Assessment of dynamic variables of fluid responsiveness to predict desufflation-induced hypotension during paediatric laparoscopic surgery

Abstract

Background: During laparoscopic surgery in paediatric patients, sudden hypotension may occur following peritoneal desufflation due to hypovolaemia or an acute increase in gastrointestinal venous capacitance by the release of intra-abdominal pressure. This study examined whether dynamic variables of fluid responsiveness during pneumoperitoneum can predict the occurrence of hypotension following desufflation.Methods: A total of 120 paediatric subjects were prospectively enrolled. A predictor was derived from the initial 83 subjects and validated thereafter in 37 high-risk subjects. The pleth variability index, respiratory variation in the pulse oximetry plethysmographic waveform (ΔPOP), systolic pressure variation and pulse pressure variation during pneumoperitoneum were obtained 1 min before desufflation. Predictors of desufflation-induced hypotension were investigated using the multivariable logistic regression analysis. Predictability was assessed using the area under the receiver-operating characteristic curve (AUC).Results: In the derivation cohort, 27% (n=23) of subjects developed hypotension. Only ΔPOP was found to be a predictor, and showed high predictability of desufflation-induced hypotension [AUC 0.87, P<0.0001, 95% confidence interval (CI): 0.78–0.93]. A ΔPOP cut-off point of 38% predicted hypotension with a sensitivity of 83% and a specificity of 90%. In the validation cohort, 43% (n=16) of subjects developed hypotension, and ΔPOP was verified to be highly predictive of the occurrence of hypotension (AUC 0.90, P<0.0001, 95% CI: 0.76–0.98). The sensitivity and specificity of a ΔPOP cut-off point of 38% to predict hypotension was 88% and 90%, respectively.Conclusions: The ΔPOP during pneumoperitoneum is useful in predicting desufflation-induced hypotension during paediatric laparoscopic surgery.Clinical trial registration: NCT02536521.

http://ift.tt/2uLdZyP

Evaluating the potential of circulating hTERT levels in glioma: can plasma levels serve as an independent prognostic marker?

Abstract

Glioma is an aggressive primary Neuro-epithelial tumor with dismal prognosis, since there is a lack of molecular work-up during routine radiological monitoring of the disease. Currently, a number of potential molecular prognostic and predictive biomarkers are being characterized in line with structured diagnosis defined in World Health Organization guidelines 2016. Human-telomerase reverse-transcriptase (hTERT), a marker of proliferation and maintenance of genomic integrity has thus been investigated for its clinical relevance as an independent prognosticator in glioma. Expression of the protein in tumor tissue and in plasma of 72 diffuse glioma patients (astrocytoma) grade II–IV was determined and compared with relevant controls using immunofluorescence-immunohistochemistry and enzyme-linked immuno-sorbent assay. Appropriate statistical tests were applied to establish a correlation between on-site tumor and circulating levels of the marker and its independence of covariates. Expression of the marker in glioma tissues was significantly different from controls (p < 0.0001) and could discriminate within grades with ≥80% sensitivity. The tissue and plasma levels were positively associated with grades (r = 0.8845, p < 0.0001) and (r = 0.2834, p = 0.0158) respectively, while an inverse correlation with overall survival (r = −0.6558, p < 0.0001) and (r = −0.3941, p = 0.0006) respectively, was recorded. Plasma hTERT was significantly correlated with corresponding intra-tumor expression of hTERT (r = 0.2794, p = 0.0175). Multivariate Cox-regression identified plasma hTERT (p < 0.0005) as a prognostic factor; not associated with age, site or extent of resection (p > 0.05). This is the first experimental evidence for association of higher plasma levels of hTERT with overall survival in both low and high grade glioma.

http://ift.tt/2u72ShE

Obturator hernia: a rare cause of bowel obstruction

An obturator hernia is a rare condition and an unusual cause of intestinal obstruction. With a challenging diagnosis, it has one of the highest mortality rates of all abdominal wall hernias. The authors present a case of an elderly woman with bowel obstruction secondary to an incarcerated obturator hernia. An 80-year-old woman presented at the emergency room with complaints for the last 2 days of nausea, vomiting, constipation and lower right abdominal pain that radiated down to the right medial thigh. Abdominal tenderness to deep palpation of the right iliac fossa and mildly distention were noted. A CT scan demonstrated bowel obstruction secondary to an incarcerated obturator hernia. The patient underwent emergency exploratory laparotomy. The incarcerated bowel was reduced and the defect was repaired with a plug of polypropylene mesh covered with peritoneum. The patient had an uneventful postoperative period and was discharged on the fifth postoperative day.

http://ift.tt/2uGZKN6

A case of deep infection after instrumentation in dorsal spinal surgery: the management with antibiotics and negative wound pressure without removal of fixation

Until today the role of spinal instrumentation in the presence of a wound infection has been widely discussed and recently many authors leave the hardware in place with appropriate antibiotic therapy. This is a case of a 65-year-old woman suffering from degenerative scoliosis and osteoporotic multiple vertebral collapses treated with posterior dorsolumbar stabilisation with screws and rods. Four months later, skin necrosis and infection appeared in the cranial wound with exposure of the rods. A surgical procedure of debridement of the infected tissue and package with a myocutaneous trapezius muscle flap was performed. One week after surgery, negative pressure wound therapy was started on the residual skin defect. The wound healed after 2 months. The aim of this case report is to focus on the utility of this method even in the case of hardware exposure and infection. This may help avoid removing instrumentation and creating instability.

http://ift.tt/2vRGmLJ

Thrombolytic therapy for the treatment of acute ischaemic stroke in adults with homozygous sickle cell disease

Stroke is a significant cause of morbidity and mortality in patients with homozygous sickle cell disease (SCD). A specific large-vessel vasculopathy is often responsible for both haemorrhagic and ischaemic strokes in patients with SCD. Although intravenous thrombolysis has been considered as a therapeutic option for acute ischaemic strokes in SCD, its use remains debated because of an increased risk of spontaneous intracranial haemorrhage reported in this disease. This risk of haemorrhage is mainly supported by the presence of a Moyamoya syndrome often associated with the specific vasculopathy in patients with homozygous SCD. We report two cases of patients with homozygous SCD treated with intravenous thrombolysis for an acute ischaemic stroke without haemorrhagic transformation. Our cases suggest that reperfusion strategy in acute ischaemic stroke in patients with homozygous SCD can be considered once associated Moyamoya syndrome has been ruled out. An international registry would be of interest as these situations are rare.

http://ift.tt/2uHjtw3

Longitudinal Midline Sacral Split Fracture - A Rare Entity

Fractures involving the central canal of the sacrum are rare injuries and can be transverse or longitudinal. Transverse fractures are by far common and associated with high incidence of neurological injuries. On the contrary, longitudinal midline split fracture is an extremely rare injury with minimal or no neurological injury. They are always associated with anterior pelvic ring fracture and are vertically stable needing only fixation of the anterior pelvic injury. Plating of the anterior pelvic ring in two planes would be beneficial than single plate to prevent gradual loss of reduction.

