Successful management of retinal metastasis from renal cancer with everolimus in a monophthalmic patient: a case report

The retina is an uncommon site for metastases, in particular from solid tumors. Some authors have reported a recent increase in the incidence of metastases in infrequent sites, such as brain or bone, probably ...

http://ift.tt/2Ah4GN1

The mechanism study of miR-125b in occurrence and progression of multiple myeloma

Abstract

Although many efforts have contributed to improve our knowledge of molecular pathogenesis about multiple myeloma (MM), the role and significance of microRNAs and long noncoding RNAs in MM cells, along with the core mechanism remains virtually absent. The mRNA levels of miR-125b and MALAT1 in MM cell lines were detected by qRT-PCR. The influence of Lenti-Sh-miR-125b on cell viability and the Notch-1 pathway-related proteins were assessed by MTT method and western blot, respectively. We also investigated the regulation effect between MALAT1 and Notch1 pathway. Moreover, the connection between Notch1 signaling and MM cell growth was discussed in-depth. The reverse effect of pcDNA-Notch1 on the cell viability and Notch-1 pathway proteins induced by Si-MALAT1 was also studied. Furthermore, miR-125b overexpressing MM cell lines were injected subcutaneously into nude mice. MiR-125b and MALAT1 were inversely expressed in MM cell lines. Lenti-Sh-miR-125b inhibited the expression of MALAT1 and Notch-1 protein. Binding sites were confirmed between miR-125b and MALAT1, and silencing MALAT1 did not alter the expression of Notch-1. The apoptosis rate was increased and the survival rate was decreased obviously in GSI XII (targeted cleavage of Notch-1 receptor) group, along with the inhibited Notch1 and HES1 proteins. Moreover, the decreased cell viability and Notch-1 pathway proteins induced by Si-MALAT1 could be reversed by pcDNA-Notch1. Lenti-Sh-miR-125b promoted survival and decreased Notch1 and HES1 proteins levels, while this effect was reversed by si -MALAT1. MiR-125b regulated MALAT1 expression via Notch1 signaling pathway to regulate cell growth, thus participating in the occurrence and progression of MM, which functioned as a therapeutic target for tracking MM.

To investigate the mechanism of long noncoding RNA MALAT1 and miR-125b in the progression of multiple myeloma (MM), through our current study, we found that loss of miR-125b contributes to lncRNA MALAT1 expression through Notch-1 pathway, further regulating cell growth. Therefore, the current findings not only provide new insight in clarifying the complex molecular mechanisms of specific miR-125b and MALAT1 but also facilitate the development.

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The mechanism study of miR-125b in occurrence and progression of multiple myeloma

Abstract

Although many efforts have contributed to improve our knowledge of molecular pathogenesis about multiple myeloma (MM), the role and significance of microRNAs and long noncoding RNAs in MM cells, along with the core mechanism remains virtually absent. The mRNA levels of miR-125b and MALAT1 in MM cell lines were detected by qRT-PCR. The influence of Lenti-Sh-miR-125b on cell viability and the Notch-1 pathway-related proteins were assessed by MTT method and western blot, respectively. We also investigated the regulation effect between MALAT1 and Notch1 pathway. Moreover, the connection between Notch1 signaling and MM cell growth was discussed in-depth. The reverse effect of pcDNA-Notch1 on the cell viability and Notch-1 pathway proteins induced by Si-MALAT1 was also studied. Furthermore, miR-125b overexpressing MM cell lines were injected subcutaneously into nude mice. MiR-125b and MALAT1 were inversely expressed in MM cell lines. Lenti-Sh-miR-125b inhibited the expression of MALAT1 and Notch-1 protein. Binding sites were confirmed between miR-125b and MALAT1, and silencing MALAT1 did not alter the expression of Notch-1. The apoptosis rate was increased and the survival rate was decreased obviously in GSI XII (targeted cleavage of Notch-1 receptor) group, along with the inhibited Notch1 and HES1 proteins. Moreover, the decreased cell viability and Notch-1 pathway proteins induced by Si-MALAT1 could be reversed by pcDNA-Notch1. Lenti-Sh-miR-125b promoted survival and decreased Notch1 and HES1 proteins levels, while this effect was reversed by si -MALAT1. MiR-125b regulated MALAT1 expression via Notch1 signaling pathway to regulate cell growth, thus participating in the occurrence and progression of MM, which functioned as a therapeutic target for tracking MM.

To investigate the mechanism of long noncoding RNA MALAT1 and miR-125b in the progression of multiple myeloma (MM), through our current study, we found that loss of miR-125b contributes to lncRNA MALAT1 expression through Notch-1 pathway, further regulating cell growth. Therefore, the current findings not only provide new insight in clarifying the complex molecular mechanisms of specific miR-125b and MALAT1 but also facilitate the development.

http://ift.tt/2k2dMlK

Development of a Web-Based Psychosocial Intervention for Adolescent and Young Adult Survivors of Pediatric Brain Tumor

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Development of a Web-Based Psychosocial Intervention for Adolescent and Young Adult Survivors of Pediatric Brain Tumor

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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HER2 copy number of circulating tumour DNA functions as a biomarker to predict and monitor trastuzumab efficacy in advanced gastric cancer

Publication date: January 2018
Source:European Journal of Cancer, Volume 88
Author(s): Haixing Wang, Beifang Li, Zhentao Liu, Jifang Gong, Lin Shao, Jun Ren, Yunyun Niu, Shiping Bo, Zhongwu Li, Yumei Lai, Sijia Lu, Jing Gao, Lin Shen
BackgroundHER2 status is significant to trastuzumab therapy; however, it is difficult to determine HER2 status accurately with few pieces of biopsies from advanced gastric cancer (AGC) due to highly heterogeneity and invasive behaviour, which will be investigated in this study.MethodsFifty-six patients with AGC were included in this study. Primary tumour tissues and matched plasmas before medication from 36 patients were retrospectively collected, and the other 20 patients with primary tumour tissues and paired plasmas were prospectively collected. HER2 expression and amplification in 56 tumour tissues were determined by immunohistochemistry (IHC) and dual in situ hybridisation (DISH), and HER2 copy number in 135 circulating tumour DNAs (ctDNAs) was judged by next-generation sequencing.ResultsFor tumour tissues, HER2 amplification by DISH was most commonly found in patients with HER2 score 3+by IHC. For plasmas, HER2 amplification defined as HER2 copy number >2.22 was identified in 26 of 56 patients. There was a high concordance of HER2 amplification between ctDNA and tumour tissues, suggesting that ctDNA could function as an alternative to screen HER2-targeted population. Moreover, the changes of HER2 copy number in ctDNA could efficiently monitor trastuzumab efficacy, the power of which was superior to commonly used markers carcinoembryonic antigen (CEA) and CA199, suggesting its potential role in clinical practice.ConclusionctDNA for HER2 analysis was strongly recommended to serve as a surrogate to screen trastuzumab-suitable population and monitor trastuzumab efficacy.



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The use of palliative medications before death from prostate cancer: Swedish population-based study with a comparative overview of European data

Publication date: January 2018
Source:European Journal of Cancer, Volume 88
Author(s): Magdalena Lycken, Linda Drevin, Hans Garmo, Pär Stattin, Jan Adolfsson, Ingela Franck Lissbrant, Lars Holmberg, Anna Bill-Axelson
BackgroundSymptoms of terminal cancer have previously been reported as undertreated. The aim of this study was to assess the use of palliative medications before death from prostate cancer.MethodsThis Swedish register study included men who died from 2009 to 2012 with prostate cancer as the underlying cause of death. We assessed the proportion who collected a prescription of androgen deprivation therapy, non-steroidal anti-inflammatory drugs, paracetamol, opioids, glucocorticoids, antidepressants, anxiolytics and sedative-hypnotics and the differences in treatment related to age, time since diagnosis, educational level, close relatives and comorbidities. Data were collected from 3 years before death from prostate cancer.ResultsWe included 8326 men. The proportion who received opioids increased from 30% to 72% during the last year of life, and 67% received a strong opioid at the time of death. Antidepressants increased from 13% to 22%, anxiolytics from 9% to 27% and sedative-hypnotics from 21% to 33%. Men without close relatives and older men had lower probability to receive opioids (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.47–0.66 for >85 years versus <70 years) and (OR 0.78, 95% CI: 0.66–0.92 for unmarried without children versus married with children).ConclusionOur results represent robust epidemiological data from Sweden for comparison of palliative care quality between countries. The findings indicate that men without close relatives and older men are disadvantaged with respect to the treatment of cancer pain and need closer attention from health care providers and highlight the importance to identify psychological distress in terminal prostate cancer.



