Segmental distribution of some common molecular markers for colorectal cancer (CRC): influencing factors and potential implications

Abstract

Proximal and distal colorectal cancers (CRCs) are regarded as distinct disease entities, evolving through different genetic pathways and showing multiple clinicopathological and molecular differences. Segmental distribution of some common markers (e.g., KRAS, EGFR, Ki-67, Bcl-2, COX-2) is clinically important, potentially affecting their prognostic or predictive value. However, this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events, associations of some markers with other clinicopathological features (stage and/or grade), and wide methodological variability in markers' assessment. All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers, whereas the role of other potential influences (e.g., pre-adjuvant treatment, interaction between markers) remains rather unclear. Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC, potentially allowing the application of a novel patient stratification for treatment, based on particular molecular profiles in combination with tumor location.

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The interaction of hepatoma-derived growth factor and β-catenin promotes tumorigenesis of synovial sarcoma

Abstract

To clarify the clinicopathological and biological role of hepatoma-derived growth factor (HDGF) and β-catenin in synovial sarcoma. Our results showed that histological type and HDGF/β-catenin expression were the two important independent prognostic factors for overall survival in synovial sarcoma patients. HDGF knockdown dramatically inhibited cellular proliferation, colony formation, and migration but induced G1 phase arrest and apoptosis in SW982 cells. Recombinant HDGF enhanced synovial sarcoma cell growth and partially retrieved the cell growth suppression in SW982 cells upon HDGF knockdown. HDGF knockdown dramatically suppressed β-catenin and its downstream gene expression in SW982 cells. Intriguingly, β-catenin knockdown dramatically suppressed HDGF expression in SW982 cells. A direct interaction of HDGF and β-catenin was found in SW982 cells. Three HDGF-binding elements in β-catenin promoter were found and specific for transcriptional activation of β-catenin in SW982 cells. In conclusion, our findings first indicate that the interaction of HDGF and β-catenin may play a crucial role in tumorigenesis of synovial sarcoma.

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John Hunter and the origin of the term “angiogenesis”

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Oncoplastic Breast-Conserving Surgery for Tumors Larger than 2 Centimeters: Is it Oncologically Safe? A Matched-Cohort Analysis

Abstract

Background

Oncoplastic surgery is a well-established approach that combines conserving treatment for breast cancer and plastic surgery techniques. Although this approach has been described for T2 tumors, no long-term oncologic follow-up and no comparison with patients undergoing mastectomy has been published. The purpose of the study was to demonstrate that oncoplastic surgery is a safe and reliable treatment for managing invasive primary T2 breast cancer.

Methods

We compared a consecutive series of 193 T2 patients who have undergone oncoplastic surgery (study group) with 386 T2 patients who have undergone mastectomy (control group). The endpoints evaluated were disease-free survival (DFS), overall survival (OS), cumulative incidence of local recurrence (CI-L), regional recurrence (CI-R), and distant recurrence (CI-D), all measured from the date of surgery.

Results

Median follow-up is 7.4 years. The OS is similar within the two groups: 87.3 and 87.1 % at 10 years in the ONC group and control group, respectively (p value, adjusted for multifocality and tumor size, 0.74). Also, the DFS is similar in both groups: 60.9 and 56.3 % at 10 years in the ONC group and control group, respectively. The incidence of local events is slightly higher in the oncoplastic group, whereas the incidence of regional events is slightly higher in the mastectomy group. These differences are not statistically significant. The cumulative incidence of distant events is similar within the two groups.

Conclusions

To our knowledge, the present study provides the best available evidence to suggest that oncoplastic approach is a safe and reliable treatment for managing invasive pT2 breast cancers.

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Local Recurrence in the Lateral Lymph Node Compartment: Improved Outcomes with Induction Chemotherapy Combined with Multimodality Treatment

Abstract

Background

Lateral nodal disease is of major importance in the treatment of rectal cancer in the East, but a mostly neglected entity in the West. In this article, the treatment of recurrences in the lateral compartment (latLRs) in a national tertiary referral center is evaluated.

Methods

Of 214 patients with locally recurrent rectal cancer who underwent multimodality treatment in the Catharina Hospital in the last 10 years, a total of 51 patients with latLR were selected (the latLR region was classified as upper, middle, or lower). Thirteen (25 %) of these patients underwent induction chemotherapy (ICT) prior to chemo(re)irradiation.

Results

LatLRs occurred mainly after low and N+ primary tumors. Seven (14 %) patients had a complete response (pCR) and 28 (55 %) underwent an R0 resection. Patients with a lower latLR had the highest chance of undergoing an abdominoperineal resection and resection of anterior organs. ICT resulted in a 31 % pCR rate compared with 8 % without ICT (p = 0.039). Patients who received ICT had an 85 % R0 resection rate, while this was 45 % in patients who did not receive ICT (p = 0.013). The 5-year local re-recurrence (LRR) rate was 64.3 %, and overall survival (OS) was 34.2 %; the only factor improving these was an R0 resection. Five-year survival after multivariate analyses was 10.3 % after an R+ resection compared with 66.8 % after an R0 resection (p = 0.011).