http://ift.tt/2vS2eqk

Thalamic and cerebellar hypermetabolism and cortical hypometabolism during absence status epilepticus

We report on a 17-year-old girl with absence status epilepticus who developed recurrent motionless confusional state and continuous generalised 3–4 Hz rhythmic delta waves on electroencephalogram (EEG). The patient had no history of absence, myoclonus or generalised convulsion. Her seizure was resistant to a combination of antiepileptic drugs including carbamazepine. Ictal positron emission tomography using [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG-PET) revealed hypermetabolism of the bilateral thalamus and cerebellum and hypometabolism of the frontal, parietal and posterior cingulate cortices. We diagnosed her seizure as absence status and obtained remission by changing medication. The findings of ictal metabolic alteration in previous studies and in our case confirm the pathogenic importance of the thalamus in absence status and that associated cortical deactivation and cerebellar activation may be related to the generation or maintenance of epileptic EEG discharges.

http://ift.tt/2uHlvfO

Acquired haemophilia A with a recalcitrant high-titre factor VIII inhibitor in the setting of interstitial lung disease

Acquired haemophilia A (AHA) is a bleeding disorder that results from autoantibodies against factor VIII (FVIII). A 70-year-old man with a history of interstitial lung disease presented with spontaneous bleeding into his thigh. He had undetectable FVIII levels and a high-titre FVIII inhibitor (>2000ââ'¬â°Bethesda units/mL) and was diagnosed with AHA. He had several relapses, required multiple haemostatic and immunosuppressive treatments but eventually achieved a stable remission after 2ââ'¬â°years of therapy.

Our patient matches the typical elderly male demographic of AHA. His relapsing course with remarkably high and persistent inhibitor titre highlights the need for close monitoring and aggressive upfront treatment. Whereas cyclophosphamide and steroids are often used first line in AHA, rituximab has also shown efficacy in refractory patients with high inhibitor levels. The FVIII and inhibitor concentration on presentation have been associated with treatment response and may be used as prognostic factors to tailor immunosuppressive regimens.

http://ift.tt/2vRHu1S

Pulsed-dose rate brachytherapy for pediatric bladder prostate rhabdomyosarcoma: Compliance and early clinical results

No data are available on the feasibility of pulsed dose rate (PDR) brachytherapy in very young children. Our experience of PDR brachytherapy for bladder prostate (BP) rhabdomyosarcoma (RMS) is reported, with focus on compliance and dosimetric parameters.

http://ift.tt/2vg2B0W

Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma

Anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of...

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Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma

Abstract

Background

Anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra- and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy. This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.

Methods

In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+) T-cell density in primary tumors and PD-1 expression on CD8(+) T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.

Results

Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors (45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+) T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes (both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression, PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.

Conclusion

The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

http://ift.tt/2hal1dd

Connecting cancer to its causes requires incorporation of effects on tissue microenvironments

In a recent paper in Science, Tomasetti et al. present an expanded model for cancer risk, which they claim demonstrates the relative contribution of mutations caused by replication errors, environment and heredity. The foundation of this model is the theory that the overwhelming driver of cancer risk is mutations. This perspective will present experimental evidence and evolutionary theory to challenge the basis of this underlying theory. An argument will be presented that the mutation-centric model of cancer suggests unrealistic solutions to cancer and distracts the research community from more promising approaches that consider tissue context.

http://ift.tt/2tR81z2

NSD1 inactivation and SETD2 mutation drive a convergence toward loss-of-function of H3K36 writers in clear-cell renal cell carcinomas

Extensive dysregulation of chromatin-modifying genes in clear-cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the crosstalk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear-cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of vascular endothelial growth factor receptor genes (FLT4, FLT1 and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss-of-function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC.

http://ift.tt/2u6vPKM

Adipose progenitor cell secretion of GM-CSF and MMP9 promotes a stromal and immunological microenvironment that supports breast cancer progression

A cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly up-regulated in WAT-derived progenitors after co-culture with breast cancer: granulocyte-macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator: breast cancer-derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the pro-tumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the pro-tumorigenic effect of WAT progenitors on local and metastatic breast cancer.

http://ift.tt/2tR3XPt

Androgen receptor variants mediate DNA repair after prostate cancer irradiation

In prostate cancer (PCa), androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. Since a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARV increase the clonogenic survival of PCa cells after irradiation in an ADT-independent manner. Notably, PCa cell irradiation trigger binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacological inhibition of DNA-PKc blocked this interaction, increased DNA damage and elevated PCa cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized PCa.

http://ift.tt/2u6xxLZ

Spi-B-mediated silencing of Claudin-2 promotes early dissemination of lung cancer cells from primary tumors

Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage-restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B-expressing cancer cells coexpressed Vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene Claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program.

http://ift.tt/2tQKyhH

Integrating models to quantify environment mediated drug resistance

Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialogue between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated melanoma; the model describes tumor-stroma dynamics both with and without treatment. Integration of experimental data into our model revealed significant variation in either the intensity of stromal promotion or intrinsic tissue carrying capacity across animal replicates.

Major Findings. Through the integration of a simple mathematical model with in vitro and in vivo experimental growth dynamics of melanoma cell lines (both with and without drug), we were able to dissect the relative contributions of intrinsic versus environmental resistance. Our study revealed significant heterogeneity in vivo, indicating that there is a diversity of either stromal promotion or tumor carrying capacity under targeted therapy. We believe this variation may be one possible explanation for the heterogeneity observed across patients and within individual patients with multiple metastases. Therefore, quantifying this variation both within in vivo model systems and in individual patients could have a significant impact on the design of future treatment strategies that target both tumor and stroma. Further, we present guidelines for building more effective and longer lasting therapeutic strategies utilizing our experimentally calibrated model. These strategies explicitly consider the protective nature of the stroma and utilize inhibitors that modulate it.

http://ift.tt/2u6ayAP

Src inhibits the Hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1

The Hippo pathway regulates cell proliferation, apoptosis and stem cell self-renewal and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers but the underlying mechanisms are not fully understood. Here we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription co-activator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis.

http://ift.tt/2tQU6cv

Gemcitabine and Chk1 inhibitor AZD7762 synergistically suppress the growth of Lkb1-deficient lung adenocarcinoma

Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model (GEMM) of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in Kras/p53/Lkb1 tumors, synergizing with the DNA damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas.

http://ift.tt/2u6L0mZ

Transglutaminase 2 inhibition reverses mesenchymal transdifferentiation of glioma stem cells by regulating C/EBP{beta} signaling

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NFκB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radio-resistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM.