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Improved stratification of pT1 melanoma according to the 8th American Joint Committee on Cancer staging edition criteria: A Dutch population-based study

Publication date: Available online 5 December 2017
Source:European Journal of Cancer
Author(s): D. Verver, W.J. Louwman, S. Koljenović, C. Verhoef, D.J. Grünhagen, A.C.J. van Akkooi
IntroductionThe 8th American Joint Committee on Cancer (AJCC) staging edition includes revisions regarding pT1 melanomas. We aimed to evaluate the expected impact of this edition on staging and survival in the Dutch pT1 melanoma population.MethodsIn total, 32,935 pT1 melanoma patients, whose data were retrieved from the Netherlands Cancer Registry between 2003 and 2015, were included in the study. Patients were stratified by the 6th AJCC edition (cohort 1: 2003–2009) and 7th edition (cohort 2: 2010–2015) and all reclassified according to the 8th edition. Stage migration, sentinel lymph node biopsy (SLNB) positivity rates and relative survival were analysed. Agreement between staging systems was calculated by Cohen's kappa coefficient.ResultsIn cohort 2, restaging according to the 8th edition led to an increase of 7% in the total number of patients staged pT1b. The kappa score for agreement between the 6th and 8th edition was 0.15 and 0.25 for agreement between 7th and 8th edition. Restaging according to the 8th edition resulted in a higher SLNB positivity rate for pT1b patients than pT1a patients (8% versus 5%, p = 0.08). Relative survival curves were predominantly similar between the staging editions.ConclusionsImplementation of the 8th AJCC staging edition will presumably not have major impact on the total number of Dutch pT1b patients. Consequently, the number of patients eligible for SLNB would roughly remain similar. In terms of SLNB positivity, the selection of high-risk pT1 melanoma patients is likely to improve. In addition, the 8th edition criteria for pT1 melanoma seem more workable for pathologists.



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Restrictive surgical approach to palliate angina in a patient with coronary three vessel disease and biventricular metastatic hepatocellular carcinoma

Abstract

Background

Metastatic cardiac tumors may cause different symptoms including angina, symptoms of heart failure and/or arrhythmia. In patients with concomitant coronary artery disease, it may be difficult to distinguish between angina caused by metastases to the heart, for example, by stealing perfusion from the coronary arteries, and angina caused by coronary stenosis. Identifying the origin of the symptoms is, however, essential for designing appropriate surgical strategies.

Case presentation

A 69-year-old male with multifocal recurrence of a hepatocellular carcinoma (HCC) presented with increasing ventricular arrhythmia and angina several weeks after posterior myocardial infarction and PCI of the RCA culprit lesion during which two further lesions present in the distal RCX and a posterolateral branch, and a chronically occluded LAD had not been addressed. MRI showed a large metastatic tumor infiltrating the walls of both ventricles as well as the interventricular septum. His debilitating symptoms were attributed to steal phenomena and/or perivascular compression caused by the metastatic tumor rather than the remaining coronary lesions, and he was offered a restrictive surgical approach consisting of debulking of the metastasis with an option for subsequent coronary intervention. The palliative surgical procedure resulted in a reduction of the tumor mass by half and sufficiently reduced the patient's symptoms so that further coronary intervention was not required.

Conclusions

Palliative surgery for metastases to the heart may benefit patients, provided that the origin of symptoms is identified correctly. It goes without saying that in a palliative setting, surgery should be limited to treating symptoms rather than performing extensive procedures addressing, for example, coronary artery or valve disease. Interventional cardiac procedures addressing not only CAD but also valve disease may supplement palliative tumor surgery.

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Restrictive surgical approach to palliate angina in a patient with coronary three vessel disease and biventricular metastatic hepatocellular carcinoma

Abstract

Background

Metastatic cardiac tumors may cause different symptoms including angina, symptoms of heart failure and/or arrhythmia. In patients with concomitant coronary artery disease, it may be difficult to distinguish between angina caused by metastases to the heart, for example, by stealing perfusion from the coronary arteries, and angina caused by coronary stenosis. Identifying the origin of the symptoms is, however, essential for designing appropriate surgical strategies.

Case presentation

A 69-year-old male with multifocal recurrence of a hepatocellular carcinoma (HCC) presented with increasing ventricular arrhythmia and angina several weeks after posterior myocardial infarction and PCI of the RCA culprit lesion during which two further lesions present in the distal RCX and a posterolateral branch, and a chronically occluded LAD had not been addressed. MRI showed a large metastatic tumor infiltrating the walls of both ventricles as well as the interventricular septum. His debilitating symptoms were attributed to steal phenomena and/or perivascular compression caused by the metastatic tumor rather than the remaining coronary lesions, and he was offered a restrictive surgical approach consisting of debulking of the metastasis with an option for subsequent coronary intervention. The palliative surgical procedure resulted in a reduction of the tumor mass by half and sufficiently reduced the patient's symptoms so that further coronary intervention was not required.

Conclusions

Palliative surgery for metastases to the heart may benefit patients, provided that the origin of symptoms is identified correctly. It goes without saying that in a palliative setting, surgery should be limited to treating symptoms rather than performing extensive procedures addressing, for example, coronary artery or valve disease. Interventional cardiac procedures addressing not only CAD but also valve disease may supplement palliative tumor surgery.

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Flat foveal contour simulating macular hole

Description

A 40-year-old healthy female was referred for macular hole in his both eyes detected during routine examination. Visual acuity was 20/20 OU unaided. Ocular examination of OD was unremarkable except for the presence of round red lesion at fovea (figure 1A, arrow) that was more prominent on green reflectance imaging (figure 1B, arrow). Spectral-domain optical coherence tomography showed a flattened foveal contour (figure 1C, arrows), which explained the appearance of macular hole. Similar findings were seen in OS. There were no ocular or systemic features suggestive of albinism.

Figure 1

Multicolour scanning laser image of right eye showing small red lesion (arrow) simulating macular hole (A) that is better seen on red free image (B). Apparent macular hole corresponds to flat foveal contour on optical coherence tomography (C).

The foveal contour and anatomy may vary...

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Complication of deep brain stimulation for Parkinsons disease

Description

A 58-year-old man with advanced Parkinson disease diagnosed 13 years before, was admitted for surgical placing of continuous bilateral high-frequency stimulation of the subthalamic nucleus.

The procedure was uneventful (lead used Medtronic DBS 3387; antibiotic prophylaxis: cefazolin 2 g at time of anaesthetic induction and 1 g every 8 hours in the first 24 hours) with a postoperative control CT scan showing good placement of the electrodes and no abnormalities (figure 1). The stimulation was switched on 72 hours after the procedure and within 24 hours the patient presented two epileptic seizures controlled with diazepam and stimulation was switched off. The head CT showed intra-axial hypodensity more prominent in the frontal area with a gaseous collection and oedema surrounding the right electrode pathway (figure 2). At the time there was no fever, no increase in inflammatory markers and a normal cell count in the lumbar puncture. However, antibiotic therapy (ceftriaxone...

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Mycobacterium tuberculosis of the elbow joint

Mycobacterium tuberculosis(TB) affecting the elbow joint is rarely reported in the developed world. We present the case of an 85-year-old Caucasian female who complained of a chronically discharging and painful wound across her left elbow during her admission for an ischaemic stroke. This was initially deemed to be either a bursitis or local manifestation of amyloid by her general practitioner and dermatologist respectively prior to admission. She was commenced on flucloxacillin by the medical team for presumed cellulitis with minimal response. A synovial fluid sample and repeated wound swabs yielded no growth from routine bacterial culture. Radiological assessment together with knowledge of her husband having previous TB raised the possibility of TB arthritis. Synovial fluid aspirate was subsequently sent for acid–alcohol fast bacilli microscopy and mycobacterial culture that confirmed M. tuberculosis. She was consequently started on multidrug TB therapy, over a year after the onset of her symptoms.

http://ift.tt/2Afmloa

Analysis of Drug Development Paradigms for Immune Checkpoint inhibitors

Immune checkpoint inhibitors have unique toxicities and response kinetics compared to cytotoxics and gene-targeted anti-cancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the US Food and Drug Administration (FDA) website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared to that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months (avelumab had the shortest timeline (52.33 months)). Response rates during early phase I trials (median =16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified.

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Analysis of Drug Development Paradigms for Immune Checkpoint inhibitors

Immune checkpoint inhibitors have unique toxicities and response kinetics compared to cytotoxics and gene-targeted anti-cancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the US Food and Drug Administration (FDA) website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared to that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months (avelumab had the shortest timeline (52.33 months)). Response rates during early phase I trials (median =16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified.

http://ift.tt/2kqWWRr

T cell densities in brain metastases are associated with patient survival times and diffusion tensor MRI changes

Brain metastases are common and are usually detected by magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) is a derivative MRI technique which can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain-tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity (MD) and fractional anisotropy (FA). The tissue samples were analysed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21, 95% CI 0.06 - 0.82, p=0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann Whitney U, p=0.037) as well as confounding completely the effect of FA in multivariate survival analyses. We conclude that the T cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, non-invasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.

http://ift.tt/2B8PP79

Mutational mechanisms that activate Wnt signaling and predict outcomes in colorectal cancer patients

APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding ß-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Further, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA data for colorectal cancer outcomes. Transcriptional patterns exhibited evidence of activated canonical Wnt signaling in both types of adenomas, with Apc-mutant adenomas also exhibiting unique changes in pathways related to proliferation, cytoskeletal organization and apoptosis. Apc-mutant adenomas were characterized by increased expression of the glial nexin Serpine2, the human ortholog of which was increased in advanced human colorectal tumors. Our results support the hypothesis that APC-mutant colorectal tumors are transcriptionally distinct from APC-wild-type colorectal tumors with canonical WNT signaling activated by other mechanisms, with possible implications for stratification and prognosis.

