Clinical and histopathological effects of presurgical treatment with sunitinib for renal cell carcinoma with inferior vena cava tumor thrombus at a single institution.

To evaluate the clinical and histopathological effects of presurgical treatment with sunitinib on inferior vena cava (IVC) tumor thrombus. Between 2010 and 2014, we treated seven patients with renal cell carcinoma and IVC tumor thrombus presurgically with sunitinib. We retrospectively evaluated primitive tumor size, the level of tumor thrombus according to Novick's classification, its distance above the renal vein, thrombus diameter at its widest segment, and histopathological change after sunitinib treatment. Three patients were diagnosed histologically. Percutaneous biopsy of the renal mass before sunitinib treatment was performed in two patients. One patient was diagnosed after sunitinib treatment following nephrectomy. The primitive tumors shrank upon sunitinib therapy in four cases; however, although the caval thrombus was downstaged (from level II to I) in one patient, the level of caval thrombus did not change in five patients and increased in one patient (from level III to IV). We evaluated the histopathological effects in two patients. In one patient, the IVC tumor thrombus was mostly replaced with necrotic tissue, but its thrombus level was not downstaged. In the other patient, the IVC tumor thrombus was downstaged, but tumor thrombus was not replaced with necrotic tissue and viable tumor cells remained. Presurgical treatment with sunitinib for renal cell carcinoma with IVC tumor thrombus appears to have limited effect on IVC tumor thrombus, in contrast to its effects on primitive tumor shrinkage. In the absence of evidence of presurgical benefits from prospective studies, this treatment may not be systematically advisable. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1hexVwJ Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Chamaejasmine induces apoptosis in HeLa cells through the PI3K/Akt signaling pathway.

Chamaejasmine is one of the major bioactive components of Stellera chamaejasme L, which is a Chinese traditional herbal medicine that has been used widely in the treatment of cancer. The aim of this study is to investigate the potential effect of chamaejasmine on cervical cancer cells and elucidate the underlying mechanisms of action. We first examined the antitumor activity of chamaejasmine both in vitro and in vivo. In the following experiments with HeLa cells, cell apoptosis and ultrastructure changes were assessed by flow cytometry and transmission electron microscopy, respectively. The effects of chamaejasmine on reactive oxygen species production and mitochondrial membrane potential ([DELTA][psi]m) were examined using 2',7'-dichlorohydrofluorescein and rhodamine-123 staining. The mRNA and protein levels of apoptosis-related proteins were detected by real-time PCR and western blot. The activity of caspases 3, 8, and 9 was measured using the corresponding assay kit. The effect of chamaejasmine on the phosphoinositide 3-kinase (PI3K)/Akt pathway was evaluated by luciferase assay and western blot, and further confirmed in Akt overexpressing HeLa cells. We found that chamaejasmine has potent antitumor effects on cervical cancer cell lines both in vitro and in vivo. Mechanistic studies showed that chamaejasmine could induce apoptosis in HeLa cells, and this apoptosis-inducing effect may be mediated through the suppression of PI3K/Akt signaling cascades. These findings not only indicate the therapeutic potential of chamaejasmine for cervical cancer, but provide valuable insight into its mechanism of action. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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The TYMS-TSER polymorphism is associated with toxicity of low-dose capecitabine in patients with advanced gastrointestinal cancer.

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Uncertainty in the Era of Precision Medicine

A National Research Council report on "precision medicine" explains that the term "refers to the tailoring of medical treatment to the individual characteristics of each patient." The report goes on to say, "It should be emphasized that in 'precision medicine' the word 'precision' is being…

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Increasing Precision in Adjuvant Therapy for Breast Cancer

Genomic testing of tumors can enable improved matching of individual patients or groups with treatments, but it can also identify situations where a specific intervention is not effective. In the recently reported results of the Trial Assigning Individualized Options for Treatment (TAILORx),…

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70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer

Women with early-stage breast cancer are often treated with adjuvant systemic therapy consisting of chemotherapy, endocrine therapy, agents against human epidermal growth factor receptor 2 (HER2), or combinations of these drugs when appropriate. Treatment decisions are based on characteristics of…

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Bispecific antibody-drug conjugate targeting HER2 and CD63

Antibody-drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. We hypothesized that we could overcome this limitation by enhancing lysosomal ADC delivery via a bispecific antibody (bsAb) approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment. We therefore designed a bsAb in which one binding arm specifically targeted CD63, a protein that is described to shuttle between the plasma membrane and intracellular compartments, and combined it in a bsAb with a HER2 binding arm, which was selected as model antigen for tumor specific binding. The resulting bsHER2xCD63his demonstrated strong binding, internalization and lysosomal accumulation in HER2-positive tumor cells, and minimal internalization into HER2-negative cells. By conjugating bsHER2xCD63his to the microtubule-disrupting agent duostatin-3, we were able to demonstrate potent cytotoxicity of bsHER2xCD63his-ADC against HER2-positive tumors, which was not observed with monovalent HER2- and CD63-specific ADCs. Our data demonstrate, for the first time, that intracellular trafficking of ADCs can be improved using a bsAb approach that targets the lysosomal membrane protein CD63 and provide a rationale for the development of novel bsADCs that combine tumor-specific targeting with targeting of rapidly internalizing antigens.

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AsiDNA sensitizes cancer cells to PARP inhibitors

Purpose: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are Poly(ADP-Ribose) Polymerase (PARP) inhibitors (PARPi), which trigger synthetic lethality in tumors with Homologous Recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and Non Homologous End Joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy. Experimental design: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells, and 3 non-tumor cells. In 12 Breast Cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways. Results: Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, non-tumor cells do not show an increase of DNA damage nor lethality. Analysis of multi-level omics data from BC cells highlighted different DNA repair and cell cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with 6 other PARPi in development. Conclusion: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.

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Combined hepatocellular and cholangiocarcinoma originating from the same clone: a pathomolecular evidence-based study

Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin r...