http://ift.tt/2tRpo2Y

Tumor Purity As an Underlying Key Factor in Glioma

Purpose: <span style="font-size: 11px;">Glioma tissues consist not only of glioma cells but also glioma-associated non-tumor cells, such as stromal cells and immune cells. These non-tumor cells dilute the purity of glioma cells and play important roles in glioma biology. Currently, the implications of variation in glioma purity are not sufficiently clarified.</span><br /><br /><br />Experimental Design: <span style="font-size: 11px;">Here, tumor purity was inferred for 2249 gliomas and 29 normal brain tissues from five cohorts. Based on the transcriptomic profiling method, we classified CGGA and TCGA-RNAseq cohorts as the RNAseq set for discovery. Cases from TCGA-microarray, REMBRANDT, and GSE16011 cohorts were grouped as a microarray set for validation. Tissues from the CGGA cohort were reviewed for histopathologic validation.</span><br /><br /><br />Results: <span style="font-size: 11px;">We found that glioma purity was highly associated with major clinical and molecular features. Low purity cases were more likely to be diagnosed as malignant entities and independently correlated with reduced survival time. Integrating glioma purity into prognostic nomogram significantly improved the predictive validity. Moreover, most recognized prognostic indicators were no longer significantly effective under different purity conditions. These results highlighted the clinical importance of glioma purity. Further analyses found distinct genomic patterns associated with glioma purity. Low purity cases were distinguished by enhanced immune phenotypes. Macrophages, microglia, and neutrophils were mutually associated and enriched in low purity gliomas, while only macrophages and neutrophils served as robust indicators for poor prognosis.</span><br /><br /><br />Conclusions: Glioma purity and relevant non-tumor cells within microenvironment confer important clinical, genomic and biological implications, which should be fully valued for precise classification and clinical prediction.

http://ift.tt/2u6uJOX

An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2-years following UCBT in AL patients. <p>Experimental design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n=2362, 65%) and validation set (n=778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.</p> <p>Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2-years OS and LFS, ranging from 70.21% (68.89-70.71, 95% CI) and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2-years OS and LFS, respectively.</p> <p>Conclusion: The UCBT score is a simple tool for risk stratification of AL patient undergoing UCBT. Widespread application of the score will require further independent validation.

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TP53 mutation and its prognostic significance in Waldenstrom's Macroglobulinemia

Purpose: TP53 is a tumor suppressor gene that functions as regulator influencing cellular responses to DNA damage, and TP53 alteration are associated to pejorative outcome in most of B lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's Macroglobulinemia (WM). <p>Experimental design: Here we have explored the incidence of TP53 alteration using sanger sequencing and ultra-deep targeted sequencing in 125 WM and 10 IgM MGUS, along with the clinical features and the associated genomic landscape using SNP array and mutational landscape in an integrative study.</p> <p>Results: Overall, we have identified alteration of TP53 locus including mutation, deletion and copy neutral loss of heterozygosity in 11,2% of WM. TP53 mutation was acquired in 7,3% of WM patients at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of IPSSWM score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signalling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, Prima^Met or CP31398 that bypass p53 pathway in WM, paving the path for future treatment tailored options.</p> <p>Conclusion: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice.

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Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8⁺ TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8⁺BTLA⁺TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. <br /><br />Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8⁺ TIL and mouse CD8⁺ T cells. Functional assays were used including single cell analysis, Reverse Phase Protein Array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as Patient-Derived Xenograft (PDX) model using Immunodeficient NOD-scid IL2Rgamma^null (NSG) tumor-bearing mice treated with autologous TIL.<br /> <p>Results: CD8⁺BTLA^- TIL could not control tumor growth in vivo as well as their BTLA⁺ counterpart and antigen-specific CD8⁺BTLA^- T cells had impaired recall response to a vaccine. However CD8⁺BTLA⁺ TIL displayed improved survival following the killing of a tumor target and heightened "serial killing" capacity. Using mutants of BTLA signaling motifs we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. <br /><br />Conclusions:Our data portrays BTLA as a molecule with the singular ability to provide both co-stimulatory and co-inhibitory signals to activated CD8⁺ T cells, resulting in extended survival, improved tumor control and the development of a functional recall response.

http://ift.tt/2uKEvZb

Real Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype

Purpose: <br /><br />Experimental Design: <br /><br />Results: <br /><br />Conclusions:

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Under-reporting of Research Biopsies from Clinical Trials in Oncology

Purpose: Research biopsies are frequently incorporated within clinical trials in oncology, and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting.<br /><br />Experimental Design: We identified a cohort of therapeutic clinical trials where non-diagnostic research biopsies were performed between January, 2005-October, 2010 from an IR database at our institution. Clinical trial protocols were compared with the highest level of corresponding publication as a manuscript or registry report.<br /><br />Results: A total of 866 research biopsies were performed across 46 clinical trials, with a median of 8 patients biopsied/trial and 19 biopsies collected/trial. After a median follow-up time of 4.3 years from trial completion, 36/46 trials(78%) reported trial results: published manuscripts(n=35), or registry report(n=1). A total of 635 conducted biopsies were reported in 18/46 trials(39%). Six(33%) of these 18 trials under-reported the number of biopsies performed. Of 33 trials with mandatory research biopsies, 13(39%) trials reported on these biopsies. Biopsy complications occurred in 8 trials (n=39 patients, 6 Grade 3/4 AEs) but only 1 trial reported these. Factors associated with biopsy reporting included a larger number of biopsies(P<0.001), and serial biopsies(P<0.001). Twelve of 16 (75%) trials with >12 biopsies performed reported on these biopsies compared to only 20%(6/30) that performed ≤12 biopsies.<br /><br />Conclusions: Despite ethical obligations to report research biopsies, the majority (61%) of trials do not report results from research biopsies. Complications are rarely reported in these studies. Improved reporting of results and AEs from research biopsies is needed.

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Exploring the screening capacity of the Fear of Cancer Recurrence Inventory – Short Form for clinical levels of fear of cancer recurrence

Abstract

Objective

Fear of cancer recurrence (FCR) is a common concern among cancer survivors. Identifying survivors with clinically significant FCR requires validated screening measures and clinical cut-offs. We evaluated the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF) clinical cut-off in two samples.

Methods

Level of FCR in study 1 participants (from an Australian randomised controlled trial: ConquerFear) was compared to FCRI-SF scores. Based on a biopsychosocial interview, clinicians rated participants as having non-clinical, sub-clinical, or clinical FCR. Study 2 participants (from a Canadian FCRI-English validation study) were classified as having clinical or non-clinical FCR using the semi-structured clinical interview for FCR (SIFCR). Receiver Operating Characteristic (ROC) analyses evaluated the screening ability of the FCRI-SF against clinician ratings (Study 1) and the SIFCR (Study 2).

Results

In Study 1, 167 cancer survivors (mean age: 53years, SD=10.1) participated. Clinicians rated 43% as having clinical FCR. In Study 2, 40 cancer survivors (mean age: 68years, SD=7.0) participated; 25% met criteria for clinical FCR according to the SIFCR. For both Study 1 and 2, ROC analyses suggested a cut-off ≥22 on the FCRI-SF identified cancer survivors with clinical levels of FCR with adequate sensitivity and specificity.