http://ift.tt/2Afgsat

Tamoxifen resistance in breast cancer is regulated by the EZH2-ER{alpha}-GREB1 transcriptional axis

Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or anti-estrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the anti-estrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.

http://ift.tt/2B8PH7F

A Systems Approach to Prostate Cancer Classification—Response

http://ift.tt/2BQfyOP

Emergence of High-Avidity Melan-A-Specific Clonotypes as a Reflection of Anti-PD-1 Clinical Efficacy

Therapeutic strategies using anti–PD-1–blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti–PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A–specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti–PD-1. We observed amplification of Melan-A–specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti–PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti–PD-1 therapy, our work describes the emergence of high-avidity Melan-A–specific clonotypes as a surrogate marker of treatment efficacy. Cancer Res; 77(24); 1–11. ©2017 AACR.

http://ift.tt/2k3Qwnv

A Systems Approach to Prostate Cancer Classification—Letter

http://ift.tt/2BQjjno

Occipitocervical Hemolymphangioma in an Adult with Neck Pain and Stiffness: Case Report and Literature Review

Introduction. Hemolymphangioma is an extremely rare malformation of the lymphatic and blood vessels. A limited number of hemolymphangioma cases occurring in the pancreas, extremities, spleen, and other organs have been reported until September 2017. To the best of our knowledge, no cases of hemolymphangioma in the occipitocervical region have been reported in the literature. Case Presentation. We reported the case of a 23-year-old male patient with an occipitocervical lesion presenting atypically as neck pain and stiffness over a period of five months. Although hemolymphangioma has historically demonstrated a female predilection (2.25 : 1 female to male) and presentation in the third to fourth decades of life, this case is an atypical manifestation occurring in a young male patient. The clinical characteristics and management choices of this uncommon case of hemolymphangioma in the occipitocervical region are discussed, and a review based on the available literature is also presented. Conclusion. Hemolymphangioma of the occipitocervical region is an uncommon presentation of a rare lesion. Although rare, hemolymphangioma should be considered a differential diagnosis for masses occurring in the occipitocervical region. Complete surgical resection is the treatment of choice and affords a good prognosis.

http://ift.tt/2ktk7KS

T cell densities in brain metastases are associated with patient survival times and diffusion tensor MRI changes

Brain metastases are common and are usually detected by magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) is a derivative MRI technique which can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain-tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity (MD) and fractional anisotropy (FA). The tissue samples were analysed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21, 95% CI 0.06 - 0.82, p=0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann Whitney U, p=0.037) as well as confounding completely the effect of FA in multivariate survival analyses. We conclude that the T cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, non-invasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.

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Mutational mechanisms that activate Wnt signaling and predict outcomes in colorectal cancer patients

APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding ß-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Further, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA data for colorectal cancer outcomes. Transcriptional patterns exhibited evidence of activated canonical Wnt signaling in both types of adenomas, with Apc-mutant adenomas also exhibiting unique changes in pathways related to proliferation, cytoskeletal organization and apoptosis. Apc-mutant adenomas were characterized by increased expression of the glial nexin Serpine2, the human ortholog of which was increased in advanced human colorectal tumors. Our results support the hypothesis that APC-mutant colorectal tumors are transcriptionally distinct from APC-wild-type colorectal tumors with canonical WNT signaling activated by other mechanisms, with possible implications for stratification and prognosis.

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Tamoxifen resistance in breast cancer is regulated by the EZH2-ER{alpha}-GREB1 transcriptional axis

Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or anti-estrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the anti-estrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.

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A Systems Approach to Prostate Cancer Classification—Response

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Emergence of High-Avidity Melan-A-Specific Clonotypes as a Reflection of Anti-PD-1 Clinical Efficacy

Therapeutic strategies using anti–PD-1–blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti–PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A–specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti–PD-1. We observed amplification of Melan-A–specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti–PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti–PD-1 therapy, our work describes the emergence of high-avidity Melan-A–specific clonotypes as a surrogate marker of treatment efficacy. Cancer Res; 77(24); 1–11. ©2017 AACR.

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A Systems Approach to Prostate Cancer Classification—Letter

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Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway

The aim of the present study was to investigate the effects of mangiferin on gastric carcinoma cells and to determine the possible mechanisms underlying such effects. The MTT assay was performed to evaluate the antiproliferative effect of mangiferin. Following treatment, apoptosis rates of SGC-7901 were established by flow cytometry and laser confocal microscopy, and western blot analysis was used to detect the expression of apoptosis-related proteins. The MTT assay showed that mangiferin inhibited the proliferation of SGC-7901 and BCG-823 cells in a dose-dependent and time-dependent manner. After SGC-7901 cells were exposed to mangiferin for 24, 48 and 72 h, the half-maximal inhibitory concentration values were 16.00, 8.63 and 4.79 µmol/l, respectively. SGC-7901 cell apoptosis induced by mangiferin was observed by Annexin V/PI doubling staining and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive staining. We found a significant decrease in Bcl-2, Bcl-xL and Mcl-1 expression and a significant increase in Bax, Bad and cleaved caspase-3 and caspase-9 expression in SGC-7901 cells by mangiferin treatment. Moreover, mangiferin significantly decreased the levels of p-PI3K, p-Akt and p-mTOR, but had no effects on those of PI3K, Akt and mTOR in epidermal growth factor-treated SGC-7901 cells. Interestingly, the proapoptotic effect of mangiferin on SGC-7901 cells was partially blocked by the Akt activator SC79, whereas LY294002 significantly increased mangiferin-induced apoptosis and growth inhibition. Taken together, our findings indicate that mangiferin effectively inhibits cell growth and induces apoptosis of gastric cancer cells through inhibiting the PI3K/Akt pathways with relative safety, and may be used as a novel chemotherapeutic agent against gastric cancer. Correspondence to Aman Xu, DSc, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, China Tel/fax: +86 551 62922205; e-mail: xuaman_1965@163.com Received July 15, 2017 Accepted November 17, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study

Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63–7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22–9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/1hexVwJ * Yong Zhang and Miaomiao Gou contributed equally to the writing of this article. Correspondence to Zhefeng Liu, PhD, General Hospital of People's Liberation Army, Beijing 100853, China Tel: +86 010 66875307; fax: +86 010 66939128; e-mail: liuzhefeng6691@hotmail.com Received September 6, 2017 Accepted November 15, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway

The aim of the present study was to investigate the effects of mangiferin on gastric carcinoma cells and to determine the possible mechanisms underlying such effects. The MTT assay was performed to evaluate the antiproliferative effect of mangiferin. Following treatment, apoptosis rates of SGC-7901 were established by flow cytometry and laser confocal microscopy, and western blot analysis was used to detect the expression of apoptosis-related proteins. The MTT assay showed that mangiferin inhibited the proliferation of SGC-7901 and BCG-823 cells in a dose-dependent and time-dependent manner. After SGC-7901 cells were exposed to mangiferin for 24, 48 and 72 h, the half-maximal inhibitory concentration values were 16.00, 8.63 and 4.79 µmol/l, respectively. SGC-7901 cell apoptosis induced by mangiferin was observed by Annexin V/PI doubling staining and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive staining. We found a significant decrease in Bcl-2, Bcl-xL and Mcl-1 expression and a significant increase in Bax, Bad and cleaved caspase-3 and caspase-9 expression in SGC-7901 cells by mangiferin treatment. Moreover, mangiferin significantly decreased the levels of p-PI3K, p-Akt and p-mTOR, but had no effects on those of PI3K, Akt and mTOR in epidermal growth factor-treated SGC-7901 cells. Interestingly, the proapoptotic effect of mangiferin on SGC-7901 cells was partially blocked by the Akt activator SC79, whereas LY294002 significantly increased mangiferin-induced apoptosis and growth inhibition. Taken together, our findings indicate that mangiferin effectively inhibits cell growth and induces apoptosis of gastric cancer cells through inhibiting the PI3K/Akt pathways with relative safety, and may be used as a novel chemotherapeutic agent against gastric cancer. Correspondence to Aman Xu, DSc, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, China Tel/fax: +86 551 62922205; e-mail: xuaman_1965@163.com Received July 15, 2017 Accepted November 17, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study

Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63–7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22–9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/1hexVwJ * Yong Zhang and Miaomiao Gou contributed equally to the writing of this article. Correspondence to Zhefeng Liu, PhD, General Hospital of People's Liberation Army, Beijing 100853, China Tel: +86 010 66875307; fax: +86 010 66939128; e-mail: liuzhefeng6691@hotmail.com Received September 6, 2017 Accepted November 15, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A method to combine target volume data from 3D and 4D planned thoracic radiotherapy patient cohorts for machine learning applications

The gross tumour volume (GTV) is predictive of clinical outcome and consequently features in many machine-learned models. 4D-planning, however, has prompted substitution of the GTV with the internal gross target volume (iGTV). We present and validate a method to synthesise GTV data from the iGTV, allowing the combination of 3D and 4D planned patient cohorts for modelling.