Conclusions

LatLRs impose a major surgical challenge and result in high LRR and low OS. More R0 resections can possibly be achieved with ICT, which is the only factor that can improve LRR and OS.

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Minor Components of Micropapillary and Solid Subtypes in Lung Adenocarcinoma are Predictors of Lymph Node Metastasis and Poor Prognosis

Abstract

Background

Lung adenocarcinoma with micropapillary and solid predominant subtypes was reported to be associated with poor prognosis; however, whether minor components (non-predominant) of micropapillary and solid subtypes predict poor prognosis remains unknown. In this study, we investigated the predictive and prognostic value of lymph node metastasis of minor micropapillary and solid components.

Methods

Specimens of resected tumors of 1244 patients were reclassified to determine the predominant subtype and minor components (>5 %, but not predominant). Of these specimens, 105 contained a micropapillary component and 210 contained a solid component. The correlation between each subtype and lymph node metastasis was analyzed, and survival analyses were used to determine the association between each subtype and patient survival.

Results

Adenocarcinomas harboring micropapillary and/or solid components held higher rates of metastatic lymph node stations (25.2 % vs. 15.6 %, p = 0.002; and 24.0 % vs. 14.9 %, p < 0.001, respectively) and lymph nodes (17.3 % vs. 10.1 %, p = 0.004; and 15.5 % vs. 9.7 %, p = 0.001, respectively). Patients with micropapillary and solid components in their tumors showed a shorter median recurrence-free survival (15.8 vs. 62.8 months, p < 0.001; and 20.8 months vs. not reached, p < 0.001) and overall survival (47.0 months vs. not reached, p < 0.001; and 69.0 months vs. not reached, p < 0.001).

Conclusions

Minor components of micropapillary and/or solid subtypes of lung adenocarcinoma are correlated with lymph node metastasis and poor prognosis. Thus, it is beneficial to focus not only on predominant subtypes but also minor components to predict prognoses and make therapeutic strategies more comprehensively.

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In Vivo Feasibility of Electrostatic Precipitation as an Adjunct to Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC)

Abstract

Background

Intraperitoneal chemotherapy is limited by tissue penetration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve drug uptake by utilizing the physical properties of gas and pressure. This study investigated the effect of adding electrostatic precipitation to further enhance the pharmacologic properties of this technique.

Methods

A comparative study was performed using an in vivo porcine model. There were 3 cases in each group, PIPAC and electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC), plus 1 negative control comparing intraperitoneal distribution and tissue uptake of 2 tracer substances (toluidine blue and DT01). Tracer uptake was determined by measuring DT01 in tissue and peritoneal fluid at the end of each procedure.

Results

Electrostatic precipitation of the aerosol was technically feasible in all ePIPAC animals. The aerosol was cleared completely from the visual field within 15 s in the ePIPAC group versus 30 min in the PIPAC group. The peritoneal surface was homogeneously stained in both groups. After 30 min, 1.5 % remaining DT01 was measured in samples of ePIPAC-treated peritoneal fluid versus 15 % in PIPAC animals (p = 0.01). Tissue concentration was increased after ePIPAC versus PIPAC (p = 0.06).

Conclusions

ePIPAC is technically feasible and improves tissue uptake of 2 tracer substances compared to PIPAC by up to tenfold. Intraperitoneal distribution was homogeneous in both groups. ePIPAC has the potential to allow more efficient drug uptake, further dose reduction, a significant shortening of the time required for PIPAC application, and improved health and safety measures.

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Using Multilevel Models to Explain Variation in Clinical Practice: Surgeon Volume and the Surgical Treatment of Breast Cancer

Abstract

Purpose

To investigate the relationship between surgeon caseload and surgery type, and variation in the surgical treatment of early stage breast cancer patients in Alberta, Canada.

Methods

All women diagnosed with stage I to III breast cancer in Alberta from 2002 to 2010 were identified from the Alberta Cancer Registry. Type of surgery, surgeon (anonymized), and hospital were obtained from provincial physician claims data. Multilevel logistic regression with surgeons and hospitals as crossed random effects was used to estimate adjusted odds ratios (OR) of receiving mastectomy by surgeon volume. Empirical Bayes estimation was used to estimate adjusted OR for individual surgeons and hospitals.

Results

Mastectomy was found to be inversely related to surgeon volume among stage I and II patients. Patients whose surgery was conducted by a low-volume surgeon had twice the odds of receiving mastectomy as those that had surgery performed by a very high-volume surgeon (stage I OR 2.36, 95 % confidence interval 1.40, 3.97; stage II OR 1.96, 95 % confidence interval 1.13, 3.42). OR of mastectomy varied widely by individual surgeon beyond the variation explained by the factors investigated.

Conclusions

Surgeon characteristics, including surgeon volume, are associated with surgery type received by breast cancer patients in Alberta. Significant variation in the likelihood of breast-conserving surgery (BCS) by surgeon is concerning given the potential benefits of BCS for those who are eligible.

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Factors Associated with Readmission After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis

Abstract

Purpose

Cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for peritoneal carcinomatosis is a morbid endeavor. Despite improvement in perioperative management of these patients, there are subsets of patients requiring hospital readmission after discharge. We sought to identify variables associated with readmission rates for CRS/HIPEC.

