Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05)

Abstract

Background

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR.

Patients and Methods

We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman's rank correlation coefficient.

Results

In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4–77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p = 0.0003; 42.8 vs. 9.0 months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r _s = 0.314, p = 0.027) as well as post-progression survival (PPS) (r _s = 0.366, p = 0.017). Interestingly, DpR was moderately associated with OS and PPS (r _s = 0.587, r _s = 0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities.

Conclusions

Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

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POSTN regulates resistance to antiangiogenic therapy

Periostin (POSTN) interacts with multiple integrins to coordinate a variety of cellular processes, including epithelial-to-mesenchymal transition (EMT) and cell migration. In our previous study, anti-vascular endothelial growth factor A (VEGF-A) therapy was associated with resistance and EMT. The present study sought to determine the role of POSTN in the resistance of glioma stem cells (GSCs) to antiangiogenic therapy. In mouse xenograft models of human glioma, POSTN expression was associated with acquired resistance to anti-VEGF-A therapy and had a synergistic effect with bevacizumab in prolonging survival and decreasing tumor volume. Resistance to anti-VEGF-A therapy regulated by POSTN was associated with increased expression of transforming growth factor beta-1 (TGF beta1) and hypoxia-inducible factor-1 alpha (HIF1 alpha) in GSCs. At the molecular level, POSTN regulated invasion and expression of EMT (caveolin-1) and angiogenesis-related genes (HIF1 alpha and VEGF-A) through activation of signal transducer and activator of transcription 3 (STAT3). Moreover, recombinant POSTN increased GSC invasion. Collectively, our findings suggest that POSTN plays an important role in glioma invasion and resistance to antiangiogenic therapy.

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Acridine Derivatives as IRE1{alpha}-XBP1 Inhibitors

Using a luciferase reporter-based high throughput chemical library screen and topological data analysis (TDA), we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as a inhibitor of the IRE1α-XBP1 pathway of the unfolded protein response (UPR). We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships (SAR) and identified N9-(3-(dimethylamino)propyl)-N3,N3,N6,N6-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, while the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma (MM) cell survival, these analogues were cytotoxic to MM cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing and the growth of MM tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of MM.

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Expression of a gap junction protein, connexin43, in a large panel of human gliomas: new insights

Abstract

Precise diagnosis of low and high grades of brain tumors permits determining therapeutical strategies. So far, diagnosis and prognosis of gliomas were based on histological and genetic criteria which need being completed by a panel of molecular markers. Highly distributed in brain, gap junction proteins, connexins, could be considered as markers of glioma progression as previous studies indicated that expression of a connexin type, connexin43 (Cx43), is inversely correlated to tumor grading. However, this assumption was weakened by the low number of glioma samples used. Taking advantage of tissue microarray technique, we pursued this analysis by studying in situ expression of Cx43 on 85 samples (37 grade IV, 18 grade III, 24 grade II, and 6 grades II to III). Our analysis confirmed the global diminution of Cx43 expression in glioblastomas that was observed in previous studies. However, this analysis brought new insights such as the following ones. First, the high number of samples permitted to show that more than 60% of glioblastomas still express Cx43. Second, no gradual decrease in Cx43 expression was observed between grades II and III, but Cx43 appeared to be a marker distinguishing oligodendrocytic and astrocytic grade III tumors. Third, independently from tumor grade, a Cx43 nuclear staining was detected in areas where leukocytes are present. In conclusion, our study emphasizes the importance of in situ immunohistochemical approaches by giving more precise insights in the subcellular localization of Cx43. It also emphasizes the necessity to carry out such analysis on a wide range of samples to circumvent the high glioma heterogeneity.

Precise diagnosis of low and high grades of brain tumors permits determining therapeutical strategies. Highly distributed in brain, gap junction proteins, such as connexin 43, could be considered as markers of glioma progression. Taking advantage of tissue microarray technique, we analyzed in situ expression of Cx43 on 85 samples (37 grade IV, 18 grade III, 24 grade II, and 6 grades II to III). The high number of samples shows that 60% of glioblastomas still express Cx43. No gradual decrease in Cx43 expression was observed between grades II and III, but Cx43 appeared to be a marker distinguishing oligodendrocytic and astrocytic grade III tumors. Third, independently from tumor grade, the detection of a Cx43 nuclear staining seemed to be related to lymphocyte infiltrations. In conclusion, our study emphasizes the importance of in situ immunohistochemical approaches by giving more precise insights in the subcellular localization of Cx43. It also emphasizes the necessity to carry out such analysis on a wide range of samples to circumvent the high glioma heterogeneity.