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Psychotropic drug dispensing in people with and without cancer in France

Abstract

Purpose

To compare annual and monthly prevalence of psychotropic drug (PD) dispensing and the number and duration of psychotropic treatment episodes among people with and without cancer over a 2-year follow-up.

Methods

We studied the following two cohorts of adult patients affiliated with the National Health Insurance Fund (NHIF): cancer patients followed for 2 years after diagnosis and individuals without cancer matched to cancer patients. Using information about anxiolytic, hypnotic, antidepressant, and antipsychotic dispensing in community pharmacies, we applied conditional log-binomial regressions to estimate adjusted relative risks for monthly dispensing of PDs.

Results

Annual prevalence of PD dispensing—all categories included—among cancer patients was significantly higher for almost all the categories we studied than among individuals without cancer. Monthly prevalence of anxiolytic/hypnotic dispensing started to rise several months before diagnosis and peaked immediately after. Among patients with cancer and their matched controls, treatment duration exceeded 1 month for hypnotics in 40 and 35 %, respectively (p < 0.01), and 3 months for anxiolytics in 23 and 23 % (p = 0.8); it was less than 6 months for antidepressants in 76 and 75 % (p = 0.5).

Conclusions

Prevalence of psychotropic treatment was higher among cancer patients than among persons without cancer. Psychotropic treatment duration was not in line with recommendations for significant fractions of cancer patients or their controls.

Implications for cancer survivors

Training of health professionals involved in cancer supportive care should be reinforced and specific guidelines developed to help them address psychological distress of cancer survivors.

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Cancer patterns in Karachi (all districts), Pakistan: First results (2010–2015) from a Pathology based cancer registry of the largest government-run diagnostic and reference center of Karachi

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Muhammad Asif Qureshi, Talat Mirza, Saeed Khan, Bushra Sikandar, Maria Zahid, Marium Aftab, Sehrish Mohsin, Shaheen Sharafat, Lubna Avesi, Saba Hassan
National level population-based cancer data have never been published from Pakistan in seven decades since independence (1947). Therefore, generation of high-quality regional data becomes highly relevant. Cancer data for the period of 2010–2015 representing the population from all districts of Karachi (14.6 million) are presented herein. After institutional approval (Ref no. IRB-459/DUHS/-14), a Pathology based cancer registry was established at the largest government-run diagnostic and reference center of Karachi. During 2010–2015, a total of 13,508 cancers (including 686 non-melanoma-skin-cancers (NMSC)) were diagnosed. Of these, 5665 (41.9%) were in males while 7843 (58.1%) were in females. Incidence rates for all cancers (excluding NMSC) were 66.7 per 100,000 (crude) and 105.1 per 100,000 (ASR) for males and 112.0 per 100,000 (crude) and 175.8 per 100,000 (ASR) for females. In males, cancer of lip and oral cavity was the most frequently diagnosed cancer (30.8%, ASR 33.1), followed by NMSC (7.7%, ASR 9.5) and colorectum (7%, ASR 7.3). In females, breast cancer was the most frequently recorded malignancy (49.5%, ASR 87.9), followed by lip and oral cavity (11.2%, ASR 22.0) and oesophagus (5.6%, ASR 10.7). We report that Karachi has the highest incidence of cancers of breast, lip and oral cavity, oesophagus and larynx in females and cancer of lip and oral cavity and larynx (2nd only to Turkey) in males compared to any of the Asian populations. Notably, incidence of tobacco associated cancers is very high in Karachi, demanding urgent attention by relevant authorities to address the un-controlled and drastically high consumption of various forms of tobacco in the city.



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Racial Disparities in Prostate Cancer Mortality in the 50 Largest US Cities

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Maureen R. Benjamins, Bijou R. Hunt, Sarah M. Raleigh, Jana L. Hirschtick, Michelle M. Hughes
IntroductionThis paper presents race-specific prostate cancer mortality rates and the corresponding disparities for the largest cities in the US over two decades.MethodsThe 50 largest cities in the US were the units of analysis. Data from two 5-year periods were analyzed: 1990–1994 and 2005–2009. Numerator data were abstracted from national death files where the cause was malignant neoplasm of prostate (prostate cancer) (ICD9=185 and ICD10=C61). Population-based denominators were obtained from US Census data. To measure the racial disparity, we calculated non-Hispanic Black: non-Hispanic White rate ratios (RRs), rate differences (RDs), and corresponding confidence intervals for each 5-year period. We also calculated correlation and unadjusted regression coefficients for 11 city-level variables, such as segregation and median income, and the RDs.ResultsAt the final time point (2005–2009), the US and all 41 cities included in the analyses had a RR greater than 1 (indicating that the Black rate was higher than the White rate) (range=1.13 in Minneapolis to 3.24 in Los Angeles), 37 of them statistically significantly so. The US and 26 of the 41 cities saw an increase in the Black:White RR between the time points. The level of disparity within a city was associated with the degree of Black segregation.ConclusionThis analysis revealed large disparities in Black:White prostate cancer mortality in the US and many of its largest cities over the past two decades. The data show considerable variation in the degree of disparity across cities, even among cities within the same state. This type of specific city-level data can be used to motivate public health professionals, government officials, cancer control agencies, and community-based organizations in cities with large or increasing disparities to demand more resources, focus research efforts, and implement effective policy and programmatic changes in order to combat this highly prevalent condition.



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Primary brain tumors and mobile cell phone usage

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Damian P. Wojcik




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Management and Outcome of Periprocedural Cardiac Perforation and Tamponade with Radiofrequency Catheter Ablation of Cardiac Arrhythmias: A Single Medium-Volume Center Experience

Abstract

Introduction

Cardiac tamponade (CT) is a life-threatening complication of radiofrequency ablation (RFA). The course and outcome of CT in low-to-medium volume electrophysiology centers are underreported.

Methods

We analyzed the incidence, management and outcomes of CT in 1500 consecutive RFAs performed in our center during 2011–2016.