Methods

We conducted a retrospective review of CRS/HIPEC cases at the University of Cincinnati between 1999 and 2014. Patient-, tumor-, and treatment-specific characteristics were evaluated. The association between patient- and outcome-specific variables for 30- and 90-day readmission were evaluated.

Results

Of 215 CRS/HIPEC patients, the 7-, 30-, and 90-day readmission rates were 9.8 % (n = 21), 14.9 % (n = 32), and 21.4 % (n = 46), respectively. The most common reasons for readmission within 90 days included abdominal pain (n = 14), intra-abdominal abscess (n = 9), malnutrition/failure to thrive (n = 8), and bowel obstruction (n = 7). The primary factor associated with readmission at all time points (7, 30, and 90 days) was the presence of an enterocutaneous fistula (p < 0.01). Six patients (2.8 %) had multiple readmissions; 3 of these had ECF. Factors not associated with higher admission rates included sex, age, race, operative blood loss, pancreatectomy or liver resection at the index operation, and postoperative complications of wound infection, line infection, and thromboembolic events.

Conclusions

In patients undergoing CRS/HIPEC, readmission was primarily associated with poor pain control, malnutrition, and infectious complications. Patients with enterocutaneous fistula were also disproportionately readmitted multiple times. These data should inform clinicians about patients at high risk for readmission after CRS/HIPEC and encourage more comprehensive coordination of postdischarge planning and care for specific patient populations.

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Advances in HSP27 and HSP90-targeting strategies for glioblastoma

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. There is a critical need for novel strategies to abolish the molecular mechanisms that support GBM growth, invasion and treatment resistance. The heat shock proteins, HSP27 and HSP90, serve these pivotal roles in tumor cells and have been identified as effective targets for developing therapeutics. Natural and synthetic inhibitors have been evaluated in clinical trials for several forms of systemic cancer but none as yet for GBM. This topic review summarizes the current preclinical evidence and rationale to define the potential of HSP27 and HSP90 inhibitors in GBM management.

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Craniospinal irradiation with concomitant and adjuvant temozolomide—a feasibility assessment of toxicity in patients with glioblastoma with a PNET component

Abstract

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35–40 Gy in 20–24 daily fractions with a focal boost to the tumour of 14–23.4 Gy in 8–13 daily fractions. Concurrent TMZ was administered at 75 mg/m² for seven of the cohort, with the other patient receiving 50 mg/m². The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.

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Pharmacokinetics, Pharmacodynamics, and Safety of MEDI4212, an Anti-IgE Monoclonal Antibody, in Subjects with Atopy: A Phase I Study

Abstract

Introduction

The anti-IgE therapy omalizumab is currently licensed for the treatment of moderate to severe allergic asthma and chronic idiopathic urticaria. Owing to limitations in the use of omalizumab, a need exists for optimized anti-IgE therapies to broaden clinical indications and patient populations, and to improve dosing schedules. The objective of this phase I, randomized, placebo/omalizumab-controlled, first-in-human, dose-escalation study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of the high-affinity, anti-IgE therapy MEDI4212 in non-Japanese and Japanese subjects with atopy and/or diagnostic IgE ≥30 IU/mL.

Methods

Subjects with atopy and/or baseline IgE ≥30 IU/mL were randomized to a single dose of subcutaneous (5, 15, 60, 150, or 300 mg) or intravenous (300 mg) MEDI4212, subcutaneous omalizumab, or placebo. Following administration, pharmacokinetic, pharmacodynamic [IgE (free and total), and cellular FcεRI expression], and safety assessments were made.

Results

MEDI4212 rapidly suppressed free serum IgE to a greater extent than omalizumab; however, recovery of free IgE to baseline in MEDI4212-dosed subjects was rapid when compared with the slow and gradual recovery seen in omalizumab-dosed individuals. The loss of IgE suppression corresponded with a rapid decrease of serum MEDI4212. FcεRI expression on dendritic cells and basophils was reduced following MEDI4212 dosing. MEDI4212 was well tolerated by subjects; adverse events were generally of low severity and no subjects discontinued due to adverse events.

Conclusions

The increased potency of MEDI4212 may be of clinical interest for individuals with high-diagnostic IgE levels where more extensive IgE suppression is required for clinical response. However, the modest duration of free IgE suppression below the target concentration noted with MEDI4212 in this study suggests limited potential for dosing schedule advantages over omalizumab.

Funding

MedImmune.

Trial registration

ClinicalTrials.gov identifier, NCT01544348.