Conclusions

Establishing clinical cut-offs on FCR screening measures is crucial to tailoring individual care and conducting rigorous research. Our results suggest using a higher cut-off on the FCRI-SF than previously reported to identify clinically significant FCR. Continued evaluation and validation of the FCRI-SF cut-off is required across diverse cancer populations.

http://ift.tt/2eV9mOT

Men's Perspectives on Cancer Prevention Behaviours Associated with HPV

Abstract

Background

The Human Papillomavirus (HPV) is associated with the diagnosis of anal, penile, and oropharyngeal cancers in men. Evidence indicates that correct condom use in addition to obtaining the HPV vaccine provides the greatest protection from HPV infections.

Aim

To explore young male's beliefs and behavioural intention in relation to receiving the HPV vaccine and using a condom correctly and consistently for sexual contact.

Methodology

A cross-sectional study underpinned by the Theory of Planned Behaviour was conducted with male participants (n=359, 18-28 years) who completed an online survey. Descriptive, correlational, and hierarchical regression analysis were performed on both status variables and variables of the Theory of Planned Behaviour

Findings

Sexual orientation (β= 0.177, p<0.01) and social influences [β=0.519, p<0.001] were identified as the most influential variables in relation to males' intention to receive the HPV vaccine. Whilst relationship status (β=-.215, p<0.001) and attitudes [β=0.394, p<0.001] presented as the most significant predictor of intention to use a condom. Summarily, 51% of the variance in intention to receive the HPV vaccine and 44% in intention to use a condom were explained by the TPB model.

Conclusion

Results from this study will impact on future sexual health research, education programmes, and interventions for both HPV preventative behaviours in the elimination of HPV related cancers in males.

http://ift.tt/2hajJz2

Perceived employer-related barriers and facilitators for work participation of cancer survivors: a systematic review of employers’ and survivors’ perspectives

Abstract

Objective

To identify employer-related barriers and facilitators for work participation of cancer survivors from the perspective of both employers and cancer survivors, and to synthesise these perceived barriers and facilitators to understand their perceived consequences.

Methods

A systematic review of qualitative studies focusing on employers' and cancer survivors' perspectives on the work participation of cancer survivors was performed. Four databases (MEDLINE, EMBASE, PsycINFO and Business Source Premier) were systematically searched and the quality of studies included was assessed using the CASP checklist. Perceived barriers and facilitators were extracted and synthesised to conduct a content analysis.

Results

Five studies representing the employers' perspectives and 47 studies representing the cancer survivors' perspectives were included. Employers perceived barriers and facilitators related to support, communication, RTW policies, knowledge about cancer, balancing interests and roles, and attitude. Survivors perceived barriers and facilitators related to support, communication, work environment, discrimination and perception of work ability. The synthesis found that the employers' willingness to support can be understood by perceptions they have of the survivor, goals of the employer, and national or organisational policies. Employers require knowledge about cancer and RTW policies to be able to support survivors.

Conclusions

This review identified a plurality of and a large variety in perceived employer-related barriers and facilitators for work participation of cancer survivors, which can be understood to be related to both employers' willingness and ability to support. There is a need for interventions targeting employers, with the aim of enhancing the sustainable work participation of cancer survivors.

http://ift.tt/2w7KZAN

Message from the Editor-in-Chief

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Predictive biomarkers of resistance to hypofractionated radiotherapy in high grade glioma

Radiotherapy plays a major role in the management of high grade glioma. However, the radioresistance of glioma cells limits its efficiency and drives recurrence inside the irradiated tumor volume leading to po...

http://ift.tt/2tKV45C

Volumetric quantification of glioblastoma: experiences with different measurement techniques and impact on survival

Abstract

The potential impact of different radiological features of glioblastoma multiforme (GBM) on overall survival (OS) like tumor volume, peritumoral edema (PTE), necrosis volume, necrosis-tumor ratio (NTR) and edema-tumor ratio (ETR) is still very controversial. To determine the influence of volumetric data on OS und to compare different measuring techniques described in literature. We prospectively evaluated preoperative MR images from 30 patients harboring a primary supratentorial GBM. All patients received gross-total tumor resection followed by standard radiation and chemotherapy (temozolomide). By 3D semi-automated segmentation, we measured tumor volume, necrosis volume, PTE, postoperative residual tumor volume and calculated ETR, NTR and the extent of resection. After critical review of the existing literature we compared alternative measuring techniques with the gold standard of 3D segmentation. Statistical analysis showed a significant impact of the preoperative tumor and necrosis volumes on OS (p = 0.041, respectively p = 0.039). Furthermore, NTR also showed a significant association with OS (p = 0.005). Comparison of previously described measuring techniques and scorings with our results showed that no other technique is reliable and accurate enough as a predictive tool. The critical review of previously published studies revealed mainly inaccurate measurement techniques and patient selection as potential reasons for inconsistent results. Preoperatively measured necrosis volume and NTR are the most important radiological features of GBM with a strong influence on OS. No other measuring techniques are specific enough and comparable with 3D segmentation.

http://ift.tt/2uFGQWH

Identification and validation of uterine stimulant methylergometrine as a potential inhibitor of caspase-1 activation

Abstract

Inflammasomes are intracellular multiprotein complexes of the innate immune system. Upon an inflammatory insult, such as infection or intracellular damage, a nucleotide-binding oligomerization domain-like receptor (NLR) sensor protein and the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) are assembled to activate protease procaspase-1. This protease processes pro-IL-1β and pro-IL-18 cytokines, which are released to induce the inflammatory response. De-regulation of inflammasome contributes to the progression of several diseases, such as Alzheimer's disease, diabetes, cancer, inflammatory and autoimmune disorders. We herein describe the identification of methylergometrine (MEM), a drug currently used as a smooth muscle constrictor during postpartum hemorrhage, as an inhibitor of the inflammasome complex in ASC-mediated procaspase-1 activation screening. MEM inhibits the activation of the nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes in cellular models upon different pro-inflammatory stimuli. Our results suggest that MEM has the potential to reposition in the treatment of inflammatory diseases with the advantages of established safety and clinical data.

http://ift.tt/2tQrrnF

SIRT1 induces resistance to apoptosis in human granulosa cells by activating the ERK pathway and inhibiting NF-κB signaling with anti-inflammatory functions

Abstract

SIRT1, a member of the sirtuin family, has recently emerged as a vital molecule in controlling ovarian function. The aims of the present study were to investigate SIRT1 expression and analyze SIRT1-mediated apoptosis in human granulosa cells (GCs). Human ovarian tissues were subjected to immunohistochemistry for localization of SIRT1 expression. SIRT1 knockdown in a human ovarian GC tumor line (COV434) was achieved by small interfering RNA, and the relationship between apoptosis and SIRT1 was assessed by quantitative reverse transcription polymerase chain reaction and western blotting. We further detected SIRT1 expression in human luteinized GCs. Associations among SIRT1 knockdown, SIRT1 stimulation (resveratrol) and expression of ERK1/2 and apoptotic regulatory proteins were analyzed in cell lines and luteinized GCs. Resveratrol downregulated the levels of nuclear factor (NF)-κB/p65, but this inhibitory effect was attenuated by suppressing SIRT1 activity. The NF-κB/p65 inhibitor pyrrolidine dithiocarbamate achieved similar anti-apoptosis effects. These results suggest that SIRT1 might play an anti-apoptotic role in apoptosis processes in GCs, possibly by sensing and regulating the ERK1/2 pathway, which has important clinical implications. Thus, our study provides a mechanistic link, whereby activation of SIRT1 function might help to sustain human reproduction by maintaining GCs as well as oocytes, offering a novel approach for developing a new class of therapeutic anti-inflammatory agents.