Results

Of 1500 RFAs performed in 1352 patients (age 55 years, interquartile range: 41–63), 569 were left-sided procedures (n = 406 with transseptal access). Conventional RFA or irrigated RFA was performed in 40.9% and 59.1% of procedures, respectively. Ablation was performed mostly for atrioventricular nodal reentrant tachycardia (25.4%), atrial fibrillation (AF; 18.5%), atrial flutter (18.4%), accessory pathway (16.5%) or idiopathic ventricular arrhythmia (VA; 12.3%), and rarely for structural VA (2.1%). CT occurred in 12 procedures (0.8%): 10 AF ablations, 1 idiopathic VA and 1 typical atrial flutter ablation. Factors significantly associated with CT were older age, pre-procedural oral anticoagulation, left-sided procedures, transseptal access, AF ablation, irrigated RFA and longer fluoroscopy time (on univariate analysis), and AF ablation (on multivariable analysis). The perforation site was located in the left atrium (n = 7), right atrium (n = 3), or in the left ventricle or coronary sinus (n = 1 each). Upon pericardiocentesis, two patients underwent urgent cardiac surgery because of continued bleeding. There was no fatal outcome. During the follow-up of 19 ± 14 months, eight patients were arrhythmia free.

Conclusion

Incidence of RFA-related CT in our medium-volume center was low and significantly associated with AF ablation. The outcome of CT was mostly favorable after pericardiocentesis, but readily accessible cardiothoracic surgery back-up should be mandatory in RFA centers.

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Diabetic Peripheral Neuropathy as a Predictor of Asymptomatic Myocardial Ischemia in Type 2 Diabetes Mellitus: A Cross-Sectional Study

Abstract

Introduction

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes and has been associated with cardiovascular disease, the leading cause of mortality in diabetes. As asymptomatic myocardial ischemia (MI) is frequent in diabetes, we hypothesized that DPN may be associated with MI in patients with type 2 diabetes mellitus and no history of cardiovascular events.

Methods

Eighty-two patients with DPN (n = 41) or without DPN (n = 41) were included. Among the DPN group, 15 had active foot ulcers. All subjects underwent Technetium-99 m sestamibi single-photon emission computed tomographic imaging for the estimation of myocardial ischemia, expressed as Summed Stress Score (SSS). The Neuropathy Disability Score (NDS) was used to quantify DPN and abnormal ratio of the longest electrocardiographic RR interval between the 28th and 32nd beats, after standing to the shortest interval between the 13th and 17th beats (RR ratio) was used as an index of cardiovascular autonomic neuropathy (CAN).

Results

Abnormal SSS was observed in 9.8% of patients without DPN and in 46.3% of patients with DPN (p < 0.001). In the multivariate analysis, NDS was the strongest predictor for SSS (β = 0.32, p = 0.003). When excluding patients with abnormal RR ratio (β = 0.32, p = 0.003) or with foot ulcers (β = 0.24, p = 0.04), this association remained significant. The RR ratio was also significantly associated with SSS in univariate (ρ = −0.30, p = 0.005) and multiple regressions (β = 0.24, p = 0.02).

Conclusions

MI was strongly associated with DPN, and this association remained significant in patients with normal RR ratio. These results suggest that DPN assessment could help in identifying patients at risk of cardiovascular disease (CVD).

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Cancers, Vol. 8, Pages 77: Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90

Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay; Results: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF; Conclusions: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.

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Vitamin insufficiencies/deficiencies in relation to sickle cell disease severity and associated morbidity

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Decreased expression of LncRNA SLC25A25-AS1 promotes proliferation, chemoresistance, and EMT in colorectal cancer cells

Abstract

Increasing evidence suggests that long non-coding RNAs (lncRNAs) are aberrantly expressed in colorectal cancer (CRC); however, only few CRC-related lncRNAs have been characterized. In this study, we aimed to dig out potential dysregulated lncRNAs that are highly involved in CRC development. Using a lncRNA-mining approach, we performed lncRNA expression profiling in a large CRC cohort from Gene Expression Ominus (GEO), GSE39582 test series (N = 585). We identified 31 downregulated lncRNAs and 16 upregulated lncRNAs from the GSE39582 test series patients (566 tumor patients and 19 normal controls). The reliability of lncRNA expression profiles was further confirmed by RT-qPCR in carcinoma tissues and paired adjacent normal tissues from 30 CRC patients, also in the serum from 109 CRC patients, and 99 normal individuals. We demonstrated that the expression of SLC25A25-AS1, which has not been reported previously, was significantly decreased in both the tumor tissues (27 out of 30) and serum of CRC patients. SLC25A25-AS1 overexpression significantly inhibited proliferation and colony formation in colorectal cancer cell lines, and downregulation of SLC25A25-AS1 obviously enhanced chemoresistance and promoted EMT process in vitro associated with Erk and p38 signaling pathway activation. Therefore, SLC25A25-AS1 was determined to play a tumor suppressive role in CRC. Our results might provide a lncRNA-based target for CRC treatment.

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Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization

Abstract

Purpose

Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) copy number (mtDNAcn) and relative telomere length (RTL) may be implicated in the tumorigenesis of several malignancies. Alterations of both RTL and mtDNAcn are generally accepted as independent biomarkers for predicting risk and prognosis in various cancers. The aim of this study was to evaluate the prognostic value of combining leukocyte RTL with mtDNAcn (RTL–mtDNAcn) in hepatocellular carcinoma (HCC).

Methods

RTL and mtDNAcn in peripheral blood leukocytes (PBLs) were measured using a real-time PCR-based method in a total of 250 HCC patients treated with transcatheter arterial chemoembolization (TACE). We evaluated the associations between RTL and/or mtDNAcn and HCC overall survival using Kaplan–Meier curve analysis and Cox proportional hazards regression model.

