A journey beyond apoptosis: new enigma of controlling metastasis by pro-apoptotic Par-4

Abstract

Prostate apoptotic response 4 (Par-4) is coined as a therapeutic protein since owing to its diverse physiologically relevant properties, especially in the cancer perspective. Albeit, Par-4 expression is not restricted to any specific tissue/organ, apart from cell death promotion (due to challenging threats), the other biological role of Par-4 is convincingly emerging. In the recent years, several laboratories have intended to dissect the signaling or mechanisms involved in Par-4 activation to augment apoptosis cascades but new developments in Par-4 research have widened its therapeutic potential. One of these important avenues is the prevention of metastasis by pro-apoptotic Par-4. In this review, we will focus on the therapeutic perspective of Par-4 with a special reference to its (Par-4) virgin prospect of devastating metastasis control.

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Methoxyflurane Analgesia in Adult Patients in the Emergency Department: A Subgroup Analysis of a Randomized, Double-blind, Placebo-controlled Study (STOP!)

Abstract

Introduction

Acute pain remains highly prevalent in the Emergency Department (ED) setting. This double-blind, randomized, placebo-controlled UK study investigated the efficacy and safety of low-dose methoxyflurane analgesia for the treatment of acute pain in the ED in the adult population of the STOP! trial.

Methods

Patients presenting to the ED requiring analgesia for acute pain (pain score of 4–7 on the Numerical Rating Scale) due to minor trauma were randomized in a 1:1 ratio to receive methoxyflurane (up to 6 mL) or placebo (normal saline), both via a Penthrox^® (Medical Developments International Limited, Scoresby, Australia) inhaler. Rescue medication (paracetamol/opioids) was available immediately upon request. Change from baseline in visual analog scale (VAS) pain intensity was the primary endpoint.

Results

300 adult and adolescent patients were randomized; data are presented for the adult subgroup (N = 204). Mean baseline VAS pain score was ~66 mm in both groups. The mean change from baseline to 5, 10, 15 and 20 min was greater for methoxyflurane (−20.7, −27.4, −33.3 and −34.8 mm, respectively) than placebo (−8.0, −11.1, −12.3 and −15.2 mm, respectively). The primary analysis showed a highly significant treatment effect overall across all four time points (−17.4 mm; 95% confidence interval: −22.3 to −12.5 mm; p < 0.0001). Median time to first pain relief was 5 min with methoxyflurane [versus 20 min with placebo; (hazard ratio: 2.32; 95% CI: 1.63, 3.30; p < 0.0001)]; 79.4% of methoxyflurane-treated patients experienced pain relief within 1–10 inhalations. 22.8% of placebo-treated patients requested rescue medication within 20 min compared with 2.0% of methoxyflurane-treated patients (p = 0.0003). Methoxyflurane treatment was rated 'Excellent', 'Very Good' or 'Good' by 77.6% of patients, 74.5% of physicians and 72.5% of nurses. Treatment-related adverse events (mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient.

Conclusion

The results of this study support the evidence from previous trials that low-dose methoxyflurane administered via the Penthrox inhaler is a well-tolerated, efficacious and rapid-acting analgesic.

Funding

Medical Developments International (MDI) Limited and Mundipharma Research GmbH & Co.KG.

Trial registration

Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

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Brain stereotactic biopsy flow cytometry for central nervous system lymphoma characterization: advantages and pitfalls

Abstract

Background

Brain stereotactic biopsy (SB) followed by conventional histopathology and immunohistochemistry (IHC) is the gold standard approach for primary central nervous system lymphoma (PCNSL) diagnosis. Flow cytometry (FCM) characterization of fine-needle aspiration cytology and core needle biopsies are increasingly utilized to diagnose lymphomas however, no biological data have been published on FCM characterization of fresh single cell suspension from PCNSL SB. The aim of this study was to establish the feasibility and utility of FCM for the diagnosis and characterization of brain lymphomas from a tissue samples obtained by a single SB disaggregation.

Methods

Twenty-nine patients with a magnetic resonance suggestive for PCNSL entered the study. A median of 6 SB were performed for each patient. A cell suspension generated from manual tissue disaggregation of a single, unfixed, brain SB, was characterized by FCM. The FCM versus standard approach was prospectively compared.

Results

FCM and IHC showed an high degree of agreement (89 %) in brain lymphoma identification. By FCM, 16 out of 18 PCNSL were identified within 2 h from biopsy. All were of B cell type, with a heterogeneous CD20 mean fluorescence intensity (MFI), CD10 positive in 3 cases (19 %) with surface Ig light chain restriction documented in 11 cases (69 %). No false positive lymphomas cases were observed. Up to 38 % of the brain leukocyte population consisted of CD8 reactive T cells, in contrast with the CD4 positive lymphocytes of the peripheral blood samples (P < 0.001). By histopathology, 18 B-PCNSL, only one CD10 positive (5 %), 1 primitive neuroectodermal tumor (PNET) and 10 gliomas were diagnosed. A median of 6 days was required for IHC diagnosis.

Conclusion

Complementary to histopathology FCM can contribute to a better characterization of PCNSL, although necrosis and previous steroid treatment can represent a pitfall of this approach. A single brain SB is a valid source for accurate FCM characterization of both lymphoma and reactive lymphocyte population, routinely applicable for antigen intensity quantification and consistently documenting an active mechanism of reactive CD8 T-lymphocytes migration in brain lymphomas. Moreover, FCM confirmed to be more sensitive than IHC for the identification of selected markers.

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Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

Cancer Biol Ther. 2016 Aug 25;:0

Authors: Miolo G, Viel A, Canzonieri V, Baresic T, Buonadonna A, Santeufemia DA, Lara DP, Corona G

Abstract
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only three cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy.