http://ift.tt/2u5AKLJ

HER2 and TOP2A Gene Amplification and Protein Expression in Upper Tract Urothelial Carcinomas

Abstract

HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC. Immunohistochemistry and chromogenic in-situ hybridization was performed on formalin-fixed, paraffin-embedded samples. HER2 protein expression was observed in 27/81 (33%) cases, of which 8 cases exhibited amplification of HER2. One of them had an additional polysomy 17, whereas 6/67 HER2 non-amplified cases revealed a polysomy 17. Coamplification of HER2 and TOP2A was found in 4 cases, whereas 3 cases showed only HER2 amplification and 20 cases only TOP2A amplification. HER2 IHC overexpression was associated with higher-grade tumors (p = 0.001), non-organ confined carcinomas (p = 0.017), HER2 amplification (p < 0.00001) and TOP2A amplification (p = 0.016). HER2 amplification was association with higher tumor grade (p = 0.001) and lymphnode metastasis (p = 0.003). TOP2A IHC positivity was significantly associated with higher tumor grade (p = 0.0004), TOP2A amplification (p = 0.0003), polysomy 17 (p = 0.035) and HER2 IHC overexpression (p = 0.28), whereas all categories of tumor stage and HER2 amplification remained not related. TOP2A amplification was significantly more frequent in tumors with higher grade, higher tumor stage, polysomy 17 and distant metastasis (p = 0.015; p = 0.042; p = 0.032; p = 0.011), respectively. In univariate analyses HER2 IHC positivity, TOP2A amplification, and polysomy 17 were associated with poor clinical outcome after surgery. HER2 IHC overexpression and TOP2A amplification are associated with features of biologically aggressive UTUC. Overexpression and/or amplification of HER2 and TOP2A could help identify patients who may benefit from targeted therapy.

http://ift.tt/2veDY4w

Carbon dioxide narcosis due to inappropriate oxygen delivery: a case report

Oxygen delivery to patients with chronic obstructive pulmonary disease may be challenging because of their potential hypoxic ventilatory drive. However, some oxygen delivery systems such as non-rebreathing fac...

http://ift.tt/2v76Rig

Renal damage induced by pemetrexed causing drug discontinuation: a case report and review of the literature

Pemetrexed maintenance therapy holds tremendous potential in improving the survival of patients with advanced pulmonary adenocarcinoma. Major side effects include myelosuppression and cutaneous reactions. Howe...

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HER2 and TOP2A Gene Amplification and Protein Expression in Upper Tract Urothelial Carcinomas

Abstract

HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC. Immunohistochemistry and chromogenic in-situ hybridization was performed on formalin-fixed, paraffin-embedded samples. HER2 protein expression was observed in 27/81 (33%) cases, of which 8 cases exhibited amplification of HER2. One of them had an additional polysomy 17, whereas 6/67 HER2 non-amplified cases revealed a polysomy 17. Coamplification of HER2 and TOP2A was found in 4 cases, whereas 3 cases showed only HER2 amplification and 20 cases only TOP2A amplification. HER2 IHC overexpression was associated with higher-grade tumors (p = 0.001), non-organ confined carcinomas (p = 0.017), HER2 amplification (p < 0.00001) and TOP2A amplification (p = 0.016). HER2 amplification was association with higher tumor grade (p = 0.001) and lymphnode metastasis (p = 0.003). TOP2A IHC positivity was significantly associated with higher tumor grade (p = 0.0004), TOP2A amplification (p = 0.0003), polysomy 17 (p = 0.035) and HER2 IHC overexpression (p = 0.28), whereas all categories of tumor stage and HER2 amplification remained not related. TOP2A amplification was significantly more frequent in tumors with higher grade, higher tumor stage, polysomy 17 and distant metastasis (p = 0.015; p = 0.042; p = 0.032; p = 0.011), respectively. In univariate analyses HER2 IHC positivity, TOP2A amplification, and polysomy 17 were associated with poor clinical outcome after surgery. HER2 IHC overexpression and TOP2A amplification are associated with features of biologically aggressive UTUC. Overexpression and/or amplification of HER2 and TOP2A could help identify patients who may benefit from targeted therapy.

http://ift.tt/2veDY4w

Detection of the alternative lengthening of telomeres pathway in malignant gliomas for improved molecular diagnosis

Abstract

Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice. The presence of C-circles significantly correlated with IDH1/2 mutation, MGMT exon 1 methylation, low Ki-67 immunostaining, increased telomeric DNA content, absence of functional ATRX protein and level of HTERT gene expression. In multivariate analysis, we observed a trend to a correlation between elevated TERRA levels and increased survival. Interestingly, the C-circles assay allowed to detect ALT activation in glioblastomas exhibiting wild-type IDH1/2 and ATRX expression. These results suggest that, after the correlations uncovered here have been confirmed on larger numbers of tumors, telomeric markers might be useful in improving diagnosis. They also point out to the utility of using the specific, sensitive and quantitative C-circle and Telo/Alu assays that can work with as few as 30 ng of tumor DNA.

http://ift.tt/2tQ40ef

Prognostic value of total tumor volume in patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy

Abstract

Background

Few studies have evaluated the prognostic value of total tumor volume (TTV), which reflects both the primary tumor volume and nodal tumor volume, in NPC. Furthermore, the relationship between TTV and survival remains unknown. The purpose of this study was to evaluate the prognostic value of TTV in patients with NPC treated with intensity-modulated radiation therapy (IMRT).

Methods

TTV was retrospectively assessed in 455 patients with newly diagnosed, non-metastatic NPC. All patients were treated using IMRT; 91.1% (288/316) of patients with stage III-IVb also received cisplatin-based chemotherapy. Receiver operating characteristic (ROC) curves were used to identify the optimal TTV cut-off point and examine the prognostic value of combined TTV with current clinical stage.