Results

We found that patients with longer leukocyte RTL or lower mtDNAcn had shorter overall survival time. The univariate analysis (HR 1.63, 95 % CI 1.23–2.17, P = 7.7 × 10⁻⁴) and multivariate analysis (HR 1.78, 95 % CI 1.31–2.42, P = 2.4 × 10⁻⁴) indicated that longer leukocyte RTL was significantly associated with poorer OS in HCC patients. Kaplan–Meier curve analysis showed that patients with longer RTL had shorter overall survival time than those with shorter RTL (log-rank P = 0.001). Patients with lower mtDNA copy number was significantly associated with poorer OS by Cox proportional hazards model using both univariate (HR 1.60, 95 % CI 1.21–2.13, P = 0.001) and multivariate analyses (HR 1.77, 95 % CI 1.30–2.41, P = 2.8 × 10⁻⁴). Kaplan–Meier curve analysis showed that patients with lower mtDNA content had significantly shorter overall survival time than those with higher mtDNA content (log-rank P = 0.001). Furthermore, combination of leukocyte RTL and mtDNAcn significantly improved the efficacy of predicting HCC prognosis. Patients with longer RTL and lower mtDNAcn exhibited a significantly poorer overall survival in both the univariate analysis (HR 2.21, 95 % CI 1.52–3.22, P = 3.5 × 10⁻⁵) and multivariate analysis (HR 2.60, 95 % CI 1.73–3.90, P = 4.3 × 10⁻⁶). The effect on patient prognosis was more evident in patients with longer RTL and lower mtDNAcn than in those with shorter RTL and lower mtDNA (HR 2.11, 95 % CI 1.34–3.32, P = 0.001) or in those with longer RTL and higher mtDNA (HR 2.10, 95 % CI 1.34–3.27, P = 0.001).

Conclusions

Our data suggest that combination of leukocyte RTL-mtDNAcn may be a potential efficient prognostic marker for HCC patients receiving the TACE treatment.

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Parental Origin of the Deletion del(20)(q) in Shwachman-Diamond Patients and Loss of the Paternally Derived Allele of the Imprinted L3MBTL1 Gene

Abstract

Shwachman–Diamond syndrome (SDS) (OMIM 260400) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal and haematological abnormalities and bone marrow (BM) dysfunction. Mutations in the SBDS gene cause SDS. Clonal chromosome anomalies are often present in BM, i(7)(q10) and del(20)(q) being the most frequent ones. We collected 6 SDS cases with del(20)(q): a cluster of imprinted genes, including L3MBTL1 and SGK2 is present in the deleted region. Only the paternal allele is expressed for these genes. Based on these data, we made the hypothesis that the loss of this region, in relation to parental origin of deletion, may be of relevance for the haematological phenotype. By comparing haematological data of our 6 cases with a group of 20 SDS patients without evidence of del(20)(q) in BM, we observed a significant difference for Hb levels (p<0.012), and a difference slightly above the significance level for RBC counts (p<0.053): in both cases the values were higher in patients with del(20)(q). We also report preliminary evidence for an increased number of BFU-E colonies in cases with paternal deletion, data on the presence of the deletion in colonies and in mature circulating lymphocytes. This article is protected by copyright. All rights reserved.

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Identification of SEC62 as a potential marker for 3q amplification and cellular migration in dysplastic cervical lesions

Abstract

Background

Chromosome 3 amplification affecting the 3q26 region is a common genomic alteration in cervical cancer, typically marking the transition of precancerous intraepithelial lesions to an invasive phenotype. Though potential 3q encoded target genes of this amplification have been identified, a functional correlation of potential oncogenic function is still missing. In this study, we investigated copy number changes and the expression level of SEC62 encoded at 3q26.2 as a new potential 3q oncogene in dysplastic cervical lesions and analyzed its role in cervical cancer cell biology.

Methods

Expression levels of Sec62 and vimentin were analyzed in liquid based cytology specimens from 107 women with varying grades of cervical dysplasia ranging from normal cases to cancer by immunofluorescence cytology. Additionally, a subset of 20 representative cases was used for FISH analyses targeting SEC62. To further explore the functional role of Sec62 in cervical cancer, HeLa cells were transfected with a SEC62 plasmid or SEC62 siRNA and analyzed for their proliferation and migration potential using real-time monitoring and trans-well systems as well as changes in the expression of EMT markers.

Results

FISH analyses of the swabbed cells showed a rising number of SEC62 gains and amplifications correlating to the grade of dysplasia with the highest incidence in high grade squamous intraepithelial lesions and squamous cell carcinomas. When analyzing the expression level of Sec62 and vimentin, we found a gradually increasing expression level of both proteins according to the severity of the dysplasia. In functional analyses, SEC62 silencing inhibited and SEC62 overexpression stimulated the migration of HeLa cells with only marginal effects on cell proliferation, the expression level of EMT markers and the cytoskeleton structure.

Conclusions

Our study suggests SEC62 as a target gene of 3q26 amplification and a stimulator of cellular migration in dysplastic cervical lesions. Hence, SEC62 could serve as a potential marker for 3q amplification, providing useful information about the dignity and biology of dysplastic cervical lesions.

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Role of vitamin D receptor gene Cdx2 and Apa1 polymorphisms in prostate cancer susceptibility: a meta-analysis

Abstract

Background

Vitamin D receptor (VDR) gene polymorphisms affect the risk of prostate cancer. However, studies investigating the relationship between VDR gene polymorphisms (Cdx2 and ApaI) and prostate cancer risk are equivocal. Therefore, we conducted a meta-analysis of all the studies to review the evidence available.

Methods

A comprehensive search of PubMed, EMBASE, and ISI Web of Science for studies published until September 2015 was conducted. Odds ratios (ORs) and 95 % confidence intervals (CIs) were analyzed to determine the association between VDR Cdx2 and ApaI polymorphisms, and prostate cancer risk.

