National Cancer Institute's Criteria Research Articles

Exceptional Responders in Oncology: A Systematic Review and Meta-Analysis of Patient Level Data.

We aim to systematically review and analyze the available literature on "exceptional responders" in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors. A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates. The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853). There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.

Tumor Hypervascularity and hand-foot-skin reaction predict better outcomes in combination treatment of TACE and Sorafenib for intermediate hepatocellular carcinoma

BackgroundTo validate the robust predictive values of tumor vascularity and hand-foot-skin reaction (HFSR) in combination treatment of transarterial chemoembolization (TACE) and sorafenib for patients with intermediate hepatocellular carcinoma (HCC), and then select the potential candidates who would survive best from such treatment.MethodsA total of 132 treatment-naive patients with intermediate HCC undergoing combination therapy of TACE and sorafenib were recruited between January 2010 and December 2014. The tumor vascularity was defined according to digital subtraction angiography (DSA) and HFSR was assessed by the national cancer institute common terminology criteria for adverse events (NCI-CTCAE). The Mann-Whitney U test was used to assess the correlation between vascularity and radiologic response; time to radiologic progression (TTP) and overall survival (OS) were evaluated using Kaplan-Meier techniques and compared by log-rank test; factors associated with them were evaluated using multivariate Cox regression analysis.ResultsDuring a median follow up of 17.3 months, it was revealed that hypervascularity and development of ≥2 grade of HFSR within 60 days after sorafenib initiation were favorable predictors for TTP (HR 0.378, p < 0.001; HR 0.627, p = 0.018) and OS (HR 0.499, p = 0.002; HR 0.555, p = 0.004). The median TTP and OS for patients with both were 12.2 and 29.1 months, which were better than patients with either of them (6.0 months, HR 1.74, p = 0.012; 16.5 months, HR 1.73, p = 0.021), as well as those with neither (2.9 months, HR 3.74, p < 0.001; 11.9 months, HR 3.17, p < 0.001).ConclusionsTumor hypervascularity and development of ≥2 grade of HFSR within 60 days were favorable predictive factors for the combination treatment of TACE and sorafenib, with both of which the patients survived longest and might be the potential candidates.

Identifying Determinants of Intervention Sustainability in Cancer Survivorship Care

Background: Substantial gains could be made in reducing the cancer burden if current scientific evidence was applied in practice. The World Health Organization estimates that, worldwide, one-third of cancer cases could be prevented and another one-third cured if evidence was consistently implemented and sustained in cancer care. However, moving evidence-based interventions into care has proven a significant challenge. Even when interventions are put into practice, they often fail to become integrated into the long-term routines of organizations. This poor sustainability means many patients do not benefit from the best care possible. There is little empirical data on the factors that influence the sustainability of interventions in clinical settings. Aim: To identify the determinants of, and explore the processes that facilitate, sustainability of interventions in cancer care survivorship. Sustainability was defined as the continued use of an intervention and its associated components and/or the continued achievement of the intended benefits after the initial funding or support period. Methods: We first conducted an environmental scan to identify interventions in cancer survivorship care implemented in Canada. This was followed by a literature review to ascertain the evidence base for each intervention and identify those meeting the US National Cancer Institute's criteria for evidence-based interventions. We then recruited key individuals relevant to the evidence-based interventions for semistructured in-depth interviews to explore issues related to their sustainability. Interview data are being analyzed through an inductive grounded theory approach using constant comparative analysis. Results: Twenty-seven individuals participated in the interviews. Preliminary findings reveal five factors that influenced whether, and the extent to which, interventions were sustained in cancer survivorship care. Participants emphasized (1) access to sufficient resources and funding is critical to sustaining interventions after the initial funding period. The ability of a team or organization to (2) evaluate a new intervention and demonstrate its quality and usefulness was often perceived as necessary to obtain continued funding as well as ongoing buy in and support from key stakeholders. In addition, the (3) extent to which the intervention can be adapted, (4) support of senior management, and (5) existence of an on-the-ground champion to continuously promote, adapt, lead, and spread the intervention were perceived as important factors that contribute to an intervention's sustained use. Conclusion: Research into determinants and processes of sustainability is critical to ensure we plan and act in ways that maximize the sustained use of interventions shown to benefit patients and our cancer systems. Issues related to evaluation, adaptability, and ongoing moral and material supports should be considered before, during, and after implementation efforts.