PMID: 27561088 [PubMed - as supplied by publisher]

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All-trans retinoic acid inhibits human colorectal cancer cells RKO migration via downregulating myosin light chain kinase expression through MAPK signaling pathway.

Related Articles

All-trans retinoic acid inhibits human colorectal cancer cells RKO migration via downregulating myosin light chain kinase expression through MAPK signaling pathway.

Nutr Cancer. 2016 Aug 26;:1-9

Authors: Zuo L, Yang X, Lu M, Hu R, Zhu H, Zhang S, Zhou Q, Chen F, Gui S, Wang Y

Abstract
All-trans-retinoic acid (ATRA) inhibits the invasive and metastatic potentials of various cancer cells. However, the underlying mechanism is unclear. Here, we demonstrate that ATRA inhibited colorectal cancer cells RKO (human colon adenocarcinoma cell) migration by downregulating cell movement and increasing cell adhesion. ATRA inhibited the expression and activation of myosin light chain kinase (MLCK) in RKO cells, while the expression level of MLC phosphatase (MLCP) had no change in RKO cells treated with or without ATRA. The expression and activity of MLC was also inhibited in RKO cells exposed to ATRA. Intriguingly, ATRA increased the expression of occludin messenger RNA (mRNA) and protein and its localization on cell membrane. However, ATRA did not change the expression of zonula occludens 1 (ZO-1), but increased the accumulation of ZO-1 on RKO cells membrane. ML-7, an inhibitor of MLCK, significantly inhibited RKO cell migration. Furthermore, knockdown of endogenous MLCK expression inhibited RKO migration. Mechanistically, we showed that MAPK-specific inhibitor PD98059 enhanced the inhibitory effect of ATRA on RKO migration. In contrast, phorbol 12-myristate 13-acetate (PMA) attenuated the effects of ATRA in RKO cells. Moreover, knocking down endogenous extracellular signal-regulated kinase (ERK) expression inhibited MLCK expression in the RKO cells. In conclusion, ATRA inhibits RKO migration by reducing MLCK expression via extracellular signal-regulated kinase 1/Mitogen-activated protein kinase (ERK1/MAPK) signaling pathway.

PMID: 27564600 [PubMed - as supplied by publisher]

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Increased risk of nasopharyngeal carcinoma with increasing levels of diet-associated inflammation in an Italian case-control study.

Related Articles

Increased risk of nasopharyngeal carcinoma with increasing levels of diet-associated inflammation in an Italian case-control study.

Nutr Cancer. 2016 Aug 26;:1-8

Authors: Shivappa N, Hébert JR, Zucchetto A, Montella M, Libra M, Garavello W, Rossi M, La Vecchia C, Serraino D

Abstract
PURPOSE: Components of diet can modulate inflammation and therefore may have an important role in the development of nasopharyngeal carcinoma (NPC). Little is known about the inflammatory potential of diet in relation to nasopharyngeal carcinogenesis.
METHODS: Data from an Italian multicenter case-control study conducted between 1992 and 2008 and including 198 cases with incident, histologically confirmed NPC, and 594 controls hospitalized for acute nonneoplastic diseases were used to estimate the relation between a dietary inflammatory index (DII) and the risk of NPC. The DII was computed based on the intake of selected dietary factors assessed by a validated 78-item food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) adjusted for study center, place of living, sex, age, year of interview, education, tobacco smoking, alcohol drinking, and energy intake using the residual method.
RESULTS: Subjects with higher DII scores had an increased risk of NPC, with each DII point increasing risk by nearly 20% [OR: 1.19; 95% confidence interval (CI): 1.05-1.36]. Compared to subjects in the lowest DII tertile, those in the highest tertile had >60% higher risk of NPC (OR: 1.64; 95% CI: 1.06-2.55; Ptrend = 0.04).
CONCLUSION: These results indicate that inflammatory potential of diet plays a role in NPC.

PMID: 27564524 [PubMed - as supplied by publisher]

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99mTc-3PRGD2 SPECT/CT Imaging for Monitoring Early Response of EGFR-TKIs Therapy in Patients with Advanced-Stage Lung Adenocarcinoma

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

Cancer Biol Ther. 2016 Aug 25;:0

Authors: Miolo G, Viel A, Canzonieri V, Baresic T, Buonadonna A, Santeufemia DA, Lara DP, Corona G

Abstract
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only three cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy.

PMID: 27561088 [PubMed - as supplied by publisher]

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Novel strategies to discover effective drug targets in metabolic and immune therapy for glioblastoma.

Novel strategies to discover effective drug targets in metabolic and immune therapy for glioblastoma.

Curr Cancer Drug Targets. 2016 May 12;

Authors: Wang G, Fu XL, Wang JJ, Guan R, Tang XJ

Abstract
Glioblastoma multiforme is a common primary brain tumor, which exhibits an imbalance between glioma cell growth and glucose metabolism. Recent discoveries have found the multiple pathways and downstream genes are involved in the dysregulated metabolic pathway allows tumor to start and progress, which is critical to the patients with glioblastoma associated with significant systemic and immunosuppression. Moreover, immune microenvironment is considered a major obstacle to generating an effective antitumor immune response. Therefore, identification of patient-specific tumor antigens through highly personalized approach, and effective combination with other therapeutic modalities such as molecular agents targeting tumor metabolic oncogene addiction and potent host immune modulators, which may provide targets for more effective therapeutic strategies for glioblastoma. In this review, we aim to highlight to the most recent findings regarding glucose uptake and proliferation, cell mobility and to expand our investigations and more comprehensive examine different aspects of glucose metabolism in glioblastoma, such as pentose phosphate pathway (PPP) and its enzymes, metabolic modulation of genetics and epigenetics and key metabolic regulators, importantly, tumor cell-induced glucose deprivation inhibits T-cell glycolysis and immunogenic functions. Furthermore, this review will concentrate on how to discover effective drug targets to regulate glucose metabolism in tumor and T cell growth for future glioblastoma therapies, and the challenges facing the field of metabolism in tumor immune microenviroment.