Results

The meta-analysis included 10 studies involving 4979 cases and 4380 controls to analyze the VDR Cdx2 polymorphism. An additional 11 studies involving 2837 cases and 2884 controls were analyzed for the VDR ApaI polymorphism. Evidence failed to support the role of VDR Cdx2 and ApaI polymorphisms in prostate cancer. For Cdx2, the pooled OR was 1.11 (95 % CI = 0.93–1.33) for AA vs. GG genotypes, 0.97 (95 % CI = 0.88–1.06) for GA vs. AA genotypes, 0.99 (95 % CI = 0.91–1.08) for AA + GA vs. GG, and 1.12 (95 % CI = 0.95–1.31) for AA vs. GA + GG. No significant relationship was observed in any subgroup analysis based on ethnicity, controls, and Hardy–Weinberg equilibrium (HWE). ORs for the ApaI polymorphism were similar.

Conclusions

VDR Cdx2 and ApaI polymorphisms are not associated with prostate cancer. Additional evidence is required to confirm this conclusion.

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Predicting clinical outcomes in chordoma patients receiving immunotherapy: a comparison between volumetric segmentation and RECIST

Abstract

Background

The Response Evaluation Criteria in Solid Tumors (RECIST) are the current standard for evaluating disease progression or therapy response in patients with solid tumors. RECIST 1.1 calls for axial, longest-diameter (or perpendicular short axis of lymph nodes) measurements of a maximum of five tumors, which limits clinicians' ability to adequately measure disease burden, especially in patients with irregularly shaped tumors. This is especially problematic in chordoma, a disease for which RECIST does not always adequately capture disease burden because chordoma tumors are typically irregularly shaped and slow-growing. Furthermore, primary chordoma tumors tend to be adjacent to vital structures in the skull or sacrum that, when compressed, lead to significant clinical consequences.

Methods

Volumetric segmentation is a newer technology that allows tumor burden to be measured in three dimensions on either MR or CT. Here, we compared the ability of RECIST measurements and tumor volumes to predict clinical outcomes in a cohort of 21 chordoma patients receiving immunotherapy.

Results

There was a significant difference in radiologic time to progression Kaplan-Meier curves between clinical outcome groups using volumetric segmentation (P = 0.012) but not RECIST (P = 0.38). In several cases, changes in volume were earlier and more sensitive reflections of clinical status.

Conclusion

RECIST is a useful evaluation method when obvious changes are occurring in patients with chordoma. However, in many cases, RECIST does not detect small changes, and volumetric assessment was capable of detecting changes and predicting clinical outcome earlier than RECIST. Although this study was small and retrospective, we believe our results warrant further research in this area.

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Outcomes of uterine sarcoma found incidentally after uterus-preserving surgery for presumed benign disease

Abstract

Background

The aims of this study were to evaluate the impact of initial uterus-preserving surgery, such as myomectomy or subtotal hysterectomy, on the recurrence rates of patients with uterine sarcoma found incidentally and to investigate the role of surgical re-exploration in this disease subset.

Methods

We performed a retrospective chart review for patients who had previously undergone either total hysterectomy or subtotal hysterectomy or myomectomy at the time of initial surgery for presumed benign uterine leiomyoma and were found to have uterine sarcoma on final pathology. Survival analysis was performed comparing patients according to the type of initial surgery.

Results

Between 2006 and 2014, 45 patients with uterine sarcoma were identified. Myomectomy or subtotal hysterectomy was performed in 15 patients, and 30 patients underwent total hysterectomy as the initial surgery. Of the patients who underwent myomectomy or subtotal hysterectomy as the initial surgery (n = 15), 14 were re-explored to complete staging. Of the patients who underwent re-exploration (n = 14), five (35.8 %) had remnant sarcoma on the remaining uterus and no patients had disseminated disease. A Kaplan–Meier curve and log-rank test showed no difference in progression-free survival (P = 0.941) between the two groups.

Conclusion

Initial uterus-preserving surgery does not appear to be associated with an adverse impact on survival outcomes for unexpected uterine sarcoma when surgical re-exploration was performed immediately. As such, surgical re-exploration may be useful for removing any remnant sarcoma.

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High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients

Abstract

Background

Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient's family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan.

Methods

Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics.

Results

Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37 % vs. 10 %, P < 0.0001). 1 % of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14 % vs. 5 %, P = 0.03), 2) diagnosed at early-age irrespective of family history (28 % vs. 11 %, P = 0.0003), 3) had a family history of breast cancer (49 % vs. 12 %, P < 0.0001), and 4) those with family history of breast and ovarian cancer (81 % vs. 28 %, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22–53) vs. 28 years (range 18–67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95 % CI 2.50–7.14; P < 0.0001).

Conclusion

Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC.

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Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

Summary

Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. In addition, studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors exhibit some efficacy in the treatment of acute myelogenous leukemia (AML) with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription (STAT) signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 (HSP90) due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.

This article is protected by copyright. All rights reserved.

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Highlights from the 2016 WIN Symposium, 27–29 June 2016, Paris: personalised therapy beyond next-generation sequencing

Richard Schilsky and Will Davies

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The variable clinicopathological categories and role of human papillomavirus in cervical adenocarcinoma: A hospital based nation-wide multi-center retrospective study across China

Abstract

We investigated HPV in adenocarcinoma presenting and managed as cervical adenocarcinoma (CADC) at 7 major representative regional cancer centres across China. From 1,051 CADC cases diagnosed locally in 2005-2010, 881 had available paraffin embedded tissue. Initial review excluded 154 cases as other diagnoses or inappropriate specimens. In 718 eligible cases consensus panel pathology diagnosis was made using an algorithm incorporating p16 and progesterone receptor immunohistochemistry (IHC). Classification of cervical adenocarcinoma categories was subject to substantial pathological disagreement. High-risk human papillomaviruses (HR-HPV) DNA was studied by the sensitive SPF10 PCR-DEIA-LiPA25 version 1 for L1 genes and type-specific HR-HPV E6/7 gene PCR's. HR-HPV prevalence in whole tissue samples in eligible tested CADC was 74.5%: 100.0% in neuro-endocrine carcinoma (NEC), 82.2% in classical cervical adenocarcinoma (ADC-CX), 40.0% in adenocarcinoma-not otherwise specified (ADC-NOS), and 33.3% in endometrioid adenocarcinoma (ADC-ENDO). Higher mean age at diagnosis correlated with histological categories showing low HPV prevalence (Linear regression: β=-13.794, P<0.001). HPV-16 and 18 were associated with early development of CADC and a lower mean age correlated with carcinogenic risk of associated HPV (β=-0.1829, P<0.001). HPV-16 or HPV-18 was found in 88.2% of all HPV positive cases including multiple-infections. HPV-18 was the commonest HPV type in NEC (58.3%), ASC (40.2%) and ADC-CX (40.9%). The proportion of HPV-unrelated CADC and in different final histological categories varied geographically and by age. Although HPV negativity was predominantly associated with special categories of CADC some HPV-negative usual adenocarcinomas indistinguishable by adjudicated microscopic diagnosis from ADC-CX were found and varied in frequency across China. This article is protected by copyright. All rights reserved.