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Radiotherapy plus temozolomide in elderly patients with glioblastoma: a “real-life” report

The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comp...

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Radiotherapy plus temozolomide in elderly patients with glioblastoma: a “real-life” report

The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comp...

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Patterns of Care and Outcomes of Hypofractionated Chemoradiation Versus Conventionally Fractionated Chemoradiation for Glioblastoma in the Elderly Population

Purpose: This study evaluated practice patterns, outcomes, and predictors of survival for elderly patients with glioblastoma (GBM) receiving definitive chemoradiotherapy (CRT) with either hypofractionated radiotherapy or conventionally fractionated radiotherapy. Materials and Methods: The National Cancer Data Base was queried for patients age 65 years and above diagnosed with GBM between 2006 and 2012 that received definitive CRT with either hypofractionated radiotherapy (hCRT) or conventionally fractionated radiotherapy (cCRT). Patient, tumor, and treatment parameters were extracted. Statistics included Kaplan-Meier analysis to evaluate overall survival (OS) as well as Cox proportional hazards modeling to determine variables associated with OS. Propensity score matching was performed in order to assess groups in a balanced manner while reducing indication biases. Results: Altogether, 5126 patients met inclusion criteria; 126 (2.5%) underwent hCRT, while 5000 (97.5%) received cCRT. Temporal trends revealed that the use of hCRT is rising, especially in more recent years. Patients undergoing hCRT were older, with worse performance status, treated with biopsy only, and more likely to receive treatment at an academic facility. cCRT was associated with improved median OS (10.7 vs. 6.2 mo, P

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Improving Patient-reported Pain During Radiotherapy Through Nurse Involvement and Patient Education

Objectives: Pain management during radiotherapy helps assess quality of care. By establishing an intervention to address pain during on-treatment visits (OTVs), we aim to lower patient-reported pain scores. Methods: A total of 171 patients were included in the analysis: 58 were retrospectively reviewed to provide a control and 113 were prospectively enrolled and evaluated after the intervention. The intervention included (1) a pain management in-service performed with the resident physician and nurses, (2) distribution of pain management educational materials, and (3) nurse consultation for patients with a pain score ≥5 within 2 days of the in-service. Study aims were to reduce the number of pain scores ≥5 by 30% and increase the number of pain scores documented during every OTV to >90%. Results: Median patient age was 65 years. Before the intervention, the average DVPRS score at initial consultation was 2 (range, 0 to 9) and 98% of patients had scores documented during OTVs. Overall, 26% (44/171) of OTV scores measured ≥5. Following the intervention, average DVPRS score at initial consultation was 2 (range, 0 to 10) and 99% of scores were documented during OTVs. About 14% (49/341) of patient-reported scores were ≥5, representing an ~50% relative reduction (P=0.023). The number of patients with 2+ pain scores ≥5 was reduced from 21% (12/58) before the intervention to 11% (12/109) after the intervention (P=0.1068). Conclusion: Involving nursing staff in the education and follow-up of patients with uncontrolled pain during radiotherapy led to an ~50% relative reduction in patient-reported DVPRS scores of 5+ during weekly OTVs. Presented at ASTRO's 58th Annual Meeting in Boston, MA, USA. The authors declare no conflicts of interest. Reprints: Anamaria R. Yeung, MD, 2000 SW Archer Road, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: areyna@ufl.edu. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hemorrhage of liver and bone metastases as a result of rapid response to dual BRAF/MEK inhibition in metastatic melanoma: a case report

Combination therapy using a BRAF and MEK inhibitor significantly improves both progression-free and overall survival in patients with BRAF V600-mutated stage IV melanoma. Dual MAPK inhibition achieves an objective response in the majority of patients. We present a case of a woman with BRAF V600E-mutated malignant melanoma and rapidly progressing liver, bone, and lymph node metastases. The patient commenced dabrafenib and trametinib with clinical and biochemical signs of response after 2 days. On day 3 she developed grade 3 liver hemorrhage, which was successfully embolized. Her anemia responded appropriately to transfusions and stabilized after interventional resolution of the hemorrhagic event. Subsequently she developed a pathological fracture of the right proximal humerus. MRI showed cystic bone metastases with stigmata of bleeding. To our knowledge, this is the first case report of a patient with hemorrhage of both liver and bone metastases of a melanoma. As the patient responded rapidly to dabrafenib and trametinib we hypothesize that the hemorrhage may be due to rapid tumor necrosis and bleeding of affected tumor supplying blood vessels. Our case demonstrates the importance of considering tumoral bleeding as a side effect of BRAF and MEK inhibition in responding melanoma patients. Mechanical intervention can be effective in resolving this treatment-related adverse event. *Tine Loyson and Emilie Werbrouck contributed equally to the writing of this article. Correspondence to Oliver Bechter, PhD, MD, 49 Herestraat, 3000 Leuven, Belgium E-mail: oliver.bechter@uzleuven.be Received May 8, 2017 Accepted November 10, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Patterns of Care and Outcomes of Hypofractionated Chemoradiation Versus Conventionally Fractionated Chemoradiation for Glioblastoma in the Elderly Population

Purpose: This study evaluated practice patterns, outcomes, and predictors of survival for elderly patients with glioblastoma (GBM) receiving definitive chemoradiotherapy (CRT) with either hypofractionated radiotherapy or conventionally fractionated radiotherapy. Materials and Methods: The National Cancer Data Base was queried for patients age 65 years and above diagnosed with GBM between 2006 and 2012 that received definitive CRT with either hypofractionated radiotherapy (hCRT) or conventionally fractionated radiotherapy (cCRT). Patient, tumor, and treatment parameters were extracted. Statistics included Kaplan-Meier analysis to evaluate overall survival (OS) as well as Cox proportional hazards modeling to determine variables associated with OS. Propensity score matching was performed in order to assess groups in a balanced manner while reducing indication biases. Results: Altogether, 5126 patients met inclusion criteria; 126 (2.5%) underwent hCRT, while 5000 (97.5%) received cCRT. Temporal trends revealed that the use of hCRT is rising, especially in more recent years. Patients undergoing hCRT were older, with worse performance status, treated with biopsy only, and more likely to receive treatment at an academic facility. cCRT was associated with improved median OS (10.7 vs. 6.2 mo, P

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Improving Patient-reported Pain During Radiotherapy Through Nurse Involvement and Patient Education

Objectives: Pain management during radiotherapy helps assess quality of care. By establishing an intervention to address pain during on-treatment visits (OTVs), we aim to lower patient-reported pain scores. Methods: A total of 171 patients were included in the analysis: 58 were retrospectively reviewed to provide a control and 113 were prospectively enrolled and evaluated after the intervention. The intervention included (1) a pain management in-service performed with the resident physician and nurses, (2) distribution of pain management educational materials, and (3) nurse consultation for patients with a pain score ≥5 within 2 days of the in-service. Study aims were to reduce the number of pain scores ≥5 by 30% and increase the number of pain scores documented during every OTV to >90%. Results: Median patient age was 65 years. Before the intervention, the average DVPRS score at initial consultation was 2 (range, 0 to 9) and 98% of patients had scores documented during OTVs. Overall, 26% (44/171) of OTV scores measured ≥5. Following the intervention, average DVPRS score at initial consultation was 2 (range, 0 to 10) and 99% of scores were documented during OTVs. About 14% (49/341) of patient-reported scores were ≥5, representing an ~50% relative reduction (P=0.023). The number of patients with 2+ pain scores ≥5 was reduced from 21% (12/58) before the intervention to 11% (12/109) after the intervention (P=0.1068). Conclusion: Involving nursing staff in the education and follow-up of patients with uncontrolled pain during radiotherapy led to an ~50% relative reduction in patient-reported DVPRS scores of 5+ during weekly OTVs. Presented at ASTRO's 58th Annual Meeting in Boston, MA, USA. The authors declare no conflicts of interest. Reprints: Anamaria R. Yeung, MD, 2000 SW Archer Road, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: areyna@ufl.edu. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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FDA Approves Alectinib For Initial Treatment of ALK-Positive Lung Cancer

FDA has approved alectinib (Alecensa) as a first-line treatment option for patients with advanced non-small cell lung cancer that is ALK positive. Alectinib is the third ALK inhibitor to be approved in this setting.

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FDA Approves Alectinib For Initial Treatment of ALK-Positive Lung Cancer

FDA has approved alectinib (Alecensa) as a first-line treatment option for patients with advanced non-small cell lung cancer that is ALK positive. Alectinib is the third ALK inhibitor to be approved in this setting.

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Advances in Chromosomal Translocations and Fusion Genes in Sarcomas and Potential Therapeutic Applications

Publication date: Available online 6 December 2017
Source:Cancer Treatment Reviews
Author(s): Xin Xiao, Cassandra C. Garbutt, Francis Hornicek, Zheng Guo, Zhenfeng Duan
Chromosomal translocations and fusion genes are very common in human cancer especially in subtypes of sarcomas, such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and liposarcoma. The discovery of novel chromosomal translocations and fusion genes in different tumors are due to the advancement of next-generation sequencing (NGS) technologies such as whole genome sequencing. Recently, many novel chromosomal translocations and gene fusions have been identified in different types of sarcoma through NGS approaches. In addition to previously known sarcoma fusion genes, these novel specific fusion genes and associated molecular events represent important targets for novel therapeutic approaches in the treatment of sarcomas. This review focuses on recent advances in chromosomal translocations and fusion genes in sarcomas and their potential therapeutic applications in the treatment of sarcomas.