Results

Mean TTV was 11.1 cm³ (range, 0.3–27.9 cm³) in stage I, 22.5 cm³ (1.3–92.4 cm³) in stage II, 40.6 cm³ in stage III (3.2–129.2 cm³), and 77.5 cm³ in stage IVa-b (7.1–284.1 cm³). For all patients, the 4-year estimated FFS, OS, DMFS, and LRRFS rates for patients with a TTV ≤ 28 vs. > 28 cm³ were 93 vs. 71.4% (P < 0.001), 95.1 vs. 75.4% (P < 0.001), 94.5 vs. 79.4% (P < 0.001), and 96.2 vs. 88% (P = 0.001). TTV was an independent prognostic factor for FFS, OS, DMFS and LRRFS in all patients. In stage III-IVb, 4-year estimated FFS, OS, DMFS, and LRRFS for a TTV ≤28 vs. >28 cm³ were 88.9 vs. 70.5% (P = 0.001), 96.2 vs. 72.7% (P < 0.001), 91.2 vs. 78.3% (P = 0.008), and 93.8 vs. 87.6% (P = 0.063). TTV was an independent prognostic factor for FFS, OS and DMFS in stage III-IVb. Receiver operating characteristic (ROC) curve analysis curves revealed adding TTV to clinical stage had superior prognostic value for treatment failure compared to clinical stage alone (P = 0.016).

Conclusions

TTV is an important prognosticator for treatment outcome and significantly improves the prognostic value of the current staging system for patients with NPC treated with IMRT.

http://ift.tt/2vQgQqo

Successful treatment with anti-programmed-death-1 antibody in a relapsed natural killer/T-cell lymphoma patient with multi-line resistance: a case report

Abstract

Background

Extranodal natural killer/T-cell lymphoma (NKTCL), nasal type, is an aggressive malignancy with poor prognosis. Currently, there is no recommended standard therapy for relapsed NKTCL.

Case presentation

A 37-year-old woman with lymphadenopathy was diagnosed with NKTCL by biopsy of an enlarged lymph node on the right side of her neck. Enhanced computed tomography revealed no metastasis. For this patient, we performed continuous chemotherapy followed by radiotherapy; however, nodule biopsy showed metastases in her lower limbs 3 months after radiotherapy, which confirmed disease progression. Unfortunately, the patient^' s temperature was persistently high and her skin ulcers could not be controlled well using multi-line treatment. Therefore, we attempted treatment with the anti-programmed-death-1 (PD-1) antibody, pembrolizumab. Surprisingly, the patient achieved clinical complete remission (CR) after four cycles of pembrolizumab treatment, despite having persistent detectable Epstein-Barr virus (EBV) DNA. Other molecular monitoring techniques were unavailable for this patient owing to the retrospective nature of the study. The only adverse event was soreness of the upper limb joints and muscles.

Conclusion

This relapsed NKTCL case treated with pembrolizumab showed that multimodal therapy including pembrolizumab would be partially or totally effective for relapsed NKTCL.

http://ift.tt/2uFv3YC

Spatio-temporal analysis of the incidence of colorectal cancer in Guangzhou, 2010–2014

Colorectal cancer (CRC) is a common type of neoplasm. This study examined the spatio-temporal distribution of the CRC incidence in Guangzhou during 2010–2014.

http://ift.tt/2uJ128t

Re: Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial. Journal of Surgical Oncology 2017;115(8):917-923.

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Issue Information - Ed Board

http://ift.tt/2tPH1zP

Issue Information - TOC

http://ift.tt/2u50Iin

Utility and reproducibility of 3-dimensional printed models in pre-operative planning of complex thoracic tumors

Background and Objectives

3D-printed models are increasingly used for surgical planning. We assessed the utility, accuracy, and reproducibility of 3D printing to assist visualization of complex thoracic tumors for surgical planning.

Methods

Models were created from pre-operative images for three patients using a standard radiology 3D workstation. Operating surgeons assessed model utility using the Gillespie scale (1 = inferior to 4 = superior), and accuracy compared to intraoperative findings. Model variability was assessed for one patient for whom two models were created independently. The models were compared subjectively by surgeons and quantitatively based on overlap of depicted tissues, and differences in tumor volume and proximity to tissues.

Results

Models were superior to imaging and 3D visualization for surgical planning (mean score = 3.4), particularly for determining surgical approach (score = 4) and resectability (score = 3.7). Model accuracy was good to excellent. In the two models created for one patient, tissue volumes overlapped by >86.5%, and tumor volume and area of tissues ≤1 mm to the tumor differed by <15% and <1.8 cm², respectively. Surgeons considered these differences to have negligible effect on surgical planning.

Conclusion

3D printing assists surgical planning for complex thoracic tumors. Models can be created by radiologists using routine practice tools with sufficient accuracy and clinically negligible variability.

http://ift.tt/2tPUc42

Re: Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial. Journal of Surgical Oncology 2017;115(8):917-923.

http://ift.tt/2u53rZu

Issue Information - Ed Board

http://ift.tt/2tPH1zP

Issue Information - TOC

http://ift.tt/2u50Iin

Utility and reproducibility of 3-dimensional printed models in pre-operative planning of complex thoracic tumors

Background and Objectives

3D-printed models are increasingly used for surgical planning. We assessed the utility, accuracy, and reproducibility of 3D printing to assist visualization of complex thoracic tumors for surgical planning.

Methods

Models were created from pre-operative images for three patients using a standard radiology 3D workstation. Operating surgeons assessed model utility using the Gillespie scale (1 = inferior to 4 = superior), and accuracy compared to intraoperative findings. Model variability was assessed for one patient for whom two models were created independently. The models were compared subjectively by surgeons and quantitatively based on overlap of depicted tissues, and differences in tumor volume and proximity to tissues.

Results

Models were superior to imaging and 3D visualization for surgical planning (mean score = 3.4), particularly for determining surgical approach (score = 4) and resectability (score = 3.7). Model accuracy was good to excellent. In the two models created for one patient, tissue volumes overlapped by >86.5%, and tumor volume and area of tissues ≤1 mm to the tumor differed by <15% and <1.8 cm², respectively. Surgeons considered these differences to have negligible effect on surgical planning.

Conclusion

3D printing assists surgical planning for complex thoracic tumors. Models can be created by radiologists using routine practice tools with sufficient accuracy and clinically negligible variability.

http://ift.tt/2tPUc42

Spatio-temporal analysis of the incidence of colorectal cancer in Guangzhou, 2010–2014

Abstract

Introduction

Colorectal cancer (CRC) is a common type of neoplasm. This study examined the spatio-temporal distribution of the CRC incidence in Guangzhou during 2010–2014.

Methods

Colorectal cancer incidence data were obtained from the Guangzhou Cancer Registry System. Spatial autocorrelation analysis and a retrospective spatio-temporal scan were used to assess the spatio-temporal cluster distribution of CRC cases.

Results

A total of 14,618 CRC cases were registered in Guangzhou during 2010–2014, with a crude incidence of 35.56/100,000 and an age-standardized rate of incidence by the world standard population (ASRIW) of 23.58/100,000. The crude incidence increased by 19.70% from 2010 (32.88/100,000) to 2014 (39.36/100,000) with an average annual percentage change (AAPC) of 4.33%. The AAPC of ASRIW was not statistically significant. The spatial autocorrelation analysis revealed a CRC incidence hot spot in central urban areas in Guangzhou City, which included 25 streets in southwestern Baiyun District, northwestern Haizhu District, and the border region between Liwan and Yuexiu Districts. Three high- and five low-incidence clusters were identified according to spatio-temporal scan of CRC incidence clusters. The high-incidence clusters were located in central urban areas including the border regions between Baiyun, Haizhu, Liwan, and Yuexiu Districts.