PMID: 27562399 [PubMed - as supplied by publisher]

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Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

Cancer Biol Ther. 2016 Aug 25;:0

Authors: Miolo G, Viel A, Canzonieri V, Baresic T, Buonadonna A, Santeufemia DA, Lara DP, Corona G

Abstract
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only three cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy.

PMID: 27561088 [PubMed - as supplied by publisher]

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[Academic carriers in oncology and radiotherapy: Explanations for the readers of Bulletin du Cancer].

[Academic carriers in oncology and radiotherapy: Explanations for the readers of Bulletin du Cancer].

Bull Cancer. 2016 Aug 22;

Authors: Soria JC, Bastian G, Bolotine L, Calais G, Céraline J, de Cremoux P, Espié M, Karayan-Tapon L, Laprie A, Mazeron JJ, Négrier S, Roché H

PMID: 27561824 [PubMed - as supplied by publisher]

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Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer

Summary

Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340 mg/day of pictilisib was administered in combination with CP + BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340 mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260 mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340 mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed.

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Treatment of malignant melanoma with nivolumab and vemurafenib combined with hypofractionated radiation therapy

Abstract

Management of metastatic malignant melanoma is challenging. Although several new systemic therapies for metastatic malignant melanoma have recently been developed, some patients still also require radiation therapy (RT) for palliative care. However, the safety and efficacy of combining use of novel drugs with RT remain unclear. Here, we report treating a patient with rapidly growing malignant melanoma with a programmed cell death protein 1 (PD-1) inhibitor and a BRAF inhibitor together with 60 Gy of hypofractionated RT without severe adverse effects. The tumor within the radiation field exhibited a more marked response than that outside it. A combination of RT with an anti-PD-1 antibody or a BRAF inhibitor may, therefore, be a useful and tolerable approach to treating metastatic BRAF-mutant melanoma.

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Blood-based biomarkers for monitoring antiangiogenic therapy in non-small cell lung cancer

Abstract

Tumor angiogenesis pathways have been identified as important therapeutic targets in non-small cell lung cancer. However, no biomarkers have been described as predictors of response to antiangiogenic therapy in these patients. In this study, plasma levels of VEGF, bFGF, E-selectin, and S-ICAM and gene expression profiles of peripheral blood mononuclear cells from non-small cell lung cancer patients treated with chemotherapy plus bevacizumab were analyzed before and after treatment. Values were correlated with clinicopathological characteristics and treatment response. Plasma factor levels were measured using commercially available ELISA kits. The TaqMan^® human angiogenesis array was used to investigate the effect of treatment on gene expression profiles. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis was performed for differentially expressed genes using WEB-based GEne SeT AnaLysis Toolkit. Our results suggest a benefit for patients with increased plasma levels of VEGF, E-selectin, and S-ICAM in the course of bevacizumab treatment. Also, we identified differentially expressed genes between paired blood samples from patients before and after treatment, and significantly perturbed pathways were predicted. These changes in gene expression and levels of plasma factors could be used to assess the effectiveness of antiangiogenic therapy, in addition to standard clinical and radiological evaluations.

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Evaluation of weekly paclitaxel, carboplatin, and cetuximab in head and neck cancer patients with incurable disease

Abstract

Weekly paclitaxel, carboplatin, and cetuximab (PCC) has been found to be efficacious and well-tolerated in patients with squamous cell carcinoma of the head and neck (SCCHN) with good performance status (PS) when used as induction chemotherapy. Use of PCC in incurable SCCHN in patients with poor PS or in a non-induction setting is an area which warrants further evaluation. Current recommendations for incurable disease consist of a platinum-based regimen with fluorouracil and cetuximab. Studied in patients with PS of 0 to 1, the fluorouracil-based regimens were associated with significant toxicities. Therefore, weekly PCC may offer an appealing, less toxic alternative for incurable patients with poor PS. This retrospective analysis evaluated 41 patients with very advanced or metastatic head and neck cancer who had received PCC (paclitaxel 80 mg/m², carboplatin AUC 2, and a cetuximab 400 mg/m² loading dose, followed by 250 mg/m² weekly) for up to 6 cycles between April 2008 and September 2014. Maximal response achieved and progression-free survival (PFS), as well as dose intensity and adverse effects, were evaluated. Of the 41 patients evaluated, baseline PS ranged as follows: PS of 2 (41 %), PS of 1 (54 %), and PS of 0 (5 %). Patients received 2 to 6 cycles, averaging 4 cycles. Thirty-one patients (76 %) required treatment to be held, delayed or dose reduced, most commonly for hematologic toxicities. Grades 3/4 neutropenia occurred in 16 patients (39 %), grades 1/2 neutropenia in 12 patients (29 %), with grades 3/4 thrombocytopenia in 1 patient (2 %), and grades 1/2 thrombocytopenia in 2 patients (4 %). No patients developed febrile neutropenia or required hospitalization due to treatment. Partial radiographic response occurred in 15 patients (37 %), complete radiographic response in 2 patients (5 %), stable disease in 14 patients (34 %), and progression in 8 patients (20 %). PFS ranged from 1.6 to 45 months, with a median duration of 4.6 months, and median overall survival of 5.25 months. Analysis indicates that use of weekly PCC appears to be an effective and well-tolerated treatment option for patients with incurable squamous cell carcinoma of the head and neck, specifically with PS of 0 to 2.