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The role and regulatory mechanism of IL-1β on the methylation of the NF2 gene in benign meningiomas and leptomeninges

Methylation of the neurofibromatosis type 2 (NF2) gene in low-grade meningioma (WHO grade I) has crucial roles in tumorigenesis and development. Meningioma formation might also occur in the setting of an inflammatory microenvironment. However, the association between inflammation and the methylation of NF2 remains unclear. The present study investigates the role and regulatory mechanism of IL-1β, one of the most important pro-inflammatory cytokines, in the methylation of NF2 in benign meningioma. Three primary low-grade meningioma cells and leptomeningeal cells were cultured. CCK-8 and BrdU assays demonstrated that proliferation of meningioma/leptomeningeal cells treated with IL-1β occurred in a dose- and time-dependent manner. Methylation-specific PCR verified that IL-1β induced methylation of the NF2 promoter and decreased NF2/merlin expression in meningioma/leptomeningeal cells. Real-time PCR, western blotting, and immunofluorescence showed that IL-1β up-regulated DNMT1 in meningioma cells and DNMT1/3b in leptomeningeal cells but did not up-regulate DNMT3a. After co-treatment with the DNMT inhibitor 5-Aza-2′-deoxycytidine and DNMT siRNA, methylation of NF2 induced by IL-1β was attenuated and merlin expression was restored. Furthermore, we showed that DNMT1 in meningiomas and DNMT1/3b in leptomeninges were regulated via activation of the MAPK (p38, ERK, JNK) and NF-κB pathways. These results suggest that IL-1β induces methylation of NF2 by up-regulating DNMT1 in benign meningioma cells and DNMT1/3b in leptomeningeal cells via MAPK and NF-κB pathways. Therefore, NF2 methylation is a linker between IL-1β and tumor development, and DNMTs might be potential therapeutic targets in meningioma for regulating NF2 and inhibiting tumor development. © 2016 Wiley Periodicals, Inc.

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Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone-rich Kava fraction

Kava (Piper methysticum Forster) extract and its major kavalactones have been shown to block chemically induced lung tumor initiation in mouse models. Here we evaluated the chemopreventive effect of a kavalactone-rich Kava fraction B (KFB), free of flavokavains, on carcinogenesis in a transgenic adenocarcinoma of mouse prostate (TRAMP) model and characterized the prostate gene expression signatures. Male C57BL/6 TRAMP mice were fed AIN93M diet with or without 0.4% KFB from 8 wk of age. Mice were euthanized at 16 or 28 wk. The growth of the dorsolateral prostate (DLP) lobes in KFB-treated TRAMP mice was inhibited by 66% and 58% at the respective endpoint. Anterior and ventral prostate lobes in KFB-treated TRAMP mice were suppressed by 40% and 49% at 28 wk, respectively. KFB consumption decreased cell proliferation biomarker Ki-67 and epithelial lesion severity in TRAMP DLP, without detectable apoptosis enhancement. Real time qRT-PCR detection of mRNA from DLP at 28 wk showed decreased expression of cell cycle regulatory genes congruent with Ki-67 suppression. Microarray profiling of DLP mRNA indicated that "oncogene-like" genes related to angiogenesis and cell proliferation were suppressed by KFB but tumor suppressor, immunity, muscle/neuro, and metabolism-related genes were upregulated by KFB in both TRAMP and WT DLP. TRAMP mice fed KFB diet developed lower incidence of neuroendocrine carcinomas (NECa) (2 out of 14 mice) than those fed the basal diet (8 out of 14 mice, χ² = 5.6, P < 0.025). KFB may, therefore, inhibit not only TRAMP DLP epithelial lesions involving multiple molecular pathways, but also NECa. © 2016 Wiley Periodicals, Inc.

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Associations of microbiota and toll-like receptor signaling pathway in esophageal adenocarcinoma

Abstract

Background

Toll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis. Using a rat model of esophageal adenocarcinoma, and human clinical samples, we investigated genes central to TLR-mediated signal transduction and characterized the esophageal microbiome across the spectrum of esophageal adenocarcinoma carcinogenesis.

Methods

We surgically induced bile/acid reflux in rats and their esophagi were harvested at 40 weeks post-surgery. Tissue samples from the model were selected for gene expression profiling. Additionally, for rat and human samples microbiome analysis was performed using PCR-ESI-MS-TOF technology with validation by fluorescence in situ hybridization.

Results

Gene expression results in the rat model indicated a significant upregulation of TLRs 1-3, 6, 7 and 9 in EAC compared to normal epithelium. PCR-ESI-MS-TOF analysis revealed a prevalence of Escherichia coli in Barrett's esophagus (60 %) and esophageal adenocarcinoma (100 %), which was validated by fluorescence in situ hybridization. In the human clinical samples, Streptococcus pneumonia was detected in high abundance in gastroesophageal reflux disease and Barrett's esophagus (50–70 %) in comparison to tumor adjacent normal epithelium, dysplasia, and esophageal adenocarcinoma (20–30 %). E. coli was detected in the Barrett's esophagus and esophageal adenocarcinoma groups but was absent in the tumor adjacent normal epithelium, dysplasia, and the gastroesophageal reflux disease groups.

Conclusions

We demonstrated an association between the TLR signaling pathway and E. coli hinting towards possible early molecular changes being mediated by microbes in the rat model of esophageal adenocarcinoma carcinogenesis. Studies on human clinical samples also corroborate results to some extent; however, a study with larger sample size is needed to further explore this association.

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Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland

Abstract

Background

Mutations in the BRCA1, BRCA2 and PALB2 genes are well-established risk factors for the development of breast and/or ovarian cancer. The frequency and spectrum of mutations in these genes has not yet been examined in the population of Southern Poland.