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Cancer Predisposition Testing in Unselected Cancer Patients

Sequencing for somatic alterations in patients' tumors is being increasingly clinically implemented to detect mutations that may guide therapy. Germline analysis of a cohort of patients undergoing tumor sequencing with matched normal has revealed that a small but significant percentage of these patients have germline variants that confer cancer susceptibility.

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MHC class II expression in pediatric ACT

Purpose: Histological markers that differentiate benign and malignant pediatric adrenocortical tumors (ACTs) are lacking. Previous studies have implicated an association of major histocompatibility complex (MHC) class II expression with ACT prognosis. Here we determined the expression of MHC class II as well as the cell of origin of these immunological markers in pediatric ACT. The impact of MHC class II gene expression on outcome was determined in a cohort of uniformly-treated children with adrenocortical carcinomas. Experimental Design: We analyzed the expression of MHC class II and a selected cluster of differentiation genes in 63 pediatric ACTs by Affymetrix Human U133 Plus 2.0 or HT HG-U133+PM gene chip analyses. Cells expressing MHC class II were identified by morphologic and immunohistochemical assays. Results: MHC class II expression was significantly greater in adrenocortical adenomas than in carcinomas (P = 4.8 x 10-6) and was associated with a higher progression-free survival (PFS) estimate (P = 0.003). Specifically, HLA-DPA1 expression was most significantly associated with PFS after adjustment for tumor weight and stage. HLA-DPA1 was predominantly expressed by hematopoietic infiltrating cells and undetectable in tumor cells in 23 of 26 cases (88%). Conclusions: MHC class II expression, which is produced by tumor- infiltrating immune cells, is an indicator of disease aggressiveness in pediatric ACT. Our results suggest that immune responses modulate adrenocortical tumorigenesis, and may allow the refinement of risk stratification and treatment for this disease.

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BMI-1 targeting in prostate tumor-initiating cells

Purpose: Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions: Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment.

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Dysregulation of c-Myb pathway in ATL malignancy

Purpose: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive human T-cell malignancy induced by human T-lymphotrophic virus-1 (HTLV-1) infection. The genetic alterations in infected cells that lead to transformation have not been completely elucidated, thus hindering the identification of effective therapeutic targets for ATL. Here, we present the first assessment of MYB proto-oncogene dysregulation in ATL and an exploration of its role in the onset of ATL. Experimental Design: We investigated the expression patterns of MYB splicing variants in ATL. The molecular characteristics of the c-Myb-9A isoform, which was overexpressed in ATL cells, were examined using chromatin immunoprecipitation and promoter assays. We further examined the biological impacts of abnormal c-Myb overexpression in ATL using overall c-Myb knockdown with small hairpin RNA or c-Myb-9A knockdown with morpholino oligomers. Results: Both total c-Myb and c-Myb-9A, which exhibited strong transforming activity, were overexpressed in ATL cells in a leukemogenesis- and progression-dependent manner. Knockdown of either total c-Myb or c-Myb-9A induced ATL cell death. c-Myb transactivates nine genes that encode essential regulators of cell proliferation and NF-B signaling. c-Myb-9A induced significantly stronger transactivation of all tested genes and stronger NF-B activation compared with wild-type c-Myb. Conclusions: Our data demonstrate that c-Myb pathway overactivation caused by unbalanced c-Myb-9A overexpression is associated with disorders in cellular homeostasis and consequently, accelerated transformation, cell proliferation, and malignancy in ATL cells. These data support the notion of the c-Myb pathway as a promising new therapeutic target for ATL.

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IPH2101 contracts and detunes NK-cells in vivo

Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. Based on data showing KIR-ligand mismatched NK-cells reduce the risk of leukemia and multiple myeloma (MM) relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK-cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK-cells, our single-arm phase II clinical trial in patients with smoldering MM was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind lack of clinical efficacy. Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and twenty-four hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK-cell phenotype and function was analyzed using high-resolution flow cytometry. Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK-cell responsiveness and KIR2D expression on the NK-cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK-cells by trogocytosis, with reductions in NK-cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the anti-myeloma cytotoxicity of remaining KIR2Ddull patient NK-cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK-cells. Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK-cell tumor killing via checkpoint inhibition.