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Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing

Abstract

Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients.

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Animated educational video to prepare children for MRI without sedation: evaluation of the appeal and value

Abstract

Background

MRI scans can be distressing for children and often require sedation. Educating children about what to expect reduces anxiety and increases likelihood of successful non-sedated MRI scans. Multimedia tools are a popular means of education. Animated video could provide a free, accessible method of preparing children for MRI scans.

Objective

To evaluate a new animation video for preparing children for MRI, specifically for decreasing in-scanner motion and examination failure.

Materials and methods

We recruited 24 healthy children ages 5–11 years. Participants underwent pre- and post-viewing questionnaires and structured interviews. We then compared median Likert scale score changes between pre- and post-animation questions and analyzed the interview framework. Participants were filmed viewing the animation to calculate time spent looking at the screen to assess how well the video retained children's attention.

Results

There were significant improvements in median scores regarding what to expect, checking for metal and keeping still. There were no significant changes in other knowledge-based topics. There were significant improvements in median scores for anxiety-based topics. On average, children watched the screen for 98.9% of the 174-s animation.

Conclusion

The animation improved knowledge, reduced anxiety, retained attention and was enjoyed by participants. It can be accessed freely via the Internet to help prepare children ages 5–11 for having an MRI scan.

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Microarray-based identification of genes associated with cancer progression and prognosis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths. The average survival and 5-year survival rates of HCC patients still remains poor. Thus, there is an urgent need to better un...

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Brain stereotactic biopsy flow cytometry for central nervous system lymphoma characterization: advantages and pitfalls

Brain stereotactic biopsy (SB) followed by conventional histopathology and immunohistochemistry (IHC) is the gold standard approach for primary central nervous system lymphoma (PCNSL) diagnosis. Flow cytometry...

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Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131I-metaiodobenzylguanidine

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Kelly E. Huibregtse, Kieuhoa T. Vo, Steven G. DuBois, Stephanie Fetzko, John Neuhaus, Vandana Batra, John M. Maris, Brian Weiss, Araz Marachelian, Greg A. Yanik, Katherine K. Matthay
Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with ¹³¹I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after ¹³¹I-MIBG have not been defined.This is a multi-institutional retrospective review of patients with neuroblastoma treated with ¹³¹I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to ¹³¹I-MIBG. A competing risk regression was used to identify potential risk factors for SMN.The analytical cohort included 644 patients treated with ¹³¹I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4–13.0%) and 14.3% (95% CI, 8.3–23.9%) at 5 and 10 years from first ¹³¹I-MIBG, respectively. No increase in SMN risk was found with increased number of ¹³¹I-MIBG treatments or higher cumulative activity per kilogram of ¹³¹I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first ¹³¹I-MIBG, bone disease, disease status at time of first ¹³¹I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1–0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma.The cumulative risk of SMN after ¹³¹I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.



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Central obesity increases risk of breast cancer irrespective of menopausal and hormonal receptor status in women of South Asian Ethnicity

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): R. Nagrani, S. Mhatre, P. Rajaraman, I. Soerjomataram, P. Boffetta, S. Gupta, V. Parmar, R. Badwe, R. Dikshit
BackgroundCurrent evidence suggests that the relationship between obesity and breast cancer (BC) risk may vary between ethnic groups.MethodsA total of 1633 BC cases and 1504 controls were enrolled in hospital-based case–control study in Mumbai, India, from 2009 to 2013. Along with detailed questionnaire, we collected anthropometric measurements on all participants. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence interval (CI) for BC risk associated with anthropometry measurements, stratified on tumour subtype and menopausal status.ResultsWaist-to-hip ratio (WHR) of ≥0.95 was strongly associated with risk of BC compared to WHR ≤0.84 in both premenopausal (OR = 4.3; 95% CI: 2.9–6.3) and postmenopausal women (OR = 3.4; 95% CI: 2.4–4.8) after adjustment for body mass index (BMI). Premenopausal women with a BMI ≥30 were at lower risk compared to women with normal BMI (OR = 0.5; 95% CI: 0.4–0.8). A similar protective effect was observed in women who were postmenopausal for <10 years (OR = 0.6; 95% CI: 0.4–0.9) but not in women who were postmenopausal for ≥10 years (OR = 1.8; 95% CI: 1.1–3.3). Overweight and obese women (BMI: 25–29.9 and ≥ 30 kg/m², respectively) were at increased BC risk irrespective of menopausal status if their WHR ≥0.95. Central obesity (measured in terms of WC and WHR) increased the risk of both premenopausal and postmenopausal BCs irrespective of hormone receptor (HR) status.ConclusionsCentral obesity appears to be a key risk factor for BC irrespective of menopausal or HR status in Indian women with no history of hormone replacement therapy.



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Microarray-based identification of genes associated with cancer progression and prognosis in hepatocellular carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths. The average survival and 5-year survival rates of HCC patients still remains poor. Thus, there is an urgent need to better understand the mechanisms of cancer progression in HCC and to identify useful biomarkers to predict prognosis.

Methods

Public data portals including Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) profiles were used to retrieve the HCC-related microarrays and to identify potential genes contributed to cancer progression. Bioinformatics analyses including pathway enrichment, protein/gene interaction and text mining were used to explain the potential roles of the identified genes in HCC. Quantitative real-time polymerase chain reaction analysis and Western blotting were used to measure the expression of the targets. The data were analysed by SPSS 20.0 software.