Methods

We examined the entire coding sequences of the BRCA1 and BRCA2 genes and genotyped a recurrent mutation of the PALB2 gene (c.509_510delGA) in 121 women with familial and/or early-onset breast or ovarian cancer from Southern Poland.

Results

A BRCA1 mutation was identified in 11 of 121 patients (9.1 %) and a BRCA2 mutation was identified in 10 of 121 patients (8.3 %). Two founder mutations of BRCA1 accounted for 91 % of all BRCA1 mutation carriers (c.5266dupC was identified in six patients and c.181 T > G was identified in four patients). Three of the seven different BRCA2 mutations were detected in two patients each (c.9371A > T, c.9403delC and c.1310_1313delAAGA). Three mutations have not been previously reported in the Polish population (BRCA1 c.3531delT, BRCA2 c.1310_1313delAAGA and BRCA2 c.9027delT). The recurrent PALB2 mutation c.509_510delGA was identified in two patients (1.7 %).

Conclusions

The standard panel of BRCA1 founder mutations is sufficiently sensitive for the identification of BRCA1 mutation carriers in Southern Poland. The BRCA2 mutations c.9371A > T and c.9403delC as well as the PALB2 mutation c.509_510delGA should be included in the testing panel for this population.

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Advances in HSP27 and HSP90-targeting strategies for glioblastoma

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. There is a critical need for novel strategies to abolish the molecular mechanisms that support GBM growth, invasion and treatment resistance. The heat shock proteins, HSP27 and HSP90, serve these pivotal roles in tumor cells and have been identified as effective targets for developing therapeutics. Natural and synthetic inhibitors have been evaluated in clinical trials for several forms of systemic cancer but none as yet for GBM. This topic review summarizes the current preclinical evidence and rationale to define the potential of HSP27 and HSP90 inhibitors in GBM management.

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Craniospinal irradiation with concomitant and adjuvant temozolomide—a feasibility assessment of toxicity in patients with glioblastoma with a PNET component

Abstract

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35–40 Gy in 20–24 daily fractions with a focal boost to the tumour of 14–23.4 Gy in 8–13 daily fractions. Concurrent TMZ was administered at 75 mg/m² for seven of the cohort, with the other patient receiving 50 mg/m². The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.

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Long-Term Extracorporeal Membrane Oxygenation as Bridging Strategies to Lung Transplantation in Rapidly Devastating Isolated Langerhans Cell Histiocytosis

Isolated pulmonary involvement in pediatric Langerhans cell histiocytosis (LCH) is extremely rare. While the multisystem-LCH course varies from spontaneous remission to rapid deterioration with lethal outcome, single system involvement is generally associated with favorable prognosis. A child with isolated pulmonary LCH had an extremely rapid progression leading to respiratory failure, despite treatment with prednisone and vinblastine. Since lung hyperinflation and cystic degeneration contraindicated conventional mechanical ventilation, extracorporeal membrane oxygenation (ECMO) was chosen for 50 days as a bridge to lung transplantation. The mechanisms involved in disease progression and the usefulness of long-term ECMO are discussed.

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Novel PTCH1 Mutation in a Young Child With Gorlin Syndrome and Medulloblastoma

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Preventing Infections in Sickle Cell Disease: The Unfinished Business

While encapsulated bacterial agents, particularly Streptococcus pneumoniae, are recognized as important microbes that are associated with serious illness in hosts with sickle cell disease (SCD), multiple pathogens are implicated in infectious manifestations of SCD. Variations in clinical practice have been an obstacle to the universal implementation of infection preventive management through active, targeted vaccination of these individuals and routine usage of antibiotic prophylaxis. Paradoxically, in low-income settings, there is evidence that SCD also increases the risk for several other infections that warrant additional infection preventive measures. The infection preventive care among patients with SCD in developed countries does not easily translate to the adoption of these recommendations globally, which must take into account the local epidemiology of infections, available vaccines and population-specific vaccine efficacy, environment, health care behaviors, and cultural beliefs, as these are all factors that play a complex role in the manifestation of SCD and the prevention of infectious disease morbidity.

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Glucose-6-Phosphate Dehydrogenase Deficiency in Brazilian Children With Sickle Cell Anemia is not Associated With Clinical Ischemic Stroke or High-Risk Transcranial Doppler

Background

Stroke is a severe complication of sickle cell anemia (SCA). The role of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the development of stroke in children with SCA is controversial.

Procedure

The aim of this study was to investigate the association of clinical ischemic stroke, high-risk transcranial Doppler measurements (TCD), and hematological features with molecular variants usually linked to G6PD deficiency or with the biochemical activity of G6PD in a cohort of 395 Brazilian children with SCA. G6PD activity was quantitatively determined using an enzymatic-colorimetric assay. G6PD mutations were determined by PCR-RFLP and sequencing. Clinical and hematological data were retrieved from the children's records.

