001), 3 (−89.3% vs −66.2%, P < .0001), and 6 months (−95.1% vs −75.9%, P = .0004).
CONCLUSIONS
The administration of immunotherapy within 4 weeks of SRS results in an improved lesional response of melanoma BrMets in comparison with treatment separated by longer than 4 weeks. Anti–PD-1 therapy also results in a greater lesional response than anti–CTLA-4 after SRS. Cancer 2016. © 2016 American Cancer Society.
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Racial disparities in the survival of American children, adolescents, and young adults with acute lymphoblastic leukemia, acute myelogenous leukemia, and Hodgkin lymphoma
BACKGROUND
Race-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time.
METHODS
Using the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time.
RESULTS
Trends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL.
CONCLUSIONS
Although survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society.
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Cigarette smoking, comorbidity, and general health among survivors of adolescent and young adult cancer
BACKGROUND
We examined the associations between cigarette smoking, comorbidity, and general health among survivors of adolescent and young adult (AYA) cancer and a comparison group.
METHODS
From the 2012 to 2014 National Health Interview Surveys, we identified 1019 survivors of AYA cancer, defined as individuals who had been diagnosed with cancer between 15 and 39 years of age and were at least 5 years after their initial cancer diagnosis. A noncancer comparison group was matched on age, sex, and other factors. Self-reported smoking status (never smoker, former smoker, or current smoker), comorbidities (eg, asthma and diabetes), and general health status (excellent, very good, or good versus poor or fair) were compared among these groups. Survivors' smoking status before diagnosis and interaction with health care professionals regarding smoking cessation were reported. Multivariable logistic regressions modeled the associations between smoking status and comorbidity and general health.
RESULTS
33% of survivors were current smokers compared with 22% in the comparison group (P < .001). Prevalence of comorbidities and fair/poor health was significantly higher among survivors. Current smokers among survivors were more likely to report greater comorbidities (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.06-2.47; P = .03) and less likely to report at least good health (OR, 0.34; 95% CI, 0.22-0.54; P < .001) than never-smokers. Among survivors who smoked currently, 92% started smoking before diagnosis, and 37% reported having no smoking-related discussions with health care professionals in the previous year.
CONCLUSIONS
Smoking among survivors of AYA cancer is associated with greater comorbidities and poorer general health. Younger survivors may need to be targeted for effective smoking cessation interventions. Addressing cigarette smoking during medical visits may encourage survivors to quit smoking. Cancer 2016. © 2016 American Cancer Society.
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Using natural products to promote caspase-8-dependent cancer cell death
Abstract
The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.
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Impact of Pre-existing NS5A-L31 or -Y93H Minor Variants on Response Rates in Patients Infected with HCV Genotype-1b Treated with Daclatasvir/Asunaprevir
Abstract
Introduction
The combination of daclatasvir (DCV, pan-genotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan, Korea and other countries for the treatment of chronic hepatitis C virus (HCV) genotype (GT)-1. A high (~90 to 100%) sustained virologic response (SVR) with DCV/ASV therapy has been achieved by excluding patients infected with HCV GT-1b with baseline NS5A resistance-associated variants (RAVs) at L31 or Y93H detected by direct sequencing (DS). We set out to determine whether patients with minor variants at NS5A-L31 or -Y93H, detected by next-generation sequencing (NGS), impacted SVR rates with DCV/ASV therapy.
Methods
Baseline samples from 222 interferon (IFN)-ineligible/intolerant (N = 135) and prior non-responder (N = 87) patients infected with GT-1b who were treated with DCV/ASV for 24 weeks in the Phase 3 clinical study AI447026 were prepared for NGS (Ion-Torrent platform). The prevalence of baseline NS5A RAVs and their impact on SVR when observed at ≥1% by NGS in a patient's virus population were examined. NGS and DS (sensitivity ≥20%) data were compared.
Results
The prevalence of baseline NS5A RAVs at L31 or Y93H was 29% (63/219) and 18% (39/214) by NGS and DS, respectively. SVR24 rates were comparable in patients without observed baseline L31 or Y93H polymorphisms whether assessed by NGS (96%; 148/154) or by the less sensitive DS platform (95%; 164/173).