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“Our Organs Have a Purpose”: Body Image Acceptance in Latina Breast Cancer Survivors

Abstract

Objective

Studies examining body image concerns among breast cancer survivors have primarily captured the experiences of non-Latina White women. Thus, little is known about body image concerns among Latinas. To address this gap, we examined Latina breast cancer survivors' lived experiences related to body image.

Methods

Twenty-seven Latina breast cancer survivors provided data through focus groups and individual interviews as part of a larger study conducted by the first author. In the current paper, we conducted a secondary thematic analysis to uncover women's experiences unique to body image concerns.

Results

We identified two themes related to women's experiences with body image: (a) Perceptions of Loss and Reconstruction, and (b) Process of Achieving Body Image Acceptance. The salience of these themes varied as a function of survivorship stage and type of surgery.

Conclusions

Body image concerns are distressing for Latina breast cancer survivors. Accepting their altered appearance was an ongoing and complex process. Clinical implications include the need for psychoeducational programs and tailored interventions to enhance women's body image acceptance.

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Role of neuroimaging in children with acute lymphoblastic leukemia and central nervous system involvement at diagnosis

Abstract

Background

Each year approximately 200 children and adolescents are diagnosed with acute lymphoblastic leukemia (ALL) in the five Nordic countries, and 3% of these have central nervous system (CNS) involvement confirmed by leukemic cells in the cerebrospinal fluid (CSF) or neurological symptoms. We sought to determine the significance of neuraxis imaging in such patients.

Procedure

Magnetic resonance images of children aged 1–17.9 with CNS leukemia at diagnosis of ALL were centrally reviewed and clinical data were retrieved from the medical records and the Nordic leukemia registry. Patients were diagnosed in the period 2000–2012 in Sweden, Finland, or Denmark.

Results

The cohort comprised 1,877 patients, and 66 (3.5%) had CNS involvement. Forty-five percent (30/66) had CNS related symptoms. Symptoms included vomiting, facial palsy, headache, visual symptoms, and impaired hearing. CNS imaging was performed in 32 of 66 children (48%), and confirmed CNS involvement in 6 of 21 patients with symptoms (29%) and 5 of 11 (45%) without (P = 0.44). There was no difference in the overall survival between CNS-positive patients with and without signs of leukemic involvement by imaging (P = 0.53).

Conclusions

Radiological imaging of asymptomatic children with CNS leukemia at diagnosis lacks clinical importance, but may be useful in patients with cranial nerve symptoms and negative CSF, as well as for follow-up. Imaging of symptomatic patients is warranted in order to exclude other causes underlying the symptoms.

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Challenges for teens with sickle cell disease extend to mental health

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Measuring the efficacy of a project for adolescents and young adults with cancer: A study from the Milan Youth Project

ABSTRACT

Background

Various projects dedicated specifically to adolescents and young adults (AYA) with cancer have been developed in recent years. A critical aspect of such programs is the ability to demonstrate its value, and therefore how to measure desired outcomes.

Methods

A list of metrics to consider for demonstrating the advantages of an AYA program was identified and used to assess the activity of the Youth Project operating at the Pediatric Oncology Unit of the Istituto Nazionale Tumori in Milan.

Results

The number of newly diagnosed AYA patients seen at the Unit has increased since the formal launch of the Youth Project, from 65 to 81.2 cases/year. Concerning the 78 AYA patients presenting with malignant neoplasms in 2015, 82% were included in clinical trials (the other 18% in prospective observational studies). Fertility preservation measures were implemented for 59% of AYA patients considered at risk, and specific psychological support was provided in 70.6% of cases; 72.5% of patients actively participated in support activities. Other parameters considered were a preliminary satisfaction questionnaire administered to patients and the program's scientific recognition and acknowledgment by the community.

Conclusions

The study proposed a number of potentially reproducible, practical parameters to consider in assessing the value of a program dedicated to AYA. These metrics were examined in terms of the activities of our Youth Project, and confirmed its efficacy. To be sustainable over time, AYA projects have to be accepted as a standard of care at the community and government levels.

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Asparaginase-associated pancreatitis is not predicted by hypertriglyceridemia or pancreatic enzyme levels in children with acute lymphoblastic leukemia

Abstract

Background

l-Asparaginase is an important drug for treatment of childhood acute lymphoblastic leukemia (ALL), but is associated with serious toxicities, including pancreatitis and hypertriglyceridemia (HTG). Asparaginase-associated pancreatitis (AAP) is a common reason for stopping asparaginase treatment. The aim of this study was to explore if HTG or early elevations in pancreatic enzymes were associated with the subsequent development of AAP.

Method

Children (1.0–17.9 years) diagnosed with ALL, treated with asparaginase for 30 weeks, according to the NOPHO ALL2008 protocol at the University Hospital Rigshospitalet, Copenhagen, Denmark, were eligible. Pancreatic enzymes, triglycerides, and cholesterol were measured regularly.

Results

Thirty-one patients were included. Seven patients were diagnosed with AAP. HTG was most evident when PEG-asparaginase and dexamethasone were administered concomitantly. Overall, there was no significant difference in triglyceride levels in patients who experienced AAP and patients who did not. An increase in triglyceride levels during concomitant dexamethasone therapy in delayed intensification was significantly associated with an increase in pancreas-specific amylase levels two weeks later (P = 0.005).