Keeping PACE with Ph Positive to Ph-Like Detection in B-Lineage Acute Lymphoblastic Leukemia: A Practical and Cost Effective (PACE) Approach in a Resource Constrained Setting.

Philadelphia (Ph)-like or BCR-ABL like acute lymphoblastic leukemia (ALL) is defined on the basis of a gene expression profile that is similar to Ph-positive ALL. It comprises a wide spectrum of genetic lesions affecting primarily the cytokine receptor and/or kinase signalling genes. It accounts for approximately 10-15% of pediatric ALL, and is more common in patients who are high-risk according to the National Cancer Institute criteria. Presence of Ph-like mutations is an independent predictor of poor outcome. However, there is vast potential to utilize targeted therapy to improve survival in this group. The sizeable range of genetic lesions varying from translocations, fusions, point mutations and deletions make the diagnosis challenging. Hence, a practical and cost effective approach is required to enable identification in resource constrained settings. Patients with recurrent cytogenetic abnormalities such as ETV6-RUNX1, high hyperdiploidy, TCF3-PBX1, BCR-ABL1 and KMT2A (MLL) rearrangement need not be tested, as these are mutually exclusive with BCR-ABL like mutations. Detection of CRLF2 overexpression, which is the commonest abnormality, is employed as the first step. In patients lacking overexpression, testing for tyrosine kinase fusions can be performed. However, the goal should be to employ a combination of molecular diagnostic techniques such as reverse transcriptase polymerase chain reaction (PCR), real time quantitative PCR, fluorescence in situ hybridization and Sanger sequencing to detect genetic lesions that are amenable to targeted therapy.

Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

BackgroundChildren with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis.Materials & methodsS-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade ≥ 3 National Cancer Institute Criteria) was used as clinical endpoint.ResultsSAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 –+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 –+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis.ConclusionsThis was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.

HPLC-DAD-ESI-MS/MS characterization of bioactive secondary metabolites from Strelitzia nicolai leaf extracts and their antioxidant and anticancer activities In vitro

Background: Strelitzia nicolai Regel and Korn (Strelitziaceae) is native to Southern Africa whose phytochemistry and pharmacology were slightly investigated. Materials and Methods: In the current work, different solvent extracts of S. nicolai were screened for their chemical profiles through high-performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS/MS) analyses. Furthermore, their in vitro antioxidant, cytotoxic, and anticancer activities were evaluated using 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) & ferric reducing antioxidant power (FRAP) and crystal violet staining (CVS) colorimetric assays, respectively. Results: HPLC-DAD-ESI-MS/MS analyses led to the identification of nineteen and eleven phenolic compounds from the ethyl acetate and n-butanol extracts, respectively including flavonoids (e.g., quercetin 3-(2 G-rhamnosylrutinoside, quercetin, quercetin-3-O-glucoside, kaempferol-3,7-O-dirhamnoside, isorhamnetin-3-O-rutinoside and kaempferol-3-O-glucoside), phenolic acids derivatives (e.g., chlorogenic acid glycoside, protocatechuic acid-O-glucoside and caftaric acid), chalcones (e.g., xanthoangelol), and phenylethanoids (e.g., ligstroside glucoside). Moreover, in the DPPH assay the IC50value of the most active ethyl acetate extract was 20.49 μg/mL, relative to 2.92 μg/mL of ascorbic acid. ABTS and FRAP results reinforced the results of DPPH assay. According to the National Cancer Institute criteria, the tested extracts showed weak to moderate cytotoxic activities with IC50values ranged from 65.23 to 451.29 μg/mL. Furthermore, the EtOAc and n-BuOH extracts showed a noticeable anticancer activity with CVS spectroscopic readings for liver hepatocellular carcinoma growth 0.806 and 0.684 at a concentration (125 μg/mL), as well as 0.730 and 0.618 at concentration (500 μg/mL), respectively against control at 1.022. Conclusion: The obtained results reveal the high efficacy of the phenolic-rich extracts from S. nicolai as naturally occurring antioxidant and anti-tumor agents. Abbreviations Used: HPLC-DAD-ESI-MS/MS: High-performance liquid chromatography-diode array detection-electrospray ionization-mass/mass; DPPH: 2,2'-Diphenyl-1-picrylhydrazyl radical; ABTS: 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulphonic acid); FRAP: Ferric reducing antioxidant power; TPTZ: Tripyridyl-s-triazine; FE: Ferrous equivalents; DMEM: Dulbecco's modified eagle's medium; DMSO: Dimethyl sulfoxide; EDTA: Ethylenediaminetetraacetic acid; PBS: Phosphate buffered saline; HepG-2: Liver hepatocellular carcinoma; CVS: Crystal violet stain; NCI: National cancer institute; Glu: Glucose; Rha: Rhamnose.