Conclusions

This study revealed the spatio-temporal cluster pattern of the incidence of CRC in Guangzhou. This information can inform allocation of health resources for CRC screening.

http://ift.tt/2eTAsG4

Nano-based delivery of RNAi in cancer therapy

Abstract

Background

RNA interference (RNAi), a newly developed method in which RNA molecules inhibit gene expression, has recently received considerable research attention. In the development of RNAi-based therapies, nanoparticles, which have distinctive size effects along with facile modification strategies and are capable of mediating effective RNAi with targeting potential, are attracting extensive interest.

Objective

This review presents an overview of the mechanisms of RNAi molecules in gene therapy and the different nanoparticles used to deliver RNAi molecules; briefly describes the current uses of RNAi in cancer therapy along with the nano-based delivery of RNA molecules in previous studies; and highlights some other carriers that have been applied in clinical settings. Finally, we discuss the nano-based delivery of RNAi therapeutics in preclinical development, including the current status and limitations of anti-cancer treatment.

Conclusion

With the growing number of RNAi therapeutics entering the clinical phase, various nanocarriers are expected to play important roles in the delivery of RNAi molecules for cancer therapeutics.

http://ift.tt/2uFkcxM

A centralized mailed program with stepped increases of support increases time in compliance with colorectal cancer screening guidelines over 5 years: A randomized trial

BACKGROUND

Screening over many years is required to optimize reductions in colorectal cancer (CRC) mortality. However, no prior trials have compared strategies for obtaining long-term adherence.

METHODS

Systems of Support to Increase Colorectal Cancer Screening and Follow-Up was implemented in an integrated health care organization in Washington State. Between 2008 and 2009, 4675 individuals aged 50 to 74 years were randomized to receive the usual care (UC), which included clinic-based strategies to increase CRC screening (arm 1), or, in years 1 and 2, mailings with a call-in number for colonoscopy and mailed fecal tests (arm 2), mailings plus brief telephone assistance (arm 3), or mailings and assistance plus nurse navigation (arm 4). Active-intervention subjects (those in arms 2, 3, and 4 combined) who were still eligible for CRC screening were randomized to mailings being stopped or continued in years 3 and 5. The time in compliance with CRC screening over 5 years was compared for persons assigned to any intervention and persons assigned to UC. Screening tests contributed time on the basis of national guidelines for screening intervals (fecal tests annually, sigmoidoscopy every 5 years, and colonoscopy every 10 years).

RESULTS

All participants contributed data, but they were censored at disenrollment, death, the age of 76 years, or a diagnosis of CRC. Compared with UC participants, intervention participants had 31% more adjusted covered time over 5 years (incidence rate ratio, 1.31; 95% confidence interval, 1.25-1.37; covered time, 47.5% vs 62.1%). Fecal testing accounted for almost all additional covered time.

CONCLUSIONS

In a health care organization with clinic-based activities to increase CRC screening, a centralized program led to increased CRC screening adherence over 5 years. Longer term data on screening adherence and its impact on CRC outcomes are needed. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2h9c3Ne

Predictive biomarkers of resistance to hypofractionated radiotherapy in high grade glioma

Abstract

Background

Radiotherapy plays a major role in the management of high grade glioma. However, the radioresistance of glioma cells limits its efficiency and drives recurrence inside the irradiated tumor volume leading to poor outcome for patients. Stereotactic hypofractionated radiotherapy is one option for recurrent high grade gliomas. Optimization of hypofractionated radiotherapy with new radiosensitizing agents requires the identification of robust druggable targets involved in radioresistance.

Methods

We generated 11 xenografted glioma models: 6 were derived from cell lines (1 WHO grade III and 5 grade IV) and 5 were patient derived xenografts (2 WHO grade III and 3 grade IV). Xenografts were treated by hypofractionated radiotherapy (6x5Gy). We searched for 89 biomarkers of radioresistance (39 total proteins, 26 phosphoproteins and 24 ratios of phosphoproteins on total proteins) using Reverse Phase Protein Array.

Results

Both type of xenografted models showed equivalent spectrum of sensitivity and profile of response to hypofractionated radiotherapy. We report that Phospho-EGFR/EGFR, Phospho-Chk1/Chk1 and VCP were associated to resistance to hypofractionated radiotherapy.

Conclusions

Several compounds targeting EGFR or CHK1 are already in clinical use and combining them with stereotactic hypofractionated radiotherapy for recurrent high grade gliomas might be of particular interest.

http://ift.tt/2v6hn9u

Therapeutic radiation for lymphoma and risk of second primary malignant mesothelioma

Abstract

Purpose

This large, population-based U.S. study of lymphoma patients followed for up to four decades enables detailed analysis of second primary mesothelioma risk after radiotherapy.

Methods

U.S. Surveillance, Epidemiology, and End Results data were used to identify second primary mesothelioma among patients diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) between 1973 and 2014. Standardized incidence ratios (SIRs) were calculated by radiotherapy. Multivariate adjusted associations were examined using competing risks survival analysis.

Results

Among 47,219 HL patients (19,538 irradiated) and 252,090 NHL patients (52,454 irradiated), second primary mesothelioma developed among 28 lymphoma patients who received radiotherapy and 59 who did not. Mesothelioma risk was increased among HL and NHL patients treated with radiotherapy [SIR = 1.78, 95% confidence interval (CI) 1.18–2.58], but not without radiotherapy. After multivariate adjustment, radiotherapy was associated with increased mesothelioma risk (relative risk = 1.64, 95% CI 1.05–2.57), especially in lymphoma patients diagnosed before 1995 and after a latency of at least 10 years, and apparently with younger age at diagnosis.

Conclusions

The increase in second primary mesothelioma risk following radiotherapy for lymphoma is independent of several patient and disease characteristics, and is higher with earlier treatment era and longer latency.

http://ift.tt/2tJIt2G

Extraneuraxial metastases in medulloblastoma: is histology and molecular biology important?

http://ift.tt/2h8zsyi

Nuclear localization of Metabolic enzymes in Immunity and Metastasis

Publication date: Available online 27 July 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Yuchen He, Menghui Gao, Yiqu Cao, Haosheng Tang, Shuang Liu, Yongguang Tao
Metabolism is essential to all living organisms that provide cells with energy, regulators, building blocks, enzyme cofactors and signaling molecules, and is in tune with nutritional conditions and the function of cells to make the appropriate developmental decisions or maintain homeostasis. As a fundamental biological process, metabolism state affects the production of multiple metabolites and the activation of various enzymes that participate in regulating gene expression, cell apoptosis, cancer progression and immunoreactions. Previous studies generally focus on the function played by the metabolic enzymes in the cytoplasm and mitochondrion. In this review, we conclude the role of them in the nucleus and their implications for cancer progression, immunity and metastasis.