Conclusion
Optimal SVR rates (≥95%) to DCV/ASV treatment were achieved using DS to exclude patients infected with GT-1b with NS5A RAVs at L31 or Y93H representing ≥20% of their virus population. Exclusion by NGS of patients with minor variants in NS5A (<20%) did not enhance SVR rates. These results suggest that the presence of minor variants in NS5A does not appear to impact the overall SVR rate in patients with GT-1b treated with DCV/ASV.
Funding
This study was sponsored by Bristol-Myers Squibb.
Trial registration
ClinicalTrials.gov identifier: NCT01497834.
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Use of endocrinological and neurological medication among 5-year survivors of young onset brain tumors
Abstract
The burden of late-effects for young onset brain tumor (BT) survivors needs more careful evaluation. Our aim was to assess the need for endocrinological and neurological medication among this specific group. We identified 5-year survivors diagnosed at the age of 0–24 years between 1988 and 2004 from the Finnish Cancer Registry (N = 602). Data on endocrinological and neurological drug purchases were collected from the Social Insurance Institution of Finland. Five years after diagnosis the most commonly purchased drugs had been: antiepileptics (44.8 %), systemic hydrocortisone (18.3 %), female sex hormones (17.6 %), thyroid hormones (11.2 %), and growth hormone (10.0 %). The survivors showed an increased hazard ratio (HR) for a need for new types of drugs still 5 years after diagnosis. Thyroid hormones (HR 10.6, 95 % CI 5.1–21.4), estrogens (HR 8.0, 95 % CI 2.1–25.7), and antiepileptics (HR 6.3, 95 % CI 3.4–11.2) were bought with high frequencies. Irradiation increased the hazard for drug-purchases other than antiepileptics. Cumulative incidence of purchases of estrogens or androgens increased still 15 years after diagnosis. The cumulative incidence of purchasing thyroid hormones and antiepileptics showed continuous increase for the youngest group, whereas survivors diagnosed at 15–24 years of age reached stable level before 15 years from diagnosis. The need for new medication continued more than a decade after BT diagnosis. Especially the need for new thyroid or sex hormone medication among childhood BT survivors may emerge long after diagnosis.
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Brainstem gangliogliomas: prognostic factors, surgical indications and functional outcomes
Abstract
To explore the prognostic factors and discuss the surgical indications of brainstem gangliogliomas. Twenty-one patients with brainstem ganglioglioma were surgically treated at our hospital between 2006 and 2014. The clinical, radiological, operative, and pathological findings of these patients were retrospectively reviewed. The 3-years overall survival and event-free survival (EFS) rates were 90.5 % and 68.4 %, respectively. Four patients (4/18, 22 %) experienced a recurrence with a mean recurrence-free survival of 5.5 months and a mean follow-up of 37 months. Three patients died of surgery-related complications. Three growth patterns were identified: exophytic (6/21), intrinsic (2/21), and endo-exophytic (13/21). Eight patients (8/15, 53 %) harbored a BRAF V600E mutation. All recurrent tumors were endo-exophytic, and except the one without molecular information, were BRAF V600E mutants. A Cox hazard proportion ratio model was used to identify factors influencing EFS, including sex, age, location, growth patterns, extent of resection (EOR), and BRAF V600E mutation status. On univariate analysis, none of these factors reached statistical significance. Among them, EOR and growth patterns were strongly associated with each other (Fisher's exact test, P < 0.01). A multivariate analysis demonstrated that growth patterns were the only factor associated with EFS (P = 0.02; HR 49.05; 95 % CI 1.76–1365.13). Growth patterns may be useful to select surgery candidates and predict prognosis for patients with brainstem gangliogliomas. BRAF V600E was frequently present and appeared to be associated with shorter recurrence-free survival. Studies on BRAF V600E-targeted therapy for patients with high surgical risks are needed.