Results

We identified 80 genes that were significantly dysregulated in HCC according to four independent microarrays covering 386 cases of HCC and 327 normal liver tissues. Twenty genes were consistently and stably dysregulated in the four microarrays by at least 2-fold and detection of gene expression by RT-qPCR and western blotting showed consistent expression profiles in 11 HCC tissues compared with corresponding paracancerous tissues. Eleven of these 20 genes were associated with disease-free survival (DFS) or overall survival (OS) in a cohort of 157 HCC patients, and eight genes were associated with tumour pathologic PT, tumour stage or vital status. Potential roles of those 20 genes in regulation of HCC progression were predicted, primarily in association with metastasis. INTS8 was specifically correlated with most clinical characteristics including DFS, OS, stage, metastasis, invasiveness, diagnosis, and age.

Conclusion

The significantly dysregulated genes identified in this study were associated with cancer progression and prognosis in HCC, and might be potential therapeutic targets for HCC treatment or potential biomarkers for diagnosis and prognosis.

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Expression of a novel endothelial marker, C-type lectin 14A, in epithelial ovarian cancer and its prognostic significance

Abstract

Objective

The purpose of this study was to evaluate microvessel density (MVD) as assessed by C-type lectin 14A (CLEC14A), which is a new marker for endothelial cells, and compare its expression to CD31 and CD105 in epithelial ovarian cancer (EOC).

Methods

MVD was evaluated in tumors (n = 50) from patients with EOC who underwent primary surgery and in patients with EOC who received preoperative chemotherapy (n = 49) using immunohistochemistry with antibodies to CLEC14A, CD31 and CD105. The median duration of follow-up was 24.5 months (range 1−101 months). The effect of prognostic factors on event-free survival (EFS) and overall survival (OS) was assessed using the Cox regression model.

Results

The amount of residual disease was found to be an independent prognostic factor in multivariate analysis with respect to EFS (P = 0.009) and OS (P < 0.001). The mean MVD of CLEC14A (MVD = 6), in tumors from patients who underwent primary surgery, was significantly lower than that of CD31 (MVD = 25, P < 0.0001) and CD105 (MVD = 11, P = 0.018). However, there was no significant correlation between MVD as detected by these markers and clinical outcome. There was no expression of CLEC14A in tumors from patients who received preoperative chemotherapy and the MVD of CD31 and CD105 was significantly reduced (P = 0.001 and 0.006, respectively) in this set of patients.

Conclusion

This study demonstrates MVD as detected by CLEC14A in EOC. Treatment with chemotherapy reduces tumor blood vessels significantly. We suggest that CLEC14A may be a more specific endothelial marker to assess tumor angiogenesis.

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Façading in transcultural interactions: examples from pediatric cancer care in Sweden

Abstract

Objective

The aim of the study was to generate a grounded theory explaining the latent pattern of behavior in transcultural care interactions in the context of pediatric cancer care, and to unify previously performed studies.

Methods

The basic tenets of classic grounded theory were applied on a theoretical sample of data from previous studies that included five focus group interviews with health care professionals (n = 35), and individual interviews with nurses (n = 12) and foreign-born parents (n = 11).

Results

Façading emerged as the core category and is the act of showing an outer appearance which will influence other people's interpretations. In transcultural interactions, façading might be misinterpreted related to different obstacles. Examples are given of different façades explored in pediatric cancer care including strength façading. Façading is a strategy aiming to protect oneself and others emotionally in care and includes: emotional façading and façading sensitive issues.

Conclusions

This grounded theory could help make health care professionals aware of different meanings of façading across cultures in health care. Also, awareness is needed of different views on emotional façading and façading sensitive issues to provide a congruent care.

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Supporting long-term follow-up of young adult survivors of childhood cancer: Correlates of healthcare self-efficacy

Abstract

Background

Healthcare self-efficacy (HCSE), the perceived confidence to manage one's health care, has been identified as a critical component in the transition process from pediatric to adult-oriented care for childhood cancer survivors (CCSs). HCSE is amenable to intervention and associated with long-term follow-up care among CCSs. However, factors associated with HCSE have not been fully explored among CCSs.

Procedure

We identified correlates of HCSE among a sample of CCSs (n = 193). Descriptive statistics and linear regression methods were used in this cross-sectional analysis.

Results

In univariate analyses, higher physical and psychosocial quality of life, posttraumatic growth, and religious/spiritual importance were associated with higher HCSE. Attendance at a survivorship clinic, having a regular source of care (both noncancer and oncologist), and any type of health insurance were also associated with HCSE. Hispanic ethnicity was negatively associated with HCSE relative to non-Hispanics. In a multivariable model, psychosocial quality of life, religious/spiritual importance, survivorship clinic attendance, having a regular oncologist, and Hispanic ethnicity remained significantly associated with HCSE.

Conclusions

CCSs who reported greater well-being, who rated religion and spirituality of high importance, and who accessed specialized cancer services expressed greater HCSE. Hispanic CCSs, however, reported less HCSE than non-Hispanics. Interventions that attend to the quality of life and spiritual needs of CCSs have potential to build HCSE to support the healthcare transition process. Because Hispanic CCSs may be at risk of lower perceived confidence to navigate their health care, culturally competent, efficacy-enhancing interventions are needed for this population.

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Short-term recovery of chemotherapy-induced peripheral neuropathy after treatment for pediatric non-CNS cancer

Abstract

Purpose

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect of pediatric cancer treatment. The presentation of CIPN, trajectory and completeness of recovery over the first 6 months postchemotherapy, and the influence of patient and treatment characteristics on recovery are described.

Patients and Methods

Sixty-seven children and adolescents treated for non-CNS cancers were evaluated for CIPN using the pediatric modified total neuropathy score (ped-mTNS) while on treatment and 3 and 6 months postchemotherapy. Differences between diagnostic groups and treatment type were evaluated as well as change in scores over time. Risk factors for on-treatment and persistent CIPN at 6 months were identified.