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Quinacrine + Sorafenib in Anaplastic Thyroid Cancer

Purpose: Anaplastic thyroid cancer (ATC) comprises ~2% of all thyroid cancers and its median survival rate remains poor. It is responsible for more than one-third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy and NFkappaB-signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the anti-malaria drug quinacrine known to target NFkappaB-signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFkappaB-p65/RelA and its target Mcl-1 was demonstrated in ATC by meta-data gene set enrichment analysis and immunohistochemistry (IHC). We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFkappaB-p65/RelA and Mcl-1 in the nucleus of a subset of ATC compared to non-neoplastic thyroid. ATC-cells were found to respond with additive/synergistic tumor cell-killing to the combination of sorafenib plus quinacrine in vitro and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC-cells as compared to mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of the pro-survival gene Mcl-1, pStat3 and dampened NFkappaB signaling. Conclusion: The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients.

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PI3K inhibition in melanoma brain metastases

Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. Additionally, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib. Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases.

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Delta One T cells for adoptive immunotherapy of CLL

Purpose: The V1+ subset of T lymphocytes is a promising candidate for cancer immunotherapy but the lack of suitable expansion/ differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a V1+ T cell-based protocol that is GMP-compatible and devoid of feeder cells for prompt clinical translation. Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (over 2-3 weeks) V1+ T cells from the peripheral blood of healthy donors and chronic lymphocytic leukemia (CLL) patients. We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL). Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic V1+ (DOT) cells. These expressed the Natural Cytotoxicity Receptors (NCRs), NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss-of-function; indeed, DOT cells proliferated and produced abundant IFN- and TNF-α, but importantly no IL-17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL. Conclusions: We provide a clinical-grade method and the preclinical proof-of-principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL.

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Optimizing adjuvant therapy and survivorship care of stage III colon cancer

Future Oncology Ahead of Print.


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Management of bronchial carcinoids: international practice survey among the European Society of Thoracic Surgeons

Future Oncology Ahead of Print.


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Risk of selected gastrointestinal and hepatic toxicities in cancer patients treated with nintedanib: a meta-analysis

Future Oncology Ahead of Print.


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Optimizing adjuvant therapy and survivorship care of stage III colon cancer

Future Oncology Ahead of Print.


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Management of bronchial carcinoids: international practice survey among the European Society of Thoracic Surgeons

Future Oncology Ahead of Print.


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Risk of selected gastrointestinal and hepatic toxicities in cancer patients treated with nintedanib: a meta-analysis

Future Oncology Ahead of Print.


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Laminin- adherent versus suspension- non-adherent cell culture conditions for the isolation of cancer stem cells in the DAOY medulloblastoma cell line

Abstract

Medulloblastoma (MB) is a highly malignant tumor of childhood. MB seems to be initiated and maintained by a small group of cells, known as cancer stem cells (CSCs). The CSC hypothesis suggests that a subset of tumor cells is able to proliferate, sustain the tumor, and develop chemoresistance, all of which make of CSC an interesting target for new anticancer therapies. The MB cell line DAOY was cultured in suspension by a medullosphere traditional culturing method and in adherent conditions by laminin-pre-coated flasks and serum-free medium enriched with specific growth factors. An increase in the stem features was shown when cells were successively cultured in hypoxia conditions. By contrast, a reduction in these properties was appreciated when cells were exposed to differentiation conditions. In addition, the CD133+ and CD133− subpopulations were isolated from cells grown in laminin-pre-coated flasks, and in vitro experiments showed that the CD133+ fraction represented the stem population and it could have CSC with a higher probability than the CD133− fraction. We can conclude that the laminin culture method in adherent conditions and the medullosphere traditional culturing method in suspension are similarly good for obtaining stem-like cells in the DAOY cell line.

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Laminin- adherent versus suspension- non-adherent cell culture conditions for the isolation of cancer stem cells in the DAOY medulloblastoma cell line

Abstract

Medulloblastoma (MB) is a highly malignant tumor of childhood. MB seems to be initiated and maintained by a small group of cells, known as cancer stem cells (CSCs). The CSC hypothesis suggests that a subset of tumor cells is able to proliferate, sustain the tumor, and develop chemoresistance, all of which make of CSC an interesting target for new anticancer therapies. The MB cell line DAOY was cultured in suspension by a medullosphere traditional culturing method and in adherent conditions by laminin-pre-coated flasks and serum-free medium enriched with specific growth factors. An increase in the stem features was shown when cells were successively cultured in hypoxia conditions. By contrast, a reduction in these properties was appreciated when cells were exposed to differentiation conditions. In addition, the CD133+ and CD133− subpopulations were isolated from cells grown in laminin-pre-coated flasks, and in vitro experiments showed that the CD133+ fraction represented the stem population and it could have CSC with a higher probability than the CD133− fraction. We can conclude that the laminin culture method in adherent conditions and the medullosphere traditional culturing method in suspension are similarly good for obtaining stem-like cells in the DAOY cell line.