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Ongoing Unmet Needs in Treating Estrogen Receptor-Positive/HER2-Negative Metastatic Breast Cancer

Publication date: Available online 6 December 2017
Source:Cancer Treatment Reviews
Author(s): Gül A. Başaran, Chris Twelves, Véronique Diéras, Javier Cortés, Ahmad Awada
Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2)−negative advanced or metastatic breast cancer (MBC) is the most common MBC subtype and currently remains incurable, with a median overall survival of 24.8 months (95% confidence interval, 21.3–30.3). Common sites of metastases are bone, viscera, and brain, causing significant symptoms that negatively affect patient functioning, quality of life (QoL), and work productivity. Guidelines state that endocrine therapy (ET) is preferable to chemotherapy as first-line treatment for patients with ER+ MBC, regardless of limited visceral metastases, unless rapid tumor response is required or ET resistance is suspected. Although response rates up to 40% have been reported for first-line MBC treatment, the majority of initial responders eventually develop ET resistance. Notwithstanding the steep decline in efficacy between first and later lines of ET, some patients may receive chemotherapy earlier than necessary. Although new treatments have been approved for patients with ER+/HER2− advanced or MBC in the past decade, neither survival nor QoL appear to have improved significantly. Thus, there remain significant unmet needs for this patient population, including improved survival, maintaining or improving patient QoL, and emphasizing the importance of treatment selection to assist healthcare practitioners managing patient care. In this review, we identify current challenges and unmet needs in this patient population, review cutting-edge treatments, and provide clinically relevant suggestions for treatment selection that can optimize outcomes and patients' health-related QoL.



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Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics

Publication date: Available online 6 December 2017
Source:Cancer Treatment Reviews
Author(s): Panagiotis F. Christopoulos, Alexandre Corthay, Michael Koutsilieris
Despite the major discoveries occurred in oncology the recent years, breast malignancies remain one of the most common causes of cancer-related deaths for women in developed countries. Development of HER2-targeting drugs has been considered a breakthrough in anti-cancer approaches and alluded to the potential of targeting growth factors in breast cancer (BrCa) therapeutics. More than twenty five years have passed since the Insulin-like Growth Factor-1 (IGF-1) system was initially recognized as a potential target candidate in BrCa therapy. To date, a growing body of studies have implicated the IGF-1 signaling with the BrCa biology. Despite the promising experimental evidence, the impression from clinical trials is rather disappointing. Several reasons may account for this and the last word regarding the efficacy of this system as a target candidate in BrCa therapeutics is probably not written yet. Herein, we provide the theoretical basis, as well as, a comprehensive overview of the current literature, regarding the different strategies targeting the various components of the IGF-1/IGF-1R axis in several pathophysiological aspects of BrCa, including the tumor micro-environment and cancer stemness. In addition, we review the rationale for targeting the IGF-1 system in the different BrCa molecular subtypes and in treatment resistant breast tumors with a focus on both the molecular mechanisms and on the clinical perspectives of such approaches in specific population subgroups. We also discuss the future challenges, as well as, the development of novel molecules and strategies targeting the system and suggest potential improvements in the field.



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Management of QT prolongation induced by anti-cancer drugs: target therapy and old agents. Different algorithms for different drugs.

Publication date: Available online 6 December 2017
Source:Cancer Treatment Reviews
Author(s): Carmela Coppola, Anna Rienzo, Giovanna Piscopo, Antonio Barbieri, Claudio Arra, Nicola Maurea

Graphical abstract

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Moving Toward Improved Outcomes in Salvage Laryngectomy

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Celebrating the Annals of Surgical Oncology’s 25-Year Anniversary: One of the Most Cited Surgical Journals in the World

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Neoadjuvant Therapy Versus Upfront Resection for Pancreatic Cancer: The Actual Spectrum and Clinical Burden of Postoperative Complications

Abstract

Background

Neoadjuvant therapy (NAT) is used for borderline-resectable or locally advanced pancreatic cancer (PDAC) and exhibits promising results in terms of pathological outcomes. However, little is known about its effect on surgical complications.

Methods

We analyzed 445 pancreatic resections for PDAC from 2014 to 2016 at The Pancreas Institute, Verona University Hospital. The Modified Accordion Severity Grading System and average complication burden (ACB) were used to compare patients treated with NAT with patients who underwent upfront surgery (UFS).

Results

Of 305 pancreaticoduodenectomies (PD), patients treated with NAT (n = 99) had less pancreatic fistula (POPF, 9.1% vs. 15.6%, p = 0.05) without grade C cases, but grade B ACB was increased (0.28 for NAT vs. 0.24 for UFS, p = 0.05). The postpancreatectomy hemorrhage (PPH) rate was lower in the NAT group (9.1% vs. 14.6%, p = 0.02), but ACB grades B (0.37 for NAT vs. 0.26 for UFS, p = 0.03) and C (0.43 for NAT vs. 0.29 for UFS, p = 0.05) were increased. Delayed gastric emptying (DGE) was increased in NAT cases (15.2% vs. 8.3%, p = 0.04), with higher grade C ACB (0.43 for NAT vs. 0.29 for UFS, p = 0.03). Of 94 distal pancreatectomies (DP), NAT patients (n = 26) developed more grade C POPF (11.5% vs. 1.5%, p = 0.04) and DGE (11.5% vs. 2.9%, p = 0.01) without differences in ACB.

Conclusions

Patients undergoing PD for PDAC after NAT exhibited reduced incidence of POPF and PPH but increased incidence of DGE compared with patients treated with UFS. Among patients developing postoperative complications after PD, those receiving NAT were associated with increased clinical burden.

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STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro

Abstract

Background

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype.

Methods

STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing.

Results

Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G₀/G₁, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls.

Conclusions

STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.

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Effects of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the Treatment of Goblet Cell Carcinoma: A Prospective Cohort Study

Abstract

Background

Goblet cell carcinoma (GCC) of the appendix is a rare disease. Treatment options vary according to disease staging. Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) may improve survival in patients with peritoneal spreading.

Objective

The aim of this study was to examine the prognosis of patients with appendiceal GCC treated per protocol, and to evaluate the results of CRS+HIPEC in cases of peritoneal spreading.

Methods

From 2009 to 2016, a total of 48 GCC patients were referred to the European Neuroendocrine Tumour Center of Excellence, Aarhus University Hospital. All patients received treatment per protocol according to disease staging. In patients with localized disease, the treatment was a right hemicolectomy. Patients with peritoneal spread who met the inclusion criteria for CRS + HIPEC, as well as patients with high-risk features of developing peritoneal spread, received CRS + HIPEC. If too-extensive disease was found, palliative chemotherapy was offered.

Results

Overall survival for patients with localized disease (n = 6) or deemed at risk of peritoneal spread (n = 8) was 100% after a median follow-up of 3.5 years. In patients with peritoneal spread and eligible for CRS+HIPEC(n = 27), the median survival was 3.2 years [95% confidence interval (CI) 2.3–4.1] and the 5-year survival rate was 57%. In contrast, the median survival for patients with too-extensive intraperitoneal disease (n = 7) was 1.3 years (95% CI 0.6–2.0), with a 3-year survival rate of 20%.

Conclusions

Long-term survival can be achieved in patients with peritoneal spread treated with CRS + HIPEC. CRS+HIPEC was associated with a favorable outcome in GCC patients at high-risk of developing peritoneal spread.

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Impact of Sarcopenia on Unplanned Readmission and Survival After Esophagectomy in Patients with Esophageal Cancer

Abstract

Background

Although sarcopenia increases postoperative complications following esophagectomy, its effects on prognosis remain unclear. This study was performed to identify the effect of sarcopenia on 90-day unplanned readmission and overall survival (OS) after esophagectomy.

Methods

Ninety-eight patients with esophageal cancer who underwent esophagectomy were enrolled in this study. Unplanned readmission was defined as any emergent hospitalization within 90 days after discharge. Sarcopenia, defined as low muscle mass plus low muscle strength and/or low physical performance according to the Asian consensus definition, was assessed prior to esophagectomy. Multivariate logistic regression analysis was performed to identify factors that contributed to 90-day unplanned readmission. OS was estimated using the Kaplan–Meier method, and a Cox proportional hazards model was used to assess the relationship between sarcopenia and OS.

Results

Thirty-one patients (31.6%) were diagnosed with sarcopenia. The 90-day unplanned readmission rate was significantly higher in patients with sarcopenia than those without (42.9% vs. 16.4%, respectively; p = 0.01). Multivariable logistic regression analysis showed that sarcopenia was an independent predictor of 90-day unplanned readmission [odds ratio 3.71, 95% confidence interval (CI) 1.29–11.05; p = 0.02], and the log-rank test showed that sarcopenia was associated with OS (p = 0.01). Moreover, sarcopenia was a significant predictor of OS after adjustment for age, sex, and pathological stage (hazard ratio 2.35, 95% CI 1.21–4.54; p = 0.01).