Results

Overall, ped-mTNSs were in the abnormal range for 86.5% during treatment and scores decreased over time (initial 9.3 ± 0.6, 6 months 4.3 ± 0.4; F = 38.14, P < 0.001). By 6 months posttreatment, mean scores and percentage of children with abnormal scores were reduced to 2.4 ± 0.3 and 11.5%, respectively, in the ALL group, but remained higher at 5.7 ± 0.7 and 57%, respectively, for lymphoma, and 5.2 ± 1.0 and 60%, respectively, for other solid tumors. At 6 months posttreatment, light touch deficits and foot strength deficits remained in 19.4 and 59.7%, respectively, compared with only 4.9 and 9.8% of the control population. Subjects who were older at exposure, female, or who received etoposide in addition to vincristine were at higher risk for on-treatment CIPN. On-treatment sensory abnormalities were associated with increased risk of persistent CIPN.

Conclusion

While CIPN improves in most pediatric patients, significant numbers, especially those treated for lymphoma or other solid tumors, have remaining neuropathic signs and symptoms 6 months posttreatment.

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The Neurological Predictor Scale: A predictive tool for long-term core cognitive outcomes in survivors of childhood brain tumors

Abstract

Objective

Prior research has demonstrated the reliability and validity of the Neurological Predictor Scale (NPS) in relation to intelligence and adaptive functioning in survivors of pediatric brain tumors. To extend these findings, this study examined the relationship between the NPS and core neurocognitive skills hypothesized to underlie broad outcome measures of IQ and adaptive functioning.

Method

Sixty-one adulthood survivors of childhood brain cancers (M_age = 24 years, SD = 6) on average 16 years after diagnosis completed neuropsychological assessments examining attention (Wechsler Memory Scale Digit Span Forward), processing speed (Symbol Digit Modalities Test), and working memory (Auditory Consonant Trigrams). The medical information necessary to compute the NPS was extracted from a thorough medical record review.

Results

The NPS score significantly predicted processing speed (R² = 0.28, P < 0.05) and working memory (R² = 0.15, P < .05) outcomes over and above each individual risk factor. NPS was significantly associated with attention outcomes after covarying for age (R² = 0.13, P < 0.05) over and above each risk factor except presence of hormone deficiency, hydrocephalus, and chemotherapy. These three variables were not significantly associated with attention outcomes in this sample.

Conclusions

Our findings suggest that survivors with more treatments and neurological sequelae experience greater deficits in working memory, processing speed, and attention. Further, the NPS affords the ability to predict how cumulative neurological factors impact core cognitive outcomes many years after initial diagnosis.

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Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center

Abstract

Background

Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined.

Procedure

This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment.

Results

The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0–10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population).

Conclusions

Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.

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Sclerosing cholangitis and intracranial lymphoma in a child with classical Wiskott–Aldrich syndrome

Abstract

Patients with Wiskott–Aldrich syndrome (WAS) are predisposed to malignancy and autoimmunity in addition to infections. We report a male child with WAS, who had presented with recurrent pneumonia, eczema, thrombocytopenia, autoimmune hemolytic anemia, and vasculitic skin lesions. Genetic analysis revealed a classical genotype WAS 155C>T; R41X. At 2 years of follow-up, he developed persistent headache and progressive hepatomegaly. Brain imaging showed a mass in the right frontal region, which on histopathology was shown to be high-grade non-Hodgkin lymphoma. Magnetic resonance cholangiopancreatography showed features of sclerosing cholangitis. This report extends the clinical spectrum and highlights unusual manifestations of sclerosing cholangitis and intracranial lymphoma in a patient with WAS.

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GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

Publication date: Available online 25 August 2016
Source:Cancer Cell
Author(s): Qing-Hai Ye, Wen-Wei Zhu, Ju-Bo Zhang, Yi Qin, Ming Lu, Guo-Ling Lin, Lei Guo, Bo Zhang, Zhen-Hai Lin, Stephanie Roessler, Marshonna Forgues, Hu-Liang Jia, Lu Lu, Xiao-Fei Zhang, Bao-Feng Lian, Lu Xie, Qiong-Zhu Dong, Zhao-You Tang, Xin Wei Wang, Lun-Xiu Qin
The mechanism of cancer metastasis remains poorly understood. Using gene profiling of hepatocellular carcinoma (HCC) tissues, we have identified GOLM1 as a leading gene relating to HCC metastasis. GOLM1 expression is correlated with early recurrence, metastasis, and poor survival of HCC patients. Both gain- and loss-of-function studies determine that GOLM1 acts as a key oncogene by promoting HCC growth and metastasis. It selectively interacts with epidermal growth factor receptor (EGFR) and serves as a specific cargo adaptor to assist EGFR/RTK anchoring on the trans-Golgi network (TGN) and recycling back to the plasma membrane, leading to prolonged activation of the downstream kinases. These findings reveal the functional role of GOLM1, a Golgi-related protein, in EGFR/RTK recycling and metastatic progression of HCC.

Graphical abstract

Teaser

Ye et al. identify GOLM1 as a key promoter of hepatocellular carcinoma (HCC) metastasis and determine its critical roles in the recycling, spatial redistribution, and signaling kinetics of EGFR/RTKs. In human HCC, GOLM1 expression is correlated with early recurrence, metastasis, and poor patient survival.


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Pharmacologic study (JP28927) of alectinib in Japanese patients with ALK+ NSCLC with or without prior crizotinib therapy

Summary

We report pharmacokinetics, efficacy, and safety data for a new 150 mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naïve and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40 mg and 150 mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg versus 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1−15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC_last ± standard deviation 3230 ± 914 h•ng/mL versus 3710 ± 1040 h•ng/mL, respectively, for 150 mg versus 20/40 mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1−2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), overall response rate was 70.0% (95% CI 50.6−85.3) and 65.0% (95% CI 40.8−84.6), and median progression-free survival was 13.9 months (95% CI 11.1−not reached) and 12.9 months (95% CI 3.9−not reached), respectively. The 150 mg capsule had a similar exposure profile to 20/40 mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.