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Intraperitoneal bevacizumab for control of malignant ascites due to advanced-stage gastrointestinal cancers: A multicentre double-blind, placebo-controlled phase II study – AIO SUP-0108

Publication date: August 2016
Source:European Journal of Cancer, Volume 63
Author(s): K. Jordan, T. Luetkens, C. Gog, B. Killing, D. Arnold, A. Hinke, M. Stahl, W. Freier, J. Rüssel, D. Atanackovic, S. Hegewisch-Becker
PurposeMalignant ascites is debilitating for patients with advanced cancer. As shown previously, tumour cell production of vascular endothelial growth factor might be a major cause of the formation of malignant ascites. Intraperitoneal bevacizumab could therefore be an option for symptom control in refractory ascites.Patients and methodsPatients with advanced gastrointestinal cancer and malignant ascites who had undergone paracentesis at least twice within the past 4 weeks were randomly assigned in a 2:1 ratio to intraperitoneal bevacizumab (400 mg absolute) or placebo after paracentesis. During the 8-week treatment period, a minimum interval of 14 d was kept between the applications of the study drug. Primary end-point was paracentesis-free survival (ParFS).ResultsFifty-three patients (median age 63 years) were randomised. Forty-nine patients received at least one study drug application and qualified for the main analysis. The proportion of patients with at least one common toxicity criteria grade III–V event was similar with 20/33 (61%) on bevacizumab and 11/16 (69%) on placebo. Median ParFS was 14 d (95% confidence interval [CI]: 11–17) in the bevacizumab arm and 10.5 d (95% CI: 7–21) on placebo (hazard ratio 0.74, 95% CI: 0.40–1.37; P = 0.16). The longest paracentesis-free period was 19 d on bevacizumab (range 6–66 d) and 17.5 d in the placebo arm (range 4–42) (P = 0.85). Median overall survival was 64 d (95% CI: 45–103) on bevacizumab compared to 31.5 d (95% CI: 20–117) on placebo (P = 0.31).ConclusionIntraperitoneal bevacizumab was well tolerated. Overall, treatment did not result in a significantly better symptom control of malignant ascites. However, patients defined by specific immune characteristics may benefit.



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Mammographic screening in BRCA1 mutation carriers postponed until age 40: Evaluation of benefits, costs and radiation risks using models

Publication date: August 2016
Source:European Journal of Cancer, Volume 63
Author(s): Inge-Marie Obdeijn, Eveline A.M. Heijnsdijk, M.G. Myriam Hunink, Madeleine M.A. Tilanus-Linthorst, Harry J. de Koning
PurposeBRCA1 mutation carriers are offered screening with magnetic resonance imaging (MRI) and mammography. The aim of this study was to weigh benefits and risks of postponing mammographic screening until age 40.MethodsWith the MISCAN microsimulation model two screening protocols were evaluated: 1) the current Dutch guidelines: annual MRI from age 25–60, annual mammography from age 30–60, and biennial mammography in the nationwide program from age 60–74, and 2) the modified protocol: with annual mammography postponed until age 40. A cost-effectiveness analysis was performed.The risks of radiation-induced breast cancer mortality were estimated with absolute and relative exposure-risk models of the 7th Biological Effects of Ionising Radiation Committee.ResultsCurrent screening guidelines prevent 13,139 breast cancer deaths per 100,000 BRCA1 mutation carriers. Postponing mammography until age 40 would increase breast cancer deaths by 23 (0.17%), but would also reduce radiation-induced breast cancer deaths by 15 or 105 using the absolute and relative risk model respectively per 100,000 women screened. The estimated net effect is an increase of eight or a reduction of 82 breast cancer deaths per 100,000 women screened (depending on the risk model used). The incremental cost of mammograms between age 30–39 is €272,900 per life year gained.ConclusionsThe modified protocol may be slightly less effective or even better than the current guidelines. The high cost-savings justify a possible small loss of effectiveness.