Impact of Initial CSF Findings on Outcome Among Patients With National Cancer Institute Standard- and High-Risk B-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/μL and blasts with/without ≥ 10 RBCs/μL or ≥ 5 WBCs/μL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/μL plus blasts with/without ≥ 10 RBCs/μL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.

An open-label expanded-access study to evaluate the safety, tolerability, and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and hepatic impairment.

2559 Background: The Phase 3 RECOURSE study showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (Mayer et al. N Engl J Med 2015;372:1909-19). A Phase 1 open-label study evaluated the safety and pharmacokinetics of FTD/TPI in patients with advanced solid tumors and varying degrees of hepatic impairment to inform dosing recommendations for these patients. Methods: Patients aged ≥18 years with advanced solid tumors, an Eastern Cooperative Oncology Group performance status ≤2, normal hepatic function, and mild, moderate, or severe impaired hepatic function according to the National Cancer Institute criteria were enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and days 8-12 of each 28-day cycle, except for those with severe impaired hepatic function (dose was to be determined). Results: 24 patients were enrolled to normal (n=8), mild (n=10), and moderate (n=6) groups. Study enrollment was stopped as 5/6 patients in the moderate group experienced elevated bilirubin levels (grade ≥3). The other baseline characteristics were similar across groups. Overall, 12 patients (50%) had at least 1 adverse event leading to study discontinuation: 2 in normal, 5 in mild, and 5 in the moderate hepatic impairment groups. Pharmacokinetic results are summarized in the table. Conclusions: The exposure to FTD or TPI was not increased by hepatic impairment and the patients who experienced grade 3 and 4 increased total bilirubin were not overexposed to FTD or TPI. Clinical trial information: NCT02301104. [Table: see text]

Chemical Composition of Essential Oil from Leaves of Schinus molle L. Growing in Taif, KSA

Climatic and geographic conditions play an important role in the variations of chemical composition of essential oils and consequently its biological activities. The chemical constituents of essential oil from leaves of S. molle L. (Family Anacardiaceae) growing in Taif, KSA were investigated using capillary GC-MS technique. Mono- and sesquiterpenes represented by fifty compounds were identified and quantified. The total sesquiterpenes had the higher quantity (594.50 mg/100 g FWL) whereas the total monoterpenes had a lower quantity (353.69 mg/100 g FWL). α-phellandrene (211.70 mg/100 g FWL, 22.33%) was the major compound in the monoterpenes whereas δ-cadinene (57.72 mg/100 g FWL) and guaiol (55.69 mg/100 g FWL) were the major compounds in the sesquiterpenes. The special climate and geographic location of Taif governorate play an important role in the variation of chemical composition of S. molle essential oil. The S. molle essential oil showed promising anticancer activity toward the HepG2 cell line with IC50 = 16.33±0.78 that fall within the range of the American National Cancer Institute (NCI) criteria which considered the agent is promising when its IC50 < 20 μg/ml. Thus, this oil considered as promising anticancer potential after more in vitro and in vivo chemical and biological investigations. According to the above results, it is recommended for widespread cultivating this tree and its related species. All parts of the tree can be used as an important raw material for the extraction of essential oil used in traditional medicine as well as food and pharmaceutical industries.

The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia.