Conclusions

Sarcopenia is a risk factor for 90-day unplanned readmission and OS following esophagectomy. Assessment of sarcopenia could help to identify patients at higher risk of a poor prognosis after esophagectomy.

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Moving Toward Improved Outcomes in Salvage Laryngectomy

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Celebrating the Annals of Surgical Oncology’s 25-Year Anniversary: One of the Most Cited Surgical Journals in the World

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Neoadjuvant Therapy Versus Upfront Resection for Pancreatic Cancer: The Actual Spectrum and Clinical Burden of Postoperative Complications

Abstract

Background

Neoadjuvant therapy (NAT) is used for borderline-resectable or locally advanced pancreatic cancer (PDAC) and exhibits promising results in terms of pathological outcomes. However, little is known about its effect on surgical complications.

Methods

We analyzed 445 pancreatic resections for PDAC from 2014 to 2016 at The Pancreas Institute, Verona University Hospital. The Modified Accordion Severity Grading System and average complication burden (ACB) were used to compare patients treated with NAT with patients who underwent upfront surgery (UFS).

Results

Of 305 pancreaticoduodenectomies (PD), patients treated with NAT (n = 99) had less pancreatic fistula (POPF, 9.1% vs. 15.6%, p = 0.05) without grade C cases, but grade B ACB was increased (0.28 for NAT vs. 0.24 for UFS, p = 0.05). The postpancreatectomy hemorrhage (PPH) rate was lower in the NAT group (9.1% vs. 14.6%, p = 0.02), but ACB grades B (0.37 for NAT vs. 0.26 for UFS, p = 0.03) and C (0.43 for NAT vs. 0.29 for UFS, p = 0.05) were increased. Delayed gastric emptying (DGE) was increased in NAT cases (15.2% vs. 8.3%, p = 0.04), with higher grade C ACB (0.43 for NAT vs. 0.29 for UFS, p = 0.03). Of 94 distal pancreatectomies (DP), NAT patients (n = 26) developed more grade C POPF (11.5% vs. 1.5%, p = 0.04) and DGE (11.5% vs. 2.9%, p = 0.01) without differences in ACB.

Conclusions

Patients undergoing PD for PDAC after NAT exhibited reduced incidence of POPF and PPH but increased incidence of DGE compared with patients treated with UFS. Among patients developing postoperative complications after PD, those receiving NAT were associated with increased clinical burden.

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STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro

Abstract

Background

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype.

Methods

STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing.

Results

Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G₀/G₁, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls.

Conclusions

STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.

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Effects of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the Treatment of Goblet Cell Carcinoma: A Prospective Cohort Study

Abstract

Background

Goblet cell carcinoma (GCC) of the appendix is a rare disease. Treatment options vary according to disease staging. Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) may improve survival in patients with peritoneal spreading.

Objective

The aim of this study was to examine the prognosis of patients with appendiceal GCC treated per protocol, and to evaluate the results of CRS+HIPEC in cases of peritoneal spreading.

Methods

From 2009 to 2016, a total of 48 GCC patients were referred to the European Neuroendocrine Tumour Center of Excellence, Aarhus University Hospital. All patients received treatment per protocol according to disease staging. In patients with localized disease, the treatment was a right hemicolectomy. Patients with peritoneal spread who met the inclusion criteria for CRS + HIPEC, as well as patients with high-risk features of developing peritoneal spread, received CRS + HIPEC. If too-extensive disease was found, palliative chemotherapy was offered.

Results

Overall survival for patients with localized disease (n = 6) or deemed at risk of peritoneal spread (n = 8) was 100% after a median follow-up of 3.5 years. In patients with peritoneal spread and eligible for CRS+HIPEC(n = 27), the median survival was 3.2 years [95% confidence interval (CI) 2.3–4.1] and the 5-year survival rate was 57%. In contrast, the median survival for patients with too-extensive intraperitoneal disease (n = 7) was 1.3 years (95% CI 0.6–2.0), with a 3-year survival rate of 20%.

Conclusions

Long-term survival can be achieved in patients with peritoneal spread treated with CRS + HIPEC. CRS+HIPEC was associated with a favorable outcome in GCC patients at high-risk of developing peritoneal spread.

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Impact of Sarcopenia on Unplanned Readmission and Survival After Esophagectomy in Patients with Esophageal Cancer

Abstract

Background

Although sarcopenia increases postoperative complications following esophagectomy, its effects on prognosis remain unclear. This study was performed to identify the effect of sarcopenia on 90-day unplanned readmission and overall survival (OS) after esophagectomy.

Methods

Ninety-eight patients with esophageal cancer who underwent esophagectomy were enrolled in this study. Unplanned readmission was defined as any emergent hospitalization within 90 days after discharge. Sarcopenia, defined as low muscle mass plus low muscle strength and/or low physical performance according to the Asian consensus definition, was assessed prior to esophagectomy. Multivariate logistic regression analysis was performed to identify factors that contributed to 90-day unplanned readmission. OS was estimated using the Kaplan–Meier method, and a Cox proportional hazards model was used to assess the relationship between sarcopenia and OS.

Results

Thirty-one patients (31.6%) were diagnosed with sarcopenia. The 90-day unplanned readmission rate was significantly higher in patients with sarcopenia than those without (42.9% vs. 16.4%, respectively; p = 0.01). Multivariable logistic regression analysis showed that sarcopenia was an independent predictor of 90-day unplanned readmission [odds ratio 3.71, 95% confidence interval (CI) 1.29–11.05; p = 0.02], and the log-rank test showed that sarcopenia was associated with OS (p = 0.01). Moreover, sarcopenia was a significant predictor of OS after adjustment for age, sex, and pathological stage (hazard ratio 2.35, 95% CI 1.21–4.54; p = 0.01).

Conclusions

Sarcopenia is a risk factor for 90-day unplanned readmission and OS following esophagectomy. Assessment of sarcopenia could help to identify patients at higher risk of a poor prognosis after esophagectomy.

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FOXA1 inhibits hepatocellular carcinoma progression by suppressing PIK3R1 expression in male patients

Forkhead box A1 (FOXA1) expression is associated with various types of tumors; however, the function and underlying mechanism of FOXA1 in the development of hepatocellular carcinoma (HCC) remains obscure.

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Identification and validation of a 44-gene expression signature for the classification of renal cell carcinomas

Renal cancers account for more than 3% of all adult malignancies and cause more than 23,400 deaths per year in China alone. The four most common types of kidney tumours include clear cell, papillary, chromopho...

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Profiling differential microRNA expression between in situ, infiltrative and lympho-vascular space invasive breast cancer: a pilot study

Abstract

Ductal carcinoma in situ (DCIS), invasive breast cancer (IBC) and lympho-vascular invasion (LVI) represent distinct stages in breast cancer progression with different clinical implications. Altered microRNA (miRNA) expression may play a role in mediating the progression of DCIS to IBC and LVI. The aim of this pilot study was to investigate whether differential miRNA expression could play a role in breast cancer progression. Cancer cells from DCIS, IBC and LVI were microdissected from formalin fixed paraffin embedded (FFPE) tissue of five breast cancer samples. MiRNA profiling of extracted RNA was performed using the TaqMan^® Array Human MicroRNA Cards A and B v3.0. Candidate miRNAs and gene targets were validated by qPCR. 3D culture of MCF10A, MCF10DCIS.com and T47D cells were used as models for normal, DCIS and IBC. Immunohistochemistry of candidate genes was performed on FFPE 3D cell cultures as well as on tissue microarray which included cores of DCIS and IBC samples. MiR-150, miR-126 and miR-155 were found to be more highly expressed in IBC and LVI compared to DCIS. Gene targets of these miRNAs, RhoA, PEG10 and MYB, were found to be more highly expressed in DCIS compared to IBC by qPCR and in MCF10A and MCF10DCIS.com cells compared to T47D cells by immunohistochemistry. There was no difference in intensity of staining of RhoA by immunohistochemistry in DCIS versus IBC samples on tissue microarray. In this pilot study, we found evidence to support a potential role for variation in miRNA levels in the transition from DCIS to IBC.

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Profiling differential microRNA expression between in situ, infiltrative and lympho-vascular space invasive breast cancer: a pilot study

Abstract

Ductal carcinoma in situ (DCIS), invasive breast cancer (IBC) and lympho-vascular invasion (LVI) represent distinct stages in breast cancer progression with different clinical implications. Altered microRNA (miRNA) expression may play a role in mediating the progression of DCIS to IBC and LVI. The aim of this pilot study was to investigate whether differential miRNA expression could play a role in breast cancer progression. Cancer cells from DCIS, IBC and LVI were microdissected from formalin fixed paraffin embedded (FFPE) tissue of five breast cancer samples. MiRNA profiling of extracted RNA was performed using the TaqMan^® Array Human MicroRNA Cards A and B v3.0. Candidate miRNAs and gene targets were validated by qPCR. 3D culture of MCF10A, MCF10DCIS.com and T47D cells were used as models for normal, DCIS and IBC. Immunohistochemistry of candidate genes was performed on FFPE 3D cell cultures as well as on tissue microarray which included cores of DCIS and IBC samples. MiR-150, miR-126 and miR-155 were found to be more highly expressed in IBC and LVI compared to DCIS. Gene targets of these miRNAs, RhoA, PEG10 and MYB, were found to be more highly expressed in DCIS compared to IBC by qPCR and in MCF10A and MCF10DCIS.com cells compared to T47D cells by immunohistochemistry. There was no difference in intensity of staining of RhoA by immunohistochemistry in DCIS versus IBC samples on tissue microarray. In this pilot study, we found evidence to support a potential role for variation in miRNA levels in the transition from DCIS to IBC.