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Long-term quality of life among localised prostate cancer survivors: QALIPRO population-based study

Publication date: August 2016
Source:European Journal of Cancer, Volume 63
Author(s): Clarisse Kerleau, Anne-Valérie Guizard, Laetitia Daubisse-Marliac, Natacha Heutte, Mariette Mercier, Pascale Grosclaude, Florence Joly
BackgroundTo evaluate quality of life (QoL) 10 years after treatments for localised prostate cancer (LPCa) patients in comparison with aged-matched healthy controls.MethodsLPCa patients diagnosed in 2001 were obtained from 11 French cancer registries. Controls were recruited among the general population and were matched to patients on age and geographic area. EORTC Quality of Life Questionnaire – Core 30 items, Expanded Prostate Cancer Index Composite, Hospital Anxiety and Depression Scale and Multidimensional Fatigue Inventory self-reported questionnaires were used to measure QoL, anxiety and fatigue. Patients were classified in three groups according to previous treatments: radical prostatectomy (RP), radiotherapy (RT) and radical prostatectomy and radiotherapy (RP+RT). The differences in QoL between patients and controls and according to treatment groups were evaluated.ResultsThere were 287 patients and 287 controls. There was no socio-demographic difference between patients and controls. Treatments were: RP (143), RT (78), PR+RT (33), baseline hormone therapy (49) and hormone therapy at the time of the study (34). Patients had similar levels of global QoL, anxiety, depression and fatigue as controls. They reported more urinary troubles (urinary function and incontinence) (p < 0.0001) and more sexual dysfunctions (p < 0.0001) than controls, whatever the treatment group. Worse bowel dysfunction was reported in patients treated by RT and RP+RT (p < 0.002). According to the treatments, RP groups had the worst urinary function and incontinence (p < 0.01), and reported more bowel bother when the treatment was combined with RT.ConclusionsEven though patients reported similar global QoL as control 10 years after treatment, patients reported numerous urinary and sexual dysfunctions. Patients treated with RP+RT reported cumulative sequelae of both treatments.



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Long-term outcomes using adjuvant pelvic intensity-modulated radiotherapy (IMRT) for endometrial carcinoma

Publication date: Available online 15 June 2016
Source:Practical Radiation Oncology
Author(s): Siping He, Beant S. Gill, Dwight E. Heron, Joseph L. Kelley, Paniti Sukumvanich, Alexander B. Olawaiye, Robert P. Edwards, John Comerci, Sushil Beriwal
PurposeTo evaluate the long-term outcome and toxicity of adjuvant intensity-modulated radiotherapy (IMRT) for high-risk endometrial carcinoma via a retrospective institutional review of patients treated in this setting with extended follow-up.Methods and MaterialsPatients with endometrial cancer who underwent comprehensive surgical staging followed by adjuvant IMRT with or without sequential chemotherapy between 1999 to 2010 were reviewed. Median doses delivered with IMRT and brachytherapy were 45 Gy in 25 fractions and 10 Gy in 2 fractions; 10.2% received extended field and 94.5% received vaginal brachytherapy. Kaplan-Meier estimates are provided for rates of locoregional (in-field) relapse (LRR), distant metastasis (DM), and disease-free (DFS) and overall (OS) survival. GI and GU toxicity reported were graded with the CTCAE 4.03.Results128 patients were identified. Median age at diagnosis was 64 years. Most patients (82.8%) had endometrioid adenocarcinoma followed by papillary serous (10.2%), clear cell (4.7%), and carcinosarcoma (2.3%). FIGO staging distribution was as follows: IA 13.3%, IB 32.8%, II 30.4%, IIIA 5.5%, IIIC1 9.4%, IIIC2 8.6%. Most (85.9%) underwent nodal dissections (28.1% pelvic only and 57.8% pelvic and para-aortic). Two patients (1.6%) experienced acute grade 3 GI toxicity; no other acute grade ≥3 GI/GU toxicities were noted. With a median follow-up of 57.0 months, 5-year LRR was 2.5%: vagina (n=3), parametrium (n=1), pelvic node (n=1). Five-year estimates of DM, DFS, and OS were 16.5%, 73.4%, and 77.4%, respectively. Five-year actuarial rates of late grade 3 GI and GU toxicities were 3.2% and 0.0%. The 5-year rate of symptomatic pelvic insufficiency fracture was 4.4%.ConclusionsThis study represents the largest cohort of endometrial cancer patients with extended follow-up receiving adjuvant IMRT. High rates of pelvic disease control and limited late toxicities demonstrate safety and efficacy of this approach in the setting of extended follow-up.