Five-year survival rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity because of methotrexate (MTX) occurs frequently. Variety in the occurrence of toxicity is partly determined by single nucleotide polymorphisms (SNPs) in coding regions. Recently, five SNPs in non-coding pre-microRNAs and microRNA processing (miRNA) genes were identified in association with MTX-induced oral mucositis. This study aimed to replicate the association of these miRNA variants in relation to MTX-induced oral mucositis in a prospective childhood ALL cohort. Three out of five SNPs with a minor allele frequency more than 0.15 [CCR4-NOT transcription complex (CNOT4) rs3812265, miR-1206 rs2114358, miR-2053 rs10505168] were analyzed in 117 pediatric ALL patients treated with 5 g/m MTX (DCOG ALL-10). Oral mucositis was defined as grade more than or equal to 3 according to the National Cancer Institute criteria. rs2114358 in miR-1206 was associated with oral mucositis [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.1-11.5], whereas we did not confirm the association of CNOT4 rs3812265 (OR: 0.69; 95% CI: 0.27-1.80) and miR-2053 rs10505168 (OR: 2.50; 95% CI: 0.76-8.24). Our results replicate the association between rs2114358 in miR-1206 and MTX-induced oral mucositis in childhood ALL. Genetic variation in miR-1206 has potential as a novel biomarker to predict MTX-induced toxicity.

Cholesterol Levels in Patients with Chronic Lymphocytic Leukemia

Low cholesterol levels may be accompanied by solid tumors or hematological malignancies such as multiple myeloma. Decreased cholesterol levels have been reported in some experimental studies about chronic lymphocytic leukemia (CLL). It may be associated with tumoral cell metabolism. Herein, we examine blood lipid profiles of patients with newly diagnosed CLL (284 male, 276 female, mean age 64 ± 11 years) as defined by National Cancer Institute criteria. The control group consisted of 71 healthy subjects with mean age 55 ± 9 years (28 male, 43 females). 60% of patients with Binet A, while 25% were Binet C. Decreased levels of total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) were observed in patients with CLL than control group (p < 0,001). There was no statistical significance between CLL and control group for triglycerides (TG) and very low density lipoprotein (VLDL), also between HDL-C, VLDL, TG and grades. Cholesterol may metabolized by abnormal lymphocytes in CLL patients.

An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia.

Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying adult patients at high-risk. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by National Cancer Institute (NCI) criteria. CEP72 promoter genotype (rs924607) was determined using polymerase chain reaction (PCR)-based single nucleotide polymorphism (SNP) genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs. 10%, P = 0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (P = 0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy.

Platinum-induced ototoxicity: a review of prevailing ototoxicity criteria

The antineoplastic agent's cisplatin and carboplatin are widely used as they are highly effective. Unfortunately, ototoxicity is a frequently encountered side effect of platinum-based chemotherapy. Clinically, patients generally develop a progressive, bilateral, and irreversible sensorineural hearing loss. With rising cancer survival rates, a greater proportion of patients are living with the side effects of their chemotherapy treatments. Consequently, the quality of life of cancer survivors has now become a major concern for clinicians. Various classification systems are currently available to grade side effects and provide a guideline for subsequent treatments. An extensive review of the literature revealed that a variety of criteria are used worldwide for grading platinum-induced hearing loss in children and adults, including the National Cancer Institute criteria, Brock's grading system, the American Speech-Hearing-Language Association criteria, the World Health Organization criteria, the Pediatric Oncology Group criteria, and the Muenster classification. Less commonly used criteria include the Chang classification, the Functional Hearing Loss scale, the HIT system (German Hirntumor study grading system), and most recently, the International Society of Pediatric Oncology Boston ototoxicity grading scale. The objective of this review is to evaluate the commonly used ototoxicity criteria and discuss their benefits and limitations.

Clinical observation of erlotinib ± brain radiotherapy for non-small cell lung cancer patients with brain metastases