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The Impact of Academic Facility Type and Case Volume On Survival in Patients Undergoing Curative Radiotherapy for Muscle-Invasive Bladder Cancer

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Amishi Bajaj, Brendan Martin, Richa Bhasin, Courtney Hentz, Alec M. Block, Matthew M. Harkenrider, Abhishek A. Solanki
BackgroundBladder-preserving curative radiation therapy (RT) has been established as an excellent treatment option for select patients with muscle-invasive bladder cancer (MIBC). However, some clinicians have concern that good outcomes are only achievable at high volume facilities and academic centers, questioning successful reproducibility of curative RT at smaller centers. The present study sought to determine if treatment at academic centers (AC) or high-volume facilities (HVF) was associated with better overall survival (OS) than treatment at non-academic centers (NAC) or lower-volume facilities (LVF).Materials and MethodsWe performed a retrospective cohort study of National Cancer Database (NCDB) patients (n=2,763) with cT2-4 N0 M0 transitional cell MIBC who received curative RT (60-70 Gy) with or without concurrent chemotherapy. Cox proportional hazards models were used to estimate the instantaneous hazard of death as a function of univariable and multivariable patient characteristics and clinical measures.ResultsUnivariable analysis (UVA) demonstrated that academic facility type was significantly associated with improved OS (HR = 0.88, 95% CI: 0.79-0.98, p=.02), while higher case volume was not associated with improved survival (HR = 0.97, 95% CI: 0.92-1.01, p=.15). MVA revealed no differences in OS for treatment at AC vs. NAC (HR = 0.94, 95% CI: 0.84-1.06; p=.31) or HVF vs. LVF (HR = 0.99, 95% CI: 0.94-1.04; p = .60). 2-year OS was 54.5% (95% CI: 52.5-56.4%) and 5-year OS was 28.9% (95% CI: 27.0-30.8%).ConclusionsAlthough some providers are cautious about offering curative radiotherapy at all centers, this large hospital-based study suggests that facility type and volume are not significantly associated with OS for patients undergoing curative RT after accounting for other clinically relevant risk factors. The results of this study demonstrate that curative RT in the treatment of MIBC may be considered for patients regardless of facility type or volume.

Teaser

We conducted a retrospective cohort study of patients in the National Cancer Database with muscle-invasive bladder cancer undergoing curative radiotherapy to identify whether the facility type and treating facility's case volume impact survival outcomes. When controlling for disease extent and treatment characteristics, patients at academic and non-academic facilities and low and high volume facilities had similar survival outcomes. Thus bladder-sparing curative radiotherapy should be discussed and offered confidently at most centers.


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Carotid Dosimetry and the Risk of Carotid Blowout Syndrome Following Re-irradiation with Head and Neck Stereotactic Body Radiation Therapy

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Brian J. Gebhardt, John A. Vargo, Diane Ling, Brianna Jones, Mary Mohney, David A. Clump, James P. Ohr, Robert L. Ferris, Dwight E. Heron
Background/PurposeStereotactic Body Radiation Therapy (SBRT) is an increasingly used technique for re-irradiation of recurrent head-and-neck cancers (rHNC). Rates of carotid blowout syndrome (CBOS), which is defined as rupture and hemorrhage from the carotid artery or its major branches following re-irradiation in the absence of residual or progressive disease, have varied from 0-17% occurring at a median of 4-5 months following SBRT. This has prompted some to aggressively spare the carotids or avoid SBRT in patients with arterial encasement. Our institutional practice has not excluded patients from SBRT based on extent of carotid involvement or carotid dose. Thus, we aimed to correlate carotid dose and risk of CBOS; hypothesizing that carotid dose does not correlate with CBOS.Methods/MaterialsWe retrospectively reviewed 186 patients with recurrent, previously-irradiated head-and-neck cancer treated between January 2008 and March 2013. Patients treated early in our experience with incomplete dosimetry were excluded from analysis (n=111). A total of 75 patients were identified providing 150 carotid arteries for analysis. Median follow-up was 8 months (range: 1-91) for all patients, and 37 months for surviving patients (range: 31-91]. Patients were treated with linear accelerator-based SBRT to a median dose up to 44Gy (range: 40-50 Gy) in 5 fractions delivered on a twice-weekly basis. Concurrent Cetuximab was utilized in 63 patients (84%). The bilateral common, internal, and external carotid arteries were delineated 2cm above and below the planning target volume. The maximum dose to 0.1cc (D0.1cc), 1cc (D1cc), 2cc (D2cc) of the carotid and the mean carotid dose from SBRT were recorded and analyzed for association with carotid bleeding events using binary logistic regression.ResultsMedian re-irradiation interval was 20 months (range: 3-423), median prior radiation dose was 70 Gy (range: 52.5-140). Sixteen patients (21.3%) received more than 1 course of SBRT, and the cumulative carotid doses from fused summary plans were recorded. The overall median D0.1cc, D1cc, D2cc, and mean carotid doses were 40.8 Gy [interquartile range (IQR): 21.6-47.6], 26.8 Gy [IQR: 14.1-42.1], 15.4 Gy [IQR: 8.4-32.7], and 15.0 Gy [IQR: 8.9-23.3], respectively. There were a total of 4 bleeding events (5.3%): 2 patients (2.7%) had mucosal bleeds that resolved following embolization of carotid branches, and 2 patients (2.7%) died from complications of CBOS. In the 2 patients suffering CBOS, the D0.1cc were 48.4 Gy and 47.6 Gy. There was no significant association between bleeding events and D1cc (p=0.280), D2cc (p=0.571), or mean dose (p=0.568). There was a trend toward increased risk of bleeding and D0.1cc (p=0.080).ConclusionsThese results demonstrate a low risk of bleeding following re-irradiation with SBRT when 5 fractions are delivered on non-consecutive days even when tumor is completely encasing the carotid artery. While limited by low number of events, no significant association was found between dose-volume parameters and the risk of carotid bleeding. No CBOS noted when D0.1cc was <47.6 Gy.

Teaser

Stereotactic body radiation therapy has emerged as a viable treatment option for recurrent head and neck cancers after prior irradiation, though carotid dose constraints are not defined. The maximum dose to 0.1cc, 1cc, 2cc of the carotid and the mean dose were analyzed for association with bleeding. No significant association was found between dose-volume parameters and risk of carotid bleeding, and no CBOS noted when D0.1cc was <47.6 Gy.


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Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Linda Chen, Jacqueline Douglass, Lawrence Kleinberg, Xiaobu Ye, Ariel E. Marciscano, Patrick M. Forde, Julie Brahmer, Evan Lipson, William Sharfman, Hans Hammers, Jarushka Naidoo, Chetan Bettegowda, Michael Lim, Kristin J. Redmond
PurposeTo characterize the effect of concurrent stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) and immune checkpoint inhibitors (ICI) on patient outcome and safety in patients with brain metastases (BM).Materials/Methods: We retrospectively identified metastatic non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) patients who had BM treated with SRS/SRT from 2010-2016 without prior whole brain radiotherapy (WBRT). We included SRS/SRT patients who were treated with anti-CTLA4 (ipilimumab) and anti-PD-1 (nivolumab, pembrolizumab). Patients who were given ICI on active or unreported clinical trials were excluded, and concurrent ICI was defined as given within 2 weeks of SRS/SRT. Patients were managed with SRS/SRT, SRS/SRT with non-concurrent ICI, and SRS/SRT with concurrent ICI. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves, and cox proportional hazard models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events (irAEs), and new BM.Results260 patients were treated with SRS/SRT to 623 brain metastases. 181 were treated with SRS/SRT only and 79 with SRS/SRT and ICI, with 35% of patients treated with concurrent SRS/SRT and ICI. Concurrent ICI was not associated with increased rates of irAEs or acute neurologic toxicity and predicted for a decreased likelihood of developing ≥ 3 new BM following SRS/SRT (p=0.045, OR 0.337). Median OS for patients treated with SRS/SRT, SRS/SRT and non-concurrent ICI, and SRS/SRT with concurrent ICI was 12.9, 14.5, and 24.7 months respectively. Concurrent SRS/SRT and ICI was associated with improved OS compared to SRS/SRT only (p=0.002, HR 2.69) and compared to non-concurrent SRS/SRT and ICI (p=0.006, HR 2.40) on multivariate analyses. The OS benefit of Concurrent SRS/SRT and ICI was significant in comparison to patients treated with SRS/SRT pre (p=0.002, HR 3.82) or post (p=0.021, HR 2.64) ICI.ConclusionDelivering SRS/SRT with concurrent ICI may be associated with decreased incidence of new BM and favorable survival outcomes without increased rates of adverse events.