This article is protected by copyright. All rights reserved.

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Association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility: a meta-analysis based on 38 case-control studies with 40,985 subjects

Abstract

Background

Studies investigating the association between the methylenetetrahydrofolate reductase (MTHFR) gene 1298A>C polymorphism and the risk of breast cancer have reported inconsistent results. So, we performed this updated meta-analysis and tried to give a more precise estimation of association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility.

Methods

Relevant studies published before 1 January 2016 were identified by searching PubMed and EMBASE. The strength of relationship between the MTHFR gene 1298A>C polymorphism and breast cancer susceptibility was assessed using odds ratio (OR) and corresponding 95 % confidence interval (95 % CI). The meta-analysis was performed using Stata 11.0 software.

Results

A total number of 38 case-control studies including 18,686 cases and 22,299 controls were identified. No association was found in five genetic models (dominant model: OR = 0.99, 95 % CI 0.99–1.00, P = 0.218; recessive model: OR = 1.00, 95 % CI 0.97–1.02, P = 0.880; homozygote genetic model: OR = 0.99, 95 % CI 0.98–1.01, P = 0.390; heterozygote genetic model: OR = 0.99, 95 % CI 0.97–1.00, P = 0.138; and allele contrast genetic model: OR = 0.99, 95 % CI 0.98–1.01) for MTHFR gene 1298 A>C polymorphism and breast cancer susceptibility. In the subgroup analysis stratified by source of control, decreased risk of breast cancer was found in studies with hospital-based controls in dominant model (OR = 0.98, 95 % CI 0.96–1.00, P = 0.037).

Conclusions

Our meta-analysis suggested that there is no significant association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility for overall population.

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Efficacy and safety of irinotecan monotherapy as third-line treatment for advanced gastric cancer

Abstract

Purpose

Although irinotecan monotherapy is often used in third-line treatment after the failure of taxanes in Japanese clinical practice, its survival benefit is still unclear. The aim of this study is to investigate the efficacy and safety of irinotecan monotherapy as third-line treatment.

Methods

Clinical data from consecutive patients in whom irinotecan had been initiated as third-line treatment between December 2003 and July 2015 in Shizuoka Cancer Center were retrospectively analyzed. Patients who were refractory or intolerant to fluoropyrimidine with or without platinum in first-line treatment and subsequent therapy with taxanes were included in this study. Irinotecan was administered at 150 mg/m² every 2 weeks.

Results

The data of 50 patients who met the inclusion criteria were analyzed. The overall response rate was 18.4 % (7/38) among the patients with measurable disease. The median progression-free survival time was 66 days, and the median survival time was 180 days from the initiation of irinotecan therapy. The major grade 3 or 4 adverse events including neutropenia, fatigue, and anorexia were observed in 12 (24 %), 8 (16 %), and 7 (14 %), respectively. No treatment-related deaths occurred. Thirteen patients (26 %) required a dose reduction to 120 mg/m² or less from the initiation of irinotecan.

Conclusions

This study suggests that irinotecan as third-line treatment has an anti-tumor effect and is feasible with optimal dose modification for advanced gastric cancer.

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Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer

Abstract

Purpose

Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B).

Methods

Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5–30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory).

Results

A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %).

Conclusions

LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC.

ClinicalTrials.gov identifier

NCT01288989.

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Place de la radiothérapie dans la prise en charge des cancers de prostate avec atteinte ganglionnaire pelvienne initiale sans métastase à distance

Publication date: Available online 27 August 2016
Source:Cancer/Radiothérapie
Author(s): S. Supiot, M. Doré, E. Rio, P. Cellier, N. Mesguez-Nebout, A. Goineau
Les cancers de prostate avec métastases ganglionnaires pelviennes inaugurales représentent une proportion faible de l'ensemble des cancers de prostate pour lesquels peu de données prospectives sont disponibles. Néanmoins, la plupart des données rétrospectives ou de cohorte sont nettement en faveur d'une place pour l'association de radiothérapie et d'hormonothérapie dans cette situation clinique. Seules des études prospectives randomisées permettraient de mieux préciser les modalités d'administration de la radiothérapie (dose totale ? fractionnement ? volume ?) et de l'hormonothérapie (place des hormonothérapies de nouvelle génération ? durée ?).Node-positive prostate cancer patients represent a small proportion of all prostate cancers for whom limited prospective information is available. Most retrospective or cohort data strongly suggest however that radiotherapy combined with androgen-depriving therapies is the preferable treatment in this setting. Only randomized clinical trials would be able to better define both radiotherapy (dose? volume? fractionation?) and androgen-depriving therapies (duration? role of novel androgen-depriving therapy?) modalities.



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Pencil beam scanning proton therapy for treatment of the retroperitoneum after nephrectomy for Wilms tumor: A dosimetric comparison study

Abstract

Background

Multimodality treatment for patients with Wilms tumor has improved patient survival, but is associated with acute and long-term toxicity, partially due to irradiation. Proton therapy using pencil beam scanning (PBS) is a promising technique to reduce dose to organs at risk (OAR). In this study, we evaluate PBS plans for postoperative irradiation in patients with Wilms tumor.