Objective To retrospectively evaluate the efficacy in non-small cell lung cancer (NSCLC) patients with brain metastases treated with erlotinib ± whole brain radiotherapy, and observe the adverse events. Methods From March 2012 to January 2015, 56 patients with NSCLC with brain metastases received oral erlotinib, at a dose of 150mg per day till disease progression or intolerable adverse events were developed, including 42 cases who had received brain radiotherapy.The objective response rate (ORR) and disease control rate (DCR) were observed between groups, the progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method with the use of log-rank method.Prognostic factors of the patients were analyzed with univariate and multivariate analysis in Cox regression model.Curative effect was evaluated with response evaluation criteria in solid tumors (RECIST) criteria, and adverse events with National Cancer Institute (NCI) criteria. Results ORR and DCR were 57.1%(32/56), and 82.1%(46/56), respectively. The median PFS was 12.3 months, and the OS was 8.0 months. The 1-, and 2-year PFS rates were 51.0%, and 20.0%, respectively. The 1-, and 2-year year OS rates were 36.0%, and 7.0%, respectively. Men had a higher DRR rate than women (P=0.009). Single brain metastasis patients had higher DCR rate than in multiple brain metastases patients (P=0.044). The non-smokers, less than Karnofsky (KPS) score of 70 and high recursive partitioning analysis (RPA) score groups had higher ORR (P=0.043, P 0.05). Univariate analysis showed that there were higher PFS rate and OS rate in high RPA score group than in low RPA score group (P<0.001, P<0.001), and in KPS score of 70 and more group than in less than score of 70 group (P<0.001, P<0.001), respectively. The non-smokers and patients with adenocarcinoma group had longer OS times. Multivariate analysis showed that KPS score was the independent prognostic factor of PFS and OS (P<0.001, P=0.005), pathological type was the independent prognostic factor of PFS (P=0.001). Conclusions Erlotinib is effective and safe for NSCLC patients with brain metastases. Men and the single brain metastasis patients, non-smokers, high KPS and RPA score groups had higher DCR rates. KPS score is the most important influencing factors for patient's PFS and OS time. Women and the patients with adenocarcinoma have higher PFS rate than those of men and squamous cell carcinoma. Key words: Quinazolines/AD; Radiotherapy; Carcinoma, non-small-cell lung/CO/TH; Brain neoplasms/SC/TH

Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases.

ObjectiveSevere myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity.MethodsWe retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups.ResultsNon-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively).ConclusionsMyelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program-Sponsored Single-Agent Phase I Studies.

Alterations in renal clearance of anticancer drugs can affect the occurrence of toxicities related to drug exposure. The National Cancer Institute and the US Food and Drug Administration (FDA) use different criteria to classify renal dysfunction. We examined those discrepancies and their potential association with the incidence of toxicities in patients enrolled onto Cancer Therapy Evaluation Program-sponsored single-agent phase I studies over three decades (1979 to 2010). Data to estimate creatinine clearance according to the Cockcroft-Gault and Jelliffe formulas were available from 10,236 patients, and data to estimate creatinine clearance according to the six- and four-variable Modification of Diet in Renal Disease formulas were available from a subset (n = 4,084). Patients were classified according to National Cancer Institute and FDA criteria, and the rates of clinically relevant toxicities were evaluated within groups and compared among groups. Cockcroft-Gault estimated renal function improved over time, which may be attributed to an increase in weight of patients in the same time frame. Approximately 36% of patients enrolled onto phase I trials had mild renal dysfunction by FDA criteria. Relative to normal function, mild renal dysfunction was associated with a statistically significant but small increase in grade 3 or 4 nonhematologic toxicity and any relevant toxicities. Patients with mild renal dysfunction by FDA criteria have routinely been enrolled onto phase I studies of antineoplastics without clinically meaningful increase in the risk of toxicity. In future oncology renal dysfunction trials based on the FDA classification, the FDA mild group may only need to be activated when the moderate and normal groups differ substantially in tolerability or pharmacokinetics.

Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.

With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment. To identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. Genome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children's Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children's Oncology Group (COG) protocol AALL0433 with toxic effects follow-up through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. Treatment with vincristine at a dose of 1.5 or 2.0 mg/m2. Vincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4). Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3×10(-9)). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%; 95% CI, 11.6%-19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 (56%; 95% CI, 41.2%-70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4×10(-6)). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine. In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.

Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial

No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy. Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 10(9)/L vs ≥50 × 10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119. 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]). Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen. Medical Research Council and Leukaemia and Lymphoma Research.

Risk factors for ovarian cancers with and without microsatellite instability.