Conclusions

AAP does not seem to be associated with HTG. Continuous monitoring of pancreas enzymes does not predict AAP.

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Outcome of children with relapsed or refractory neuroblastoma: A meta-analysis of ITCC/SIOPEN European phase II clinical trials

Abstract

Background

Few randomized trials have been conducted in children with relapsed/refractory neuroblastoma and data about outcomes including progression-free survival (PFS) in these patients are scarce.

Procedure

A meta-analysis of three phase II studies of children with relapsed/refractory neuroblastoma conducted in Europe (temozolomide, topotecan–vincristine–doxorubicin and topotecan–temozolomide) was performed. Individual patient data with extended follow-up were collected from the trial databases after publication to describe trial outcomes (response rate, clinical benefit ratio, duration of treatment, PFS, and overall survival [OS]). Characteristics of subjects with relapsed/refractory neuroblastoma were compared.

Results

Data from 71 children and adolescents with relapsed/refractory neuroblastoma were collected. Response definitions were not homogeneous in the three trials. Patients were on study for a median of 3.5 months (interquartile range [IQR] 1.9–6.2). Of those, 35.2% achieved a complete or partial response, 26.3% experienced a response after more than two cycles, and 23.9% received more than six cycles. Median PFS from study entry for all, refractory, and relapsed patients was 6.4 ± 1.0, 12.5 ± 6.8, and 5.7 ± 1.0 months, respectively (P = 0.006). Median OS from study entry for all, refractory, and relapsed patients was 16.1 ± 4.3, 27.9 ± 20.2, and 11.0 ± 1.6 months, respectively (P = 0.03).

Conclusions

Baseline data for response rate, clinical benefit ratio, duration of treatment, PFS, and OS were provided. Two subpopulations (relapsed/refractory) were clearly distinct and should be included in the interpretation of all trials. These results should help informing the design of forthcoming studies in relapsed/refractory neuroblastoma.

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Health care institutional charges associated with ambulatory bloodstream infections in pediatric oncology and stem cell transplant patients

Abstract

Background

The impact of ambulatory bloodstream infections (Amb-BSIs) in pediatric oncology and stem cell transplant (PO/SCT) patients is poorly understood, although a large portion of their treatment increasingly occurs in this setting. This study aimed to understand the economic impact and length of stay (LOS) associated with these infections.

Procedure

Charges and LOS were retrospectively collected and analyzed for Amb-BSI events leading to a hospital admission between 2012 and 2013 in a tertiary, university-affiliated hospital. Events were grouped as BSI-MIXED when hospitalizations with care unrelated to the infection-extended LOS by more than 24 hr or as BSI-PURE for all others. Billing codes were used to group charges and main drivers were analyzed.

Results

Seventy-four BSI events were identified in 61 patients. Sixty-nine percent met definition for central line-associated BSI (CLABSI). Median total charge and LOS for an Amb-BSI were $40,852 (interquartile range [IQR] $44,091) and 7 days (IQR 6), respectively. Median charges for BSI-PURE group (N = 62) were $36,611 (IQR $34,785) and $89,935 (IQR $153,263) in the BSI-MIXED (N = 12) group. Median LOS was 6 (IQR 5) days in the BSI-PURE group and 15 (IQR 24) in the BSI-MIXED. Room, pharmacy, and procedure charges accounted for more than 70% of total charges in all groups.

Conclusions

Amb-BSIs in PO/SCT patients result in significant healthcare charges and unplanned extended hospital admissions. This analysis suggests that efforts aiming at reducing rates of infections could result in substantial system savings, validating the need for increased efforts to prevent Amb-BSIs.

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Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Abstract

Background

Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2 and currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors.

Procedures

Tazemetostat was tested against the Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using a dose of 400 mg/kg administered twice daily by oral gavage for 28 days. H3K27me3:H3 ratios were determined in control and treated tumors.

Results

Tazemetostat induced significant differences in event-free survival (EFS) distribution compared with control in nine of 30 (30%) of the xenografts studied. Significant differences in EFS distribution were observed in five of seven (71%) rhabdoid tumor xenograft lines compared with four of 23 (17%) nonrhabdoid xenograft lines (chi-square [χ²] test P = 0.006). Tazemetostat induced tumor growth inhibition meeting criteria for intermediate and high EFS treated-to-control (T/C) activity in two of 25 (8%) and one of 25 (4%) xenografts, respectively. Intermediate and high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (three of five rhabdoid tumor vs 0 of 22 nonrhabdoid tumors (χ² test P < 0.001). One rhabdoid tumor xenograft (G401) showed stable disease. For one rhabdoid tumor (G401), delayed tumor regression to tazemetostat was noted following 1 week of tumor growth. Tazemetostat induced significant reduction of H3K27me3 levels in the majority of tumors compared with controls.

Conclusions

Tazemetostat demonstrated significant antitumor activity in rhabdoid tumor models but showed no consistent activity against any other histology. Tazemetostat reduced H3K27me3 levels irrespective of tumor response. Further preclinical testing to evaluate tazemetostat in combination with other anticancer agents is warranted.

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Excellent remission rates with limited toxicity in relapsed/refractory Langerhans cell histiocytosis with pulse dexamethasone and lenalidomide in children

Abstract

Refractory/relapsed Langerhans cell histiocytosis (LCH) has a difficult course with a guarded prognosis. We used a novel protocol including six cycles of pulse dexamethasone and lenalidomide in four children with LCH refractory to first-line agents and courses of cladribine and cytarabine or single-agent cladribine. All four children completed the protocol without any significant adverse effects and remain in complete and durable remission 15–18 months posttreatment. The novel protocol we propose for relapsed/refractory LCH is cost-effective and outpatient-based with durable remission and minimal toxicity. This is particularly suited for resource-limited settings.

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Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases

Abstract

Background

Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases.