Teaser

Radiation is hypothesized to augment the immunogenicity of tumor cells. We retrospectively evaluated survival outcomes, incidence of new brain metastases, and treatment-related adverse events in patients who received stereotactic radiosurgery for brain metastases with concurrent immune checkpoint inhibition, with non-concurrent immune checkpoint inhibition, and with stereotactic radiosurgery alone. Delivering SRS with concurrent ICI may be associated with decreased incidence of new BM and favorable survival outcomes without increased rates of adverse events.


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Locally ablative radio therapy of a primary human small cell lung cancer tumor decreases the number of spontaneous metastases in two xenograft models

Publication date: Available online 6 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Thorsten Frenzel, Jordana Siekmann, Carsten Grohmann, Ursula Valentiner, Rüdiger Schmitz, Kristoffer Riecken, Boris Fehse, Udo Schumacher, Tobias Lange, Andreas Krüll
IntroductionCancer patients mainly die from distant metastases, for which small cell lung cancer (SCLC) serves as an instructive example. As it is still under debate whether radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT) or chemotherapy (ChT) may promote metastatic spread, we investigated the influence of these treatments on SCLC metastases in two xenograft models.Methods and materials1 x 10⁶ human SCLC cells (OH1, H69) were subcutaneously injected into SCID mice to form a local primary tumor node at the lower trunk. RT, OP, RChT, or ChT were started after development of palpable tumors. ChT was given as a single intraperitoneal injection of cisplatin. RT was 5 x 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control groups A) and at the end of the experiment (control groups B). Pro-apoptotic, anti-proliferative, anti-angiogenic, and hypoxic effects were assessed by Feulgen, Ki-67, S1P1 receptor, and HIF1α staining, respectively. Quantitative Alu-PCR was used to determine circulating tumor cells (CTCs) in the blood, and disseminated tumor cells (DTCs) in the lungs, bone marrow, liver, and brain.ResultsIn both xenograft models, RT and RChT abrogated local tumor growth indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination, but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in case of relapse-free surgery, similar effects could be achieved by OP.ConclusionOur models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regards to suppression of CTCs and DTCs.

Teaser

The influence of radiotherapy, surgery, chemotherapy, and radio-chemotherapy on local primary tumor growth and on spontaneous distant metastasis formation was investigated in two human small cell lung cancer xenograft mouse models. Local tumor control was most important to suppress metastasis formation. Most interestingly, radiotherapy was not only locally ablative and prevented spontaneous distant metastasis formation over time, but even reduced the metastatic cell load in distant organs pre-existing at the time of therapy induction.


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The Impact of Academic Facility Type and Case Volume On Survival in Patients Undergoing Curative Radiotherapy for Muscle-Invasive Bladder Cancer

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Amishi Bajaj, Brendan Martin, Richa Bhasin, Courtney Hentz, Alec M. Block, Matthew M. Harkenrider, Abhishek A. Solanki
BackgroundBladder-preserving curative radiation therapy (RT) has been established as an excellent treatment option for select patients with muscle-invasive bladder cancer (MIBC). However, some clinicians have concern that good outcomes are only achievable at high volume facilities and academic centers, questioning successful reproducibility of curative RT at smaller centers. The present study sought to determine if treatment at academic centers (AC) or high-volume facilities (HVF) was associated with better overall survival (OS) than treatment at non-academic centers (NAC) or lower-volume facilities (LVF).Materials and MethodsWe performed a retrospective cohort study of National Cancer Database (NCDB) patients (n=2,763) with cT2-4 N0 M0 transitional cell MIBC who received curative RT (60-70 Gy) with or without concurrent chemotherapy. Cox proportional hazards models were used to estimate the instantaneous hazard of death as a function of univariable and multivariable patient characteristics and clinical measures.ResultsUnivariable analysis (UVA) demonstrated that academic facility type was significantly associated with improved OS (HR = 0.88, 95% CI: 0.79-0.98, p=.02), while higher case volume was not associated with improved survival (HR = 0.97, 95% CI: 0.92-1.01, p=.15). MVA revealed no differences in OS for treatment at AC vs. NAC (HR = 0.94, 95% CI: 0.84-1.06; p=.31) or HVF vs. LVF (HR = 0.99, 95% CI: 0.94-1.04; p = .60). 2-year OS was 54.5% (95% CI: 52.5-56.4%) and 5-year OS was 28.9% (95% CI: 27.0-30.8%).ConclusionsAlthough some providers are cautious about offering curative radiotherapy at all centers, this large hospital-based study suggests that facility type and volume are not significantly associated with OS for patients undergoing curative RT after accounting for other clinically relevant risk factors. The results of this study demonstrate that curative RT in the treatment of MIBC may be considered for patients regardless of facility type or volume.

Teaser

We conducted a retrospective cohort study of patients in the National Cancer Database with muscle-invasive bladder cancer undergoing curative radiotherapy to identify whether the facility type and treating facility's case volume impact survival outcomes. When controlling for disease extent and treatment characteristics, patients at academic and non-academic facilities and low and high volume facilities had similar survival outcomes. Thus bladder-sparing curative radiotherapy should be discussed and offered confidently at most centers.


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Carotid Dosimetry and the Risk of Carotid Blowout Syndrome Following Re-irradiation with Head and Neck Stereotactic Body Radiation Therapy

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Brian J. Gebhardt, John A. Vargo, Diane Ling, Brianna Jones, Mary Mohney, David A. Clump, James P. Ohr, Robert L. Ferris, Dwight E. Heron
Background/PurposeStereotactic Body Radiation Therapy (SBRT) is an increasingly used technique for re-irradiation of recurrent head-and-neck cancers (rHNC). Rates of carotid blowout syndrome (CBOS), which is defined as rupture and hemorrhage from the carotid artery or its major branches following re-irradiation in the absence of residual or progressive disease, have varied from 0-17% occurring at a median of 4-5 months following SBRT. This has prompted some to aggressively spare the carotids or avoid SBRT in patients with arterial encasement. Our institutional practice has not excluded patients from SBRT based on extent of carotid involvement or carotid dose. Thus, we aimed to correlate carotid dose and risk of CBOS; hypothesizing that carotid dose does not correlate with CBOS.Methods/MaterialsWe retrospectively reviewed 186 patients with recurrent, previously-irradiated head-and-neck cancer treated between January 2008 and March 2013. Patients treated early in our experience with incomplete dosimetry were excluded from analysis (n=111). A total of 75 patients were identified providing 150 carotid arteries for analysis. Median follow-up was 8 months (range: 1-91) for all patients, and 37 months for surviving patients (range: 31-91]. Patients were treated with linear accelerator-based SBRT to a median dose up to 44Gy (range: 40-50 Gy) in 5 fractions delivered on a twice-weekly basis. Concurrent Cetuximab was utilized in 63 patients (84%). The bilateral common, internal, and external carotid arteries were delineated 2cm above and below the planning target volume. The maximum dose to 0.1cc (D0.1cc), 1cc (D1cc), 2cc (D2cc) of the carotid and the mean carotid dose from SBRT were recorded and analyzed for association with carotid bleeding events using binary logistic regression.ResultsMedian re-irradiation interval was 20 months (range: 3-423), median prior radiation dose was 70 Gy (range: 52.5-140). Sixteen patients (21.3%) received more than 1 course of SBRT, and the cumulative carotid doses from fused summary plans were recorded. The overall median D0.1cc, D1cc, D2cc, and mean carotid doses were 40.8 Gy [interquartile range (IQR): 21.6-47.6], 26.8 Gy [IQR: 14.1-42.1], 15.4 Gy [IQR: 8.4-32.7], and 15.0 Gy [IQR: 8.9-23.3], respectively. There were a total of 4 bleeding events (5.3%): 2 patients (2.7%) had mucosal bleeds that resolved following embolization of carotid branches, and 2 patients (2.7%) died from complications of CBOS. In the 2 patients suffering CBOS, the D0.1cc were 48.4 Gy and 47.6 Gy. There was no significant association between bleeding events and D1cc (p=0.280), D2cc (p=0.571), or mean dose (p=0.568). There was a trend toward increased risk of bleeding and D0.1cc (p=0.080).ConclusionsThese results demonstrate a low risk of bleeding following re-irradiation with SBRT when 5 fractions are delivered on non-consecutive days even when tumor is completely encasing the carotid artery. While limited by low number of events, no significant association was found between dose-volume parameters and the risk of carotid bleeding. No CBOS noted when D0.1cc was <47.6 Gy.

Teaser

Stereotactic body radiation therapy has emerged as a viable treatment option for recurrent head and neck cancers after prior irradiation, though carotid dose constraints are not defined. The maximum dose to 0.1cc, 1cc, 2cc of the carotid and the mean dose were analyzed for association with bleeding. No significant association was found between dose-volume parameters and risk of carotid bleeding, and no CBOS noted when D0.1cc was <47.6 Gy.


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