In a population-based sample of epithelial ovarian cancers, the objective of this study was to evaluate the association between microsatellite instability (MSI) status and the following factors: (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes. Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer; tumor DNA was analyzed using 5 standardized microsatellite markers to assess the MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to the National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. A total of 917 ovarian cancer patients were included. One hundred twenty-seven cases of cancer (13.8%) were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significance differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 patients with BRCA2 mutations. The proportions of different ovarian cancer histologies among the various MSI subgroups were similar. The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologies. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant.

Evaluation Of Anemia After Long-Term Treatment With Imatinib In Chronic Myeloid Leukemia In Chronic Phase

The incidence of Grade 3 (hemoglobin [Hb] level 6.5–8 g/dL) or Grade 4 (Hb level < 6.5 g/dL) anemia was reported to be 3% with imatinib therapy for newly diagnosed CML in the IRIS trial, with a median follow-up of 19 months and 7% for chronic-phase (CP) chronic myeloid leukemia (CML) after IFN-α failure. However, there is few data regarding development of anemia after long-term follow-up and its causes.The aim of this work was to evaluate the incidence of anemia after at least two years of treatment of CML patients in CP treated with imatinib and to identify other contributing causes of anemia in this population. Patients and MethodsBetween 2006 and 2010 121 patients with CML were treated with imatinib 400-800 mg in our center. Forty-six patients were excluded from the analysis for accelerated phase at diagnosis (n=20), discontinuation of imatinib before 2 years of treatment (n=21) and 5 for other causes. A total of 65 patients were evaluated. Hb levels were analyzed at diagnosis, at imatinib start, and at two years of imatinib. Anemia developed after the second year of imatinib therapy was classified as grade 1 (Hb level < 10.0 g/dL), grade 2 (Hb level of 8.0 to < 10 g/dL), or grade 3 (Hb level of < 8.0 g/dL) for the purpose of treatment evaluation according to National Cancer Institute (NCI) Common Toxicity Criteria - Version 4.0. Other comorbidities were analyzed. ResultsThe median age was 53 years (24-86 years), 34 male (52%). 38% of the patients did not present other medical conditions. Comorbidities found in 62% of the patients: systemic arterial hypertension (31%), diabetes mellitus (6.7%), cardiopathy (5%), hypothyroidism (6.1%) and renal failure (only one patient with renal dysfunction in dialysis). Two patients received interferon: one prior imatinib and another during pregnancy, requiring interruption of imatinib in this period. Patient's responses: 54 (83%) achieved complete cytogenetic response (CCR) and 10 lost response; eight of them developed anemia; 7 had (10.7%) partial response, 1 minor response (1,5%), 1 no response and 1 was not available. Fifty-three patients (81.5%) achieved major molecular response, with loss of response during follow-up in 8 cases (12.5%), seven of these developed anemia.The median Hb (g/dL) level was 12.1, 13 and 13.2 at diagnosis, at imatinib start and at 2 years of treatment respectively. Most of the patients developed Hb bellow the reference level (73.8%; n = 48) during the follow-up, after the second year of treatment. Anemia classification according to NCI criteria: 41 cases presented grade 1, 6 (12.5%) grade 2 and one grade 3. Of these, 68.7% (n = 33) had no etiological causes for the anemia, five patients (10.4%) were resistant, two (4.2%) were not adherent to treatment and in 8 cases (16.7%) the etiology of anemia was identified: hypothyroidism (n=1), erosive gastritis (Helicobacter Pylori positive)(n=1), B12 vitamin deficiency (n=2), HIV/AIDS (n=1), pulmonary tuberculosis (n=1) and renal failure (n=2). Fourteen (29.2%) patients had normalization of Hb levels without medical intervention and the majority (56.2%) still persists with the anemic status until the last follow-up. Four (8.3%) patients had resolution of the anemia after switching to a second generation inhibitor and 3 (6.2%) showed clinical improvement after treatment of the cause.In summary, several degrees of anemia may occur in patients with CML on long-term imatinib therapy, most of them not severe. Regular hematological follow-up is required to identify causes not CML related that can be corrected or if related to imatinib toxicity, dose modification or change of therapy. It should be emphasized the importance of investigating secondary causes for anemia, especially in patients with good adherence to treatment and satisfactory therapeutic response. Disclosures:No relevant conflicts of interest to declare.