Results

The prevalence of molecularly defined deficiency (hereafter, molecular deficiency) was 4.3% (95% confidence interval: 2.3–6.3%). The mean G6PD activity was 16.88 U/g hemoglobin (Hb) (standard error of the mean [SEM] 0.28) in the group without G6PD molecular deficiency and 8.43 (SEM 1.01) U/g Hb in the group with G6PD A⁻ molecular deficiency. G6PD molecular deficiency was not associated with any hematological features. No effects of G6PD molecular deficiency on clinical ischemic stroke or high-risk TCD were detected. The mean G6PD activity was similar in children who had clinical ischemic stroke and in those without stroke. Similar results were obtained in analyses comparing children who had high-risk TCD and those without high-risk TCD.

Conclusions

Our study demonstrated that G6PD molecular deficiency was not associated either with clinical ischemic stroke or high-risk TCD. Similarly, we found no associations between G6PD enzyme activity and stroke or high-risk TCD. Small sample size precludes definitive conclusions.

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Indication of Mild Hemolytic Reaction Among Preterm Infants With ABO Incompatibility

Background

Among term infants, ABO incompatibility is a leading cause of hemolytic disease and neonatal jaundice. With respect to preterm infants, data are lacking.

Objective

To evaluate the incidence and severity of ABO incompatibility hemolytic disease among preterm infants with respect to hemolytic and jaundice parameters.

Design

Clinical and laboratory data were collected retrospectively from the medical records of 118 ABO-incompatible preterms born at gestational age (GA) 29–34 weeks, as well as 118 controls matched for GA, birth weight, and multiplicity. All infants were born at the Sheba Medical Center Tel-Hashomer between 2009 and 2012.

Results

The study and control groups were similar on all maternal and neonatal outcome parameters. No differences between the groups were recorded throughout hospitalization regarding hematocrit levels or the need for blood transfusion. Bilirubin levels were higher among the study (ABO-incompatible) group during the first 10 days of life; however, no significant differences were found regarding the need for phototherapy. Upon evaluating subgroups divided by GA, we found no differences on any hematological and jaundice factors among preterms of 29–31 weeks, whereas among preterms of 32–34 weeks higher positive direct antiglobulin test (DAT) results (7% vs. 0% in the control, P = 0.014) as well as higher bilirubin levels were documented.

Conclusions

Among ABO-incompatible preterm infants with GA 29–34 weeks, there is no evidence of significant hemolytic reaction derived from placental transfer of antibodies. With increasing GA, antibody transfer becomes more significant, resulting in more positive DAT results and greater incidence of neonatal jaundice.

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Frequent Emergency Department Utilizers Among Children with Cancer

Background

Pediatric frequent emergency department (ED) utilizers contribute a significant proportion of ED visits, but no studies specifically address children with cancer.

Methods

A retrospective study of Pediatric Health Information System analyzing ED visits for children with cancer, including ED visits within 365 days from the first inpatient encounter with a discharge diagnosis code for malignancy. We defined frequent ED utilizers as those with four or more visits in the year (top 10th percentile). Patient characteristics and ED services (medications, laboratory, or imaging) for discharged children were assessed. Factors associated with being a frequent ED utilizer were examined with multivariable regression.

Results

Frequent utilizers accounted for 58% of ED visits. Frequent utilizers differed from infrequent utilizers in terms of type of cancer; 39.3% of frequent utilizers had acute lymphoblastic leukemia (ALL) and 16.0% had central nervous system (CNS) tumors compared with infrequent utilizers (21.9% had ALL and 24.8% CNS tumors, P-value < 0.001). Frequent utilization was associated with age 5–9 years (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.2–1.6) or 1–4 years (OR = 2.1, 95% CI 1.8–2.4) or <1 year (OR = 2.2, 95% CI 1.9–2.6) compared to 15–19 years and Hispanic ethnicity (OR 1.3, 95% CI 1.1–1.5) compared to white, non-Hispanics, and urban residence (OR = 1.5, 95% CI 1.3–1.7). Few children with cancer received no medication, laboratory, or imaging during their ED visit (frequent 11.0% vs. infrequent 12.5%, P = 0.01).

Conclusions

The ED is integral to the care provided to children with cancer. The subset of frequent utilizers should be the focus of future research and quality improvement efforts.

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Reply: The Optimal Dose of Hypofractionated Radiotherapy in Diffuse Intrinsic Pontine Glioma (DIPG)

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MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1)

The importance of individual microRNAs (miRNAs) in tumor has been established in different cancers. However, their association with tumor chemoresistance has not been fully understood. Previously, we found two...

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[Biosimilar drugs in oncology].

Related Articles

[Biosimilar drugs in oncology].

Bull Cancer. 2016 Jan 29;

Authors: Levêque D

Abstract
Biosimilar drugs are biologic drugs clinically similar to the reference products. They correspond to a generic approach applied to biologic agents. Biosimilars are aimed to provide cheaper drugs by enhancing the concurrency. The approval of biosimilars is abbreviated when compared to that of the reference biologics but includes clinical trials (distinguishing them from the generics). Current available biosimilars in oncology are filgrastim and epoietin alpha. In the next future, will be launched rituximab and trastuzumab. In France, the development of biosimilars is faced with many hurdles that necessitates a better information of physicians and a greater price discount in the out-patient setting. More globally, harmonisation of recommendations particularly concerning extrapolation of indications and nomenclature are needed for a better acceptance.