Procedure

In this study, a self-administered questionnaire was used to retrospectively compare efficacy and safety in 49 patients undergoing second HSCT (n = 13) or donor lymphocyte infusion (DLI; n = 36) as treatment for MC.

Results

The response rate to DLI of patients with secondary graft failure (GF) (25.0%) was significantly lower than that of patients without secondary GF (81.3%; P = 0.041). Among patients undergoing DLI, the rates of successful response were significantly higher in patients having at least 30% donor chimerism (94.1%) than in patients having less than 30% donor chimerism (61.1%; P = 0.041). Furthermore, the rates of successful response were significantly higher in patients receiving larger first or maximum doses of DLI. Sixteen (50.0%) of 32 patients without secondary GF attained complete chimerism after DLI. The cumulative incidence of grade II–IV acute graft-versus-host disease and cytopenia was 37.6 and 26.1%, respectively.

Conclusions

DLI yields promising response rates in most patients with higher donor chimerism levels, whereas second HSCT is more likely to benefit patients with lower donor chimerism levels.

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Pediatric malignant germ cell tumors: A comparison of the neuro-oncology and solid tumor experience

Abstract

Malignant germ cell tumors (GCT) arise from abnormal migration of primordial germ cells and are histologically identical whether they occur inside or outside the central nervous system (CNS). However, the treatment strategy for GCTs varies greatly depending on the location of the tumor. These differences are in part due to the increased morbidity of surgery in the CNS but may also reflect differential sensitivity of the tumors to chemotherapy and radiation therapy (RT) or not-yet-understood biologic differences between these tumors. Historically, specialists caring for extracranial and intracranial GCT in the United States have practiced separately without much cross communication. The focus of this review is a discussion of differences between the management of CNS and extra-CNS GCTs and opportunities for collaboration and future research.

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The fraction of breast cancer attributable to smoking: The Norwegian women and cancer study 1991–2012

The fraction of breast cancer attributable to smoking: The Norwegian women and cancer study 1991–2012

British Journal of Cancer 115, 616 (23 August 2016). doi:10.1038/bjc.2016.154

Authors: Inger T Gram, Melissa A Little, Eiliv Lund & Tonje Braaten

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Medical treatment of renal cancer: new horizons

Medical treatment of renal cancer: new horizons

British Journal of Cancer 115, 505 (23 August 2016). doi:10.1038/bjc.2016.230

Authors: Basma Greef & Tim Eisen

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Digital vs screen-film mammography in population-based breast cancer screening: performance indicators and tumour characteristics of screen-detected and interval cancers

Digital vs screen-film mammography in population-based breast cancer screening: performance indicators and tumour characteristics of screen-detected and interval cancers

British Journal of Cancer 115, 517 (23 August 2016). doi:10.1038/bjc.2016.226

Authors: Linda de Munck, Geertruida H de Bock, Renée Otter, Dick Reiding, Mireille JM Broeders, Pax HB Willemse & Sabine Siesling

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Comment on ‘The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study’

Comment on 'The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study'

British Journal of Cancer 115, e3 (23 August 2016). doi:10.1038/bjc.2016.224

Authors: A V Paradiso, M Digennaro & D Sambiasi

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Screening women for cervical cancer carcinoma with a HPV mRNA test: first results from the Venice pilot program

Screening women for cervical cancer carcinoma with a HPV mRNA test: first results from the Venice pilot program

British Journal of Cancer 115, 525 (23 August 2016). doi:10.1038/bjc.2016.216

Authors: Tiziano Maggino, Rocco Sciarrone, Bruno Murer, Maria Rosa Dei Rossi, Chiara Fedato, Michela Maran, Melania Lorio, Marika Soldà, Fiorella Zago, Paolo Giorgi Rossi & Manuel Zorzi

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Past cervical intraepithelial neoplasia grade 3, obesity, and earlier menopause are associated with an increased risk of vulval cancer in postmenopausal women

Past cervical intraepithelial neoplasia grade 3, obesity, and earlier menopause are associated with an increased risk of vulval cancer in postmenopausal women

British Journal of Cancer 115, 599 (23 August 2016). doi:10.1038/bjc.2016.165

Authors: Kate Coffey, Kezia Gaitskell, Valerie Beral, Karen Canfell, Jane Green, Gillian Reeves & Isobel Barnes

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Symptoms and patient factors associated with longer time to diagnosis for colorectal cancer: results from a prospective cohort study

Symptoms and patient factors associated with longer time to diagnosis for colorectal cancer: results from a prospective cohort study

British Journal of Cancer 115, 533 (23 August 2016). doi:10.1038/bjc.2016.221

Authors: Fiona M Walter, Jon D Emery, Silvia Mendonca, Nicola Hall, Helen C Morris, Katie Mills, Christina Dobson, Clare Bankhead, Margaret Johnson, Gary A Abel, Matthew D Rutter, William Hamilton & Greg P Rubin

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Comment on ‘an Association of Cancer Physicians’ strategy for improving services and outcomes for cancer patients’

Comment on 'an Association of Cancer Physicians' strategy for improving services and outcomes for cancer patients'

British Journal of Cancer 115, e1 (23 August 2016). doi:10.1038/bjc.2016.168

Authors: Peter Selby & Johnathan Joffe

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Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a multicentre external validation study

Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a multicentre external validation study

British Journal of Cancer 115, 542 (23 August 2016). doi:10.1038/bjc.2016.227

Authors: A Sayasneh, L Ferrara, B De Cock, S Saso, M Al-Memar, S Johnson, J Kaijser, J Carvalho, R Husicka, A Smith, C Stalder, M C Blanco, G Ettore, B Van Calster, D Timmerman & T Bourne

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Comment on: ‘Long-term impact of liver function on curative therapy for hepatocellular carcinoma: application of the ALBI grade’

Comment on: 'Long-term impact of liver function on curative therapy for hepatocellular carcinoma: application of the ALBI grade'

British Journal of Cancer 115, e5 (23 August 2016). doi:10.1038/bjc.2016.196

Authors: Alessandro Cucchetti, Matteo Cescon & Antonio Daniele Pinna

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