Procedure

Patients were treated with anterior-posterior–posterior-anterior (AP–PA) photon fields encompassing the preoperative tumor volume. Patients requiring whole lung irradiation were treated with AP–PA photon fields covering the bilateral lungs. Prescription doses were generally 1,080 and 1,200 cGy, respectively. Flank PBS plans encompassing the ipsilateral retroperitoneum and para-arotic nodes were generated for dosimetric evaluation.

Results

Treatment records and comparison plans of 11 patients were reviewed. Mean dose and median dose to 50% or more of the contralateral kidney (D50) were 135 cGy and 139 cGy with photons and 52 cGy relative biological effectiveness (RBE) (P = 0.009) and 5 cGy RBE (P = 0.000001) with PBS. Mean dose and median D50 to bowel was 639 cGy and 979 cGy with photons and 379 cGy RBE (P = 0.001) and 47 cGy RBE (P = 0.004) with PBS. Mean dose and median D50 to the liver were 755 cGy and 1,013 cGy with photons and 411 cGy RBE (P = 0.02) and 132 cGy RBE (P = 0.02) with PBS. For patients with right-sided tumors, mean liver dose following sequential whole lung irradiation was 1,252 cGy with photons and 845 cGy RBE (P = 0.04) with PBS.

Discussions

PBS proton therapy is a feasible method for irradiating the retroperitoneum and provides significant sparing of dose to critical OAR. This may translate to improved long-term health outcomes for patients and warrants further clinical investigation.

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Successful treatment of recurrent CNS disease post-bone marrow transplant in children with familial hemophagocytic lymphohistiocytosis

Abstract

Background

Central nervous system (CNS) involvement is a major cause of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis (HLH). Current standard of care for CNS disease utilizes high-dose systemic dexamethasone plus intrathecal methotrexate and hydrocortisone prior to transplantation. However, the morbidity and mortality remains high and there are no clear guidelines posttransplantation for screening and treatment of CNS disease.

Procedure

We report a single-center retrospective case series of five patients with familial HLH (FHLH) who had CNS involvement post-bone marrow transplantation (BMT). All patients were monitored with monthly lumbar punctures (LPs) prior to developing neurologic symptoms. Treatment utilized systemic dexamethasone for CNS disease control.

Results

Five patients were monitored with monthly or bimonthly surveillance LPs and treated with systemic dexamethasone to control CNS relapse post-BMT. All patients are alive, a median of 34 months posttransplant (range 14–66 months). Four patients have mild neurological deficits, including mild speech delay (3) and one patient who exhibited brainstem herniation on day 0, due to CNS HLH, has made a substantial recovery of function with residual deficits of focal weakness on the right side. One patient has no deficits.

Conclusion

Our data support vigilant screening posttransplant for occult CNS disease prior to the development of symptoms and the use of systemic dexamethasone to reverse disease progression. Future prospective trials are needed to evaluate this treatment strategy.

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Clinical effects of single nucleotide polymorphisms on drug-related genes in Japanese metastatic renal cell carcinoma patients treated with sunitinib.

Although sunitinib is a well-established chemotherapeutic for metastatic renal cell carcinoma (mRCC), there are no robust markers that predict efficacy and toxicity. We analyzed the effect of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics on clinical outcomes in Japanese patients with mRCC. We analyzed the effect of SNPs in genes involved in sunitinib pharmacokinetics on the clinical outcome in mRCC patients in a Japanese population. We evaluated seven SNPs in four candidate genes, the transport proteins ATP-binding cassette (ABC) B1 (rs1045642, rs1128503, rs2032582, and rs7779562) and ABCG2 (rs2231142), and the metabolic proteins cytochrome P450 (CYP) 3A4 (rs35599367) and CYP3A5 (rs776746) in 70 patients. No significant association was observed between the genotypes of each SNP and time to dose reduction, progression-free survival, overall survival, and best objective response. Meanwhile, the incidence of grade 2 or greater hypertension and hand-foot syndrome, and multiple adverse events (>3), was significantly higher in patients carrying the ABCB1 rs2032582 GG genotype [odds ratio (OR): 5.37, 95% confidence interval (CI) 1.02-14.63, P=0.035; OR: 3.17, 95% CI 1.06-9.52, P=0.036, OR: 3.35; 95% CI 1.14-9.84; P=0.025, respectively]. In conclusion, our data showed that the ABCB1 rs2032582 GG genotype was associated with individual adverse events' susceptibility among Japanese patients treated with sunitinib in routine clinical settings. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Age-associated vulval integrity is an important marker of nematode healthspan

Abstract

Improving healthspan, defined as the period where organisms live without frailty and/or disease, is a major goal of biomedical research. While healthspan measures in people are relatively easy to identify, developing robust markers of healthspan in model organisms has proven challenging. Studies using the nematode Caenorhabditis elegans have provided vital information on the basic mechanisms of aging; however, worm health is difficult to define, and the impact of interventions that increase lifespan on worm healthspan has been controversial. Here, we describe a marker of population healthspan in C. elegans that we term age-associated vulval integrity defects, or Avid, frequently described elsewhere as rupture or exploding. We connect the presence of this phenotype with temperature, reproduction, diet, and longevity. Our results show that Avid occurs in post-reproductive worms under common laboratory conditions at a frequency that correlates negatively with temperature; Avid is rare in worms kept at 25 °C and more frequent in worms kept at 15 °C. We describe the kinetics of Avid, link the phenotype to oocyte production, and describe how Avid involves the ejection of worm proteins and/or internal organ(s) from the vulva. Finally, we find that Avid is preventable by removing worms from food, suggesting that Avid results from the intake, digestion, and/or absorption of food. Our results show that Avid is a significant cause of death in worm populations maintained under laboratory conditions and that its prevention often correlates with worm longevity. We propose that Avid is a powerful marker of worm healthspan whose underlying molecular mechanisms may be conserved.

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