PMID: 26832422 [PubMed - as supplied by publisher]

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[Impact of driving restrictions disclosure on quality of life of patients with a glial tumor: A prospective study].

Related Articles

[Impact of driving restrictions disclosure on quality of life of patients with a glial tumor: A prospective study].

Bull Cancer. 2016 Jan 29;

Authors: Bergot L, Cuchard S, Mazeaud S, Magro E, Seizeur R

Abstract
INTRODUCTION: Disclosure of driving restrictions on patients with glial tumors is a complex and difficult task. The difficulty of such task lies in the moral and ethical conflicts it generates for the patient on one hand and caregivers on the other. These aforementioned conflicts impinge upon the patient's quality of life which is one of the important aspects of neuro-oncologic care.
PATIENTS AND METHOD: In a prospective survey of 31 patients diagnosed with glial tumors, we studied how the patient perceived the disclosure of driving restrictions specifically the amount of retained information, and the level of distress.
RESULTS: It seems that patients fail to assess the juridical implications of driving restrictions. The impact on quality of life as well as psychological and social aspects of these restrictions must not be taken lightly especially in young patients with low-grade glioma who has a long life expectancy.
CONCLUSION: Therefore, we believe that planning a specific psychological and social accompaniment of the patient in relation to driving restrictions is an undeniable necessity.

PMID: 26832421 [PubMed - as supplied by publisher]

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[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management].

Related Articles

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management].

Bull Cancer. 2016 Jan 29;

Authors: Bretagne M, Boudou-Rouquette P, Huillard O, Thomas-Schoemann A, Chahwakilian A, Orvoen G, Arrondeau J, Tlemsani C, Cessot A, Cabanes L, Blanchet B, Coriat R, Alexandre J, Goldwasser F

Abstract
Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

PMID: 26832420 [PubMed - as supplied by publisher]

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[A point on a new year].

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[A point on a new year].

Bull Cancer. 2016 Jan;103(1):1-2

Authors: Bay JO, L'Allemain G, Massard C, Vignot S, Comité de rédaction

PMID: 26831268 [PubMed - in process]

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Trends in UK regional cancer mortality 1991–2007

Trends in UK regional cancer mortality 1991–2007

British Journal of Cancer 114, 340 (02 February 2016). doi:10.1038/bjc.2015.428

Authors: Dominic C Marshall, Thomas E Webb, Richard A Hall, Justin D Salciccioli, Raghib Ali & Mahiben Maruthappu

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Relation of statin use with non-melanoma skin cancer: prospective results from the Women’s Health Initiative

Relation of statin use with non-melanoma skin cancer: prospective results from the Women's Health Initiative

British Journal of Cancer 114, 314 (02 February 2016). doi:10.1038/bjc.2015.376

Authors: Ange Wang, Marcia L Stefanick, Kristopher Kapphahn, Haley Hedlin, Manisha Desai, Jo Ann E Manson, Howard Strickler, Lisa Martin, Jean Wactawski-Wende, Michael Simon & Jean Y Tang

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Bone marrow micrometastases in early breast cancer–30-year outcome

Bone marrow micrometastases in early breast cancer–30-year outcome

British Journal of Cancer 114, 243 (02 February 2016). doi:10.1038/bjc.2015.447

Authors: J Mansi, J Morden, J M Bliss, M Neville & R C Coombes

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Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers

Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers

British Journal of Cancer 114, 298 (02 February 2016). doi:10.1038/bjc.2015.437

Authors: Hyuna Sung, Montserrat Garcia-Closas, Jenny Chang-Claude, Fiona M Blows, H Raza Ali, Jonine Figueroa, Heli Nevanlinna, Rainer Fagerholm, Päivi Heikkilä, Carl Blomqvist, Graham G Giles, Roger L Milne, Melissa C Southey, Catriona McLean, Arto Mannermaa, Veli-Matti Kosma, Vesa Kataja, Reijo Sironen, Fergus J Couch, Janet E Olson, Emily Hallberg, Curtis Olswold, Angela Cox, Simon S Cross, Peter Kraft, Rulla M Tamimi, A Heather Eliassen, Marjanka K Schmidt, Manjeet K Bolla, Qin Wang, Douglas Easton, William J Howat, Penny Coulson, Paul DP Pharoah, Mark E Sherman & Xiaohong R Yang

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Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-α-negative breast cancer

Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-α-negative breast cancer

British Journal of Cancer 114, 248 (02 February 2016). doi:10.1038/bjc.2015.464

Authors: Erik Hilborn, Jelena Gacic, Tommy Fornander, Bo Nordenskjöld, Olle Stål & Agneta Jansson

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Factors associated with completion of bowel cancer screening and the potential effects of simplifying the screening test algorithm

Factors associated with completion of bowel cancer screening and the potential effects of simplifying the screening test algorithm

British Journal of Cancer 114, 327 (02 February 2016). doi:10.1038/bjc.2015.469

Authors: Benjamin Kearns, Sophie Whyte, Helen E Seaman, Julia Snowball, Stephen P Halloran, Piers Butler, Julietta Patnick, Claire Nickerson & Jim Chilcott

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Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma