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Conditional survival after diagnosis with malignant brain and central nervous system tumor in the United States, 1995–2012
Abstract
General population-based survival statistics for primary malignant brain or other central nervous system (CNS) tumors do not provide accurate estimations of prognosis for individuals who have survived for a significant period of time. For these persons, the use of conditional survival percentages provides more accurate information to estimate potential outcomes. Using information from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program from 1995 to 2012, conditional survival percentages were calculated for 1 or 5 years of additional survival for all primary malignant brain and CNS tumors overall and by gender, race, ethnicity and age. Rates were calculated to include 1, 2, 3, 4, 5, 10 and 15 years post diagnosis. Conditional survival was also calculated in intervals from 1995–2004 to 2005–2012, to examine the potential effect that the introduction of new treatment protocols may have had on survival rates. The percentage of patients surviving one or five additional years varied by histology, age at diagnosis, gender, race and ethnicity. Younger persons (age <15 years at diagnosis) had higher conditional survival percentages for all histologies as compared to all histologies in older patients (age ≥15 years at diagnosis). The longer the amount of time post-diagnosis of a malignant brain or other CNS tumor, the higher the conditional survival. Younger persons at diagnosis had the highest conditional survival irrespective of histology. Use of conditional survival rates provides relevant additional information for patients and their families, as well as for clinicians and researchers, and helps with understanding prognosis.
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Cancers, Vol. 8, Pages 55: RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1
Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, the expression relationship between RASSF1A and its downstream target, modulator of apoptosis 1 (MOAP-1), is poorly understood. In this study, we have explored the mRNA expression of RASSF1A, MOAP-1 and the well-characterized splice variant of RASSF1, RASSF1C, in cancer cell lines and primary tumors. We confirmed that the RASSF1A promoter is robustly methylated within a 32-CpG region in solid tumors and results in lower mRNA expression. The MOAP-1 promoter contains ~110 CpG sites, but was not found to be methylated in cancer cell lines when 19 predicted CpG sites were explored. Interestingly, MOAP-1 mRNA expression positively correlated with RASSF1A expression in numerous cancers, whereas RASSF1C expression remained the same or was increased in cell lines or tissues with epigenetic loss of RASSF1A. We speculate that MOAP-1 and RASSF1A may be more intimately connected than originally thought, and the expression of both are warranted in experimental designs exploring the biology of the RASSF1A/MOAP-1 molecular pathway.
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Issue Information
The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery
Abstract
Background
Colorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5–10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes.
Conclusions
The picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.
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CD44 SNP rs187115 predicts survival in PDAC
Purpose: Although pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, like other common cancers, it displays a wide range of biology. However, at present, there are no reliable tests to predict patients' cancer-specific outcomes and guide personalized treatment decisions. In this study, we aim to identify such biomarkers in resectable PDAC by studying single nucleotide polymorphisms (SNPs) in the CD44 gene, which drives the progression of pancreatic cancer. Experimental Design: 348 PDAC patients from three independent cohorts (Switzerland, Germany, The Cancer Genome Atlas (TCGA)) who underwent pancreatic resection are included in the study. Information on the haplotype structure of the CD44 gene is obtained using 1000 Genomes Project data and the genotypes of the respective tagging SNPs are determined. Cox proportional hazards models are utilized to analyze the impact of SNP genotype on patients' survival. Results: We identify a SNP in the CD44 gene (SNPrs187115) that independently associates with allelic differences in prognosis in all study cohorts. Specifically, in 121 Swiss patients, we observe an up-to 2.38-fold (p=0.020) difference in tumor-related death between the genotypes of SNPrs187115. We validate those results in both the German (hazard ratio (HR)=2.32, p=0.044, 101 patients) and the TCGA cohort (HR=2.36, p=0.044, 126 patients). Conclusions: CD44 SNPrs187115 can serve as a novel biomarker readily available at the time of PDAC diagnosis that identifies patients at risk for faster tumor progression and guide personalized treatment decisions. It has the potential to significantly expand the pool of patients that would benefit from tumor resection.
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Circulating tumor DNA in Ewing sarcoma
Purpose: The application of the tumor specific genomic fusion sequence as non-invasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated. Experimental Design: EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic <i>EWSR1-FLI1</i> copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. <i>EWSR1</i> fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared to tumor volumes calculated from magnetic resonance imaging (MRI) or computed tomography (CT) imaging studies. Results: Kinetics of <i>EWSR1</i> fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development. Conclusions: Genomic fusion sequences represent promising non-invasive biomarkers for improved therapy monitoring in Ewing sarcoma. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response.
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