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Magnetic Resonance Image-guided Radiation Therapy For Primary Splenic Diffuse Large B-cell Lymphoma: A Teaching Case

Publication date: Available online 15 June 2016
Source:Practical Radiation Oncology
Author(s): Benjamin W. Fischer-Valuck, Olga Green, Thomas Mazur, Harold Li, Anupama Chundury, James Rao, Nancy L. Bartlett, Sasa Mutic, Jiayi Huang




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Gemcitabine Induced Radiation Recall Myositis in a Patient with Relapsed Nasopharyngeal Carcinoma

Publication date: Available online 15 June 2016
Source:Practical Radiation Oncology
Author(s): Sagar C. Patel, Arnold C. Paulino, Danielle Johnston, Lee Wiederhold, Richard Castillo, Rajkumar Venkatramani




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Efficiency versus effectiveness: impact of molecular testing on healthcare costs and clinical outcome of patients with indeterminate thyroid nodules

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Diagnostic and prognostic significance of serum apolipoprotein C-I in triple-negative breast cancer based on mass spectrometry

10.1080/15384047.2016.1156262<br/>Dongjian Song

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Effects of supportive-expressive discussion groups on loneliness, hope and quality of life in breast cancer survivors: a randomized control trial

Abstract

Purpose

Evaluation of the effect of supportive expressive discussion groups on loneliness, hope and quality of life in breast cancer survivors.

Methods

A randomized control trial including breast cancer patients who had completed chemotherapy and randomly allocated into two groups: intervention (n = 41) and control (n = 40). The intervention consisted of twelve weekly 90-min sessions for groups of six to eight breast cancer survivors. Data were obtained pre-to -post the intervention and at 8-week follow-up. The data were analyzed using a repeated-measures analysis of variance (ANOVA).

Results

The findings revealed a significant reduction in loneliness scores (F = 69.85, p < 0.001), promotion in total hope (F = 20.8, p < 0.05) and enhancement in quality of life from pre- to post-intervention, and then over the 8-week follow-up period in the intervention group, while scores of control participants did not show this pattern during the study. The strongest effects were found for global quality of life (effect size) = 0.59), for future perspectives (effect size = 0.51), emotional functioning (effect size = 0.35) and social functioning (effect size = 0.31).

Conclusion

The intervention was effective on loneliness, hope and quality of life in the intervention group. The intervention needs further evaluation in a larger study and with other cancer types. Copyright © 2016 John Wiley & Sons, Ltd.

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Malignant Peripheral Nerve Sheath Tumors: A Single Institution's Experience Using Combined Surgery and Radiation Therapy.

Purpose: The purpose of this study is to investigate local control (LC), survival outcomes, and associated prognostic factors for patients with malignant peripheral nerve sheath tumors (MPNSTs) treated with combined surgery and radiation therapy (RT). Methods: We reviewed the medical records of 71 consecutive patients treated with surgery and RT for localized MPNST between 1965 and 2012. Preoperative RT was used to treat 23 patients (32%) to a median dose of 50 Gy (range, 50 to 60 Gy), whereas 48 (68%) received postoperative RT to a median dose of 64 Gy (range, 45 to 70 Gy). Results: Median follow-up for living patients was 118 months (range, 21 to 512 mo). The 5-year LC, distant metastatic free survival, and disease-specific survival rates were 84%, 62%, and 66%, respectively. To identify predictors of outcome, several multivariate models were constructed: (1) positive/uncertain surgical margin status was the only factor adversely associated local relapse at 5 years (28% vs. 5% for negative margins; P=0.02; hazard ratios 5.92; 95% confidence interval, 1.3-27.4). (2) No factors were significantly associated with distant metastatic free survival. Of the 35 patients (49%) who sustained disease relapse, only 3 were ultimately salvaged. Only 2 patients had grade 2 late toxicities (necrosis, fibrosis) based on Common Terminology Criteria for Adverse Events version 4.03 criteria, and 1 patient had grade 1 edema. Conclusions: Combination therapy with surgery and RT provides favorable LC. Distant recurrences, however, continue to be challenging with limited salvage success at the time of relapse. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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