British Journal of Cancer 114, 256 (02 February 2016). doi:10.1038/bjc.2015.467

Authors: S Diem, B Kasenda, L Spain, J Martin-Liberal, R Marconcini, M Gore & J Larkin

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Epidemiologic studies of the human microbiome and cancer

Epidemiologic studies of the human microbiome and cancer

British Journal of Cancer 114, 237 (02 February 2016). doi:10.1038/bjc.2015.465

Authors: Emily Vogtmann & James J Goedert

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Phase I trial outcomes in older patients with advanced solid tumours

Phase I trial outcomes in older patients with advanced solid tumours

British Journal of Cancer 114, 262 (02 February 2016). doi:10.1038/bjc.2015.477

Authors: K H Khan, T A Yap, A Ring, L R Molife, S Bodla, K Thomas, A Zivi, A Smith, I Judson, U Banerji, J S de Bono & S B Kaye

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Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway

Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway

British Journal of Cancer 114, 305 (02 February 2016). doi:10.1038/bjc.2015.444

Authors: W Wang, H Chen, Z Liu, P Qu, J Lan, H Chen, L Zou & J Qiu

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Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer

Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer

British Journal of Cancer 114, 269 (02 February 2016). doi:10.1038/bjc.2015.478

Authors: Srinivasa P Pothula, Zhihong Xu, David Goldstein, Andrew V Biankin, Romano C Pirola, Jeremy S Wilson & Minoti V Apte

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Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening

Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening

British Journal of Cancer 114, 321 (02 February 2016). doi:10.1038/bjc.2015.413

Authors: Rosalind Raine, Stephen W Duffy, Jane Wardle, Francesca Solmi, Stephen Morris, Rosemary Howe, Ines Kralj-Hans, Julia Snowball, Nicholas Counsell, Sue Moss, Allan Hackshaw, Christian von Wagner, Gemma Vart, Lesley M McGregor, Samuel G Smith, Stephen Halloran, Graham Handley, Richard F Logan, Sandra Rainbow, Steve Smith, Mary C Thomas & Wendy Atkin

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Measuring the biological effect of presurgical metformin treatment in endometrial cancer

Measuring the biological effect of presurgical metformin treatment in endometrial cancer

British Journal of Cancer 114, 281 (02 February 2016). doi:10.1038/bjc.2015.453

Authors: V N Sivalingam, S Kitson, R McVey, C Roberts, P Pemberton, K Gilmour, S Ali, A G Renehan, H C Kitchener & E J Crosbie

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What prompts help-seeking for cancer ‘alarm’ symptoms? A primary care based survey

What prompts help-seeking for cancer 'alarm' symptoms? A primary care based survey

British Journal of Cancer 114, 334 (02 February 2016). doi:10.1038/bjc.2015.445

Authors: K L Whitaker, C Friedemann Smith, K Winstanley & J Wardle

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Prognostic and diagnostic potential of miR-146a in oesophageal squamous cell carcinoma

Prognostic and diagnostic potential of miR-146a in oesophageal squamous cell carcinoma

British Journal of Cancer 114, 290 (02 February 2016). doi:10.1038/bjc.2015.463

Authors: Cong Wang, Shanghui Guan, Fang Liu, Xuan Chen, Lihui Han, Ding Wang, Effat Un Nesa, Xintong Wang, Cihang Bao, Nana Wang & Yufeng Cheng

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Patterns of hydroxyurea use and clinical outcomes among patients with polycythemia vera in real-world clinical practice: a chart review

Abstract

Background

Hydroxyurea (HU) is among the most commonly used cytoreductive treatments for polycythemia vera (PV), but previous research and clinical experience suggest that not all patients respond optimally, consistently, or durably to HU treatment. This study investigated patterns of HU use and impact on disease control among patients with PV in real-world clinical practice in the United States.

Methods

Oncologists and hematologists recruited between April and July 2014 reported data from patient charts. Treatment history and disease symptom comparisons between HU subgroups were performed using Chi square tests or one-way analyses of variance for categorical and continuous variables. Other analyses were performed using descriptive statistics.

Results

Overall, 329 physicians participated and provided data on 1309 patients with PV (62.3 % male; mean age = 62.5 years, mean time since diagnosis = 5.2 years). In the 229 (17.5 %) patients who had stopped HU, the most common reasons for HU discontinuation—as assessed by the treating clinician—were inadequate response (29.3 %), intolerance (27.5 %), and disease progression (12.7 %). Among patients currently on HU, a significant proportion had elevated blood cell counts: 34.4 % had hematocrit values ≥45 %, 59.4 % had platelet levels >400 × 10⁹/L, and 58.2 % had WBC counts > 10 × 10⁹/L. Two-thirds (66.3 %) of patients had ≥1 elevated count, 40.3 % had ≥2 elevated counts, and 19.8 % had all 3 counts elevated. The most common PV-related signs and symptoms among all patients were fatigue and splenomegaly.

Conclusions

Although many patients with PV benefit from HU therapy, some continue to have suboptimal control of their disease, as evidenced by persistence of abnormally elevated blood cell counts and the continued experience of disease-related manifestations (signs and symptoms). These data further denote a significant medical need for some patients with PV currently or previously treated with HU.

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