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de Garengeot hernia with appendicitis treated by two-way-approach surgery: a case report

Abstract

de Garengeot hernia is a rare subtype of a femoral hernia with incarceration of the appendix. This type of hernia usually presents with therapeutic dilemmas, especially because of the risk of surgical site infection (SSI). Our patient was a 74-year-old woman with a bulging mass and tenderness in the right inguinal area. Computed tomography revealed an incarcerated appendix, with appendicitis in the femoral hernia. Laparoscopic appendectomy was initially performed, followed by hernioplasty via the anterior approach to prevent properitoneal contamination. Some authors have recently reported cases successfully treated by laparoscopy. However, this type of hernia has a higher risk for SSI, compared with the risk involved in usual hernioplasty. Therefore, selection of the appropriate surgical approach to prevent wound infection is important, especially in the presence of appendicitis. We would like to highlight the usefulness of hybrid surgery, laparoscopic appendectomy and hernioplasty via the anterior approach to prevent SSIs.

http://ift.tt/2uJ5YdE

Acute presentation of congenital diaphragmatic hernia requiring damage control laparotomy in an adult patient

Abstract

Congenital diaphragmatic hernias constitute an infrequent but potentially serious presentation of bowel obstruction in the adult patient. Herein, we present a rare case of an adult patient with strangulation of colon within a Morgagni's hernia where timely recognition and intervention were life-saving. An 18-year-old female presented with an acute abdomen, respiratory failure, and shock secondary to a strangulated, previously undiagnosed Morgagni hernia requiring emergency laparotomy, reduction of hernia contents and resection of non-viable colon. The patient underwent repair of the hernia with restoration of bowel continuity and reconstruction of her abdominal wall in sequential fashion. Although congenital diaphragmatic hernias have been previously described in the adult population, there are few if any reports of such pathology presenting in such an acute, life-threatening fashion. This case highlights the importance of a high index of suspicion, early recognition, and timely surgical intervention for this rare, potentially fatal condition.

http://ift.tt/2uIT6nJ

Dislocation of a mandibular condyle in the middle cranial fossa, diagnosed 54 years after trauma

Abstract

Dislocation of the mandibular condyle into the middle cranial fossa is a rare complication of mandibular trauma. We report the remarkable case of a 63-year-old patient in whom trauma 54 years prior to consultation resulted in intrusion of the right mandibular condyle into the middle cranial fossa. The diagnosis was missed because of insufficient data provided by conventional radiographies. Failure of timely diagnosis and lack of appropriate treatment resulted in temporomandibular joint ankylosis with functional impairment, disturbance of mandibular growth and dentofacial asymmetry. We emphasize the need for careful radiological investigation in case of a suspected condylar fracture or dislocation, especially when the mechanism of injury is likely to facilitate condylar intrusion. The use of CT and MR-imaging is therefore advocated.

http://ift.tt/2uIVo6w

Congenital lipomatous tumour, presented as a polypoidal projection on upper eyelid

Abstract

A Japanese baby was born with a polypoidal projection with hair, on the lateral corner of upper eyelid. The tumour had extent to bulbar sub-conjunctival area. He presented no other malformation nor pathological symptoms. There was no sign of association with Goldenhar, hemifacial macrosomia, epidermal nevus or linear nevus sebaceous syndromes. The tumour was resected at his age of 4 months. The ocular conjunctiva was incised but not excised. Histopathologically, it was mainly consisted of multi-lobuled mature adipose tissue, dense fibrous tissue was observed at the centre of mass, assumed to be the link of palpebral tarsal plate to lateral canthal ligament. As for the location and component, the tumour was diagnosed as a lipomatous hamartoma. Detached tarsal plate was reattached to the lateral canthal ligament. Satisfactory result was achieved aesthetically and functionally. Congenital lipomatous hamartoma, with protuberant appendage appearance on eyelid, without syndromic association, is presented.

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Diabetic ketoacidosis in a postoperative gastric bypass patient

Abstract

We report a case of postoperative life threatening metabolic acidosis in a young Type-2 diabetic woman who had no history of diabetic ketoacidosis. The patient underwent a non-complicated laparoscopic Roux-en-Y gastric bypass 6 days earlier. We discuss her clinical features, pathogenesis, management and outcome. We would like to make the surgical field aware of this potentially fatal diabetic complication since bariatric procedures are now indicated for the management of diabetic m'orbid obesity and Type-2 diabetes prevalence is on the rise, particularly in young individuals.

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Intra-scrotal testicular torsion of a classical seminoma in an elderly patient: a case report and literature review

Abstract

Intra-scrotal testicular torsion of a seminoma is extremely rare and has been reported scarcely in literature. On the other hand testicular torsion by itself is rare in old age as well. We report a 63-year-old male who was presented to our Emergency Department with a right scrotal swelling and pain for 1 week. The patient had intra-scrotal testicular torsion of a seminoma which was overlooked initially by Doppler ultrasound, progression of symptoms led to a computed tmomgraphy scan which showed a testicular torsion. Intra-operative findings showed a torsed right testis with completely engorged cord. Right radical orchiectomy was done and indecently histopathology revealed a classical seminoma. Urologist should be aware and more vigilant of testicular torsion as a presentation of malignancy in old age especially with the presence of diagnostic limitations.

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Osteochondral fracture in weight-bearing portion of lateral femoral condyle associated with patellar dislocation

Abstract

Osteochondral fracture (OCF) in the weight-bearing surface of the lateral femoral condyle, associated with patellar dislocation, is an uncommon lesion. We report three cases of acute lateral patellar dislocation with large OCF in the weight-bearing portion of the lateral femoral condyle. In patients with lateral patella dislocation or lateral femoral condyle OCF, careful physical examination, radiography and MRI are recommended to rule out any associated injury.

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Invasive Paget’s disease of the male nipple: a case report

Abstract

Male mammary Paget's disease (MPD) is extremely rare. Furthermore, MPD with invasion downward into the dermis of the male nipple has been reported rarely. A 56-year-old Japanese man presented with a lump and eczema in the right nipple–areola area. Ultrasonography revealed only a cystic lesion below the right areola. With a diagnosis of MPD with invasion into the dermis associated with ductal carcinoma in situ, mastectomy and sentinel lymph node biopsy were performed. MPD with dermal invasion is extremely rare, and only one male case has been reported in the English literature; therefore, the current case is the second case of male MPD with dermal invasion.

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Pneumomediastinum and subcutaneous emphysema after successful laparoscopic supra-cervical hysterectomy

Abstract

Laparoscopic hysterectomy is a commonly performed gynecological procedure. Although the outcomes are favorable, severe life threatening complications such as pneumothorax, pneumomediastinum and subcutaneous emphysema can occur during laparoscopy secondary to carbon dioxide insufflation. We report a 46-year-old female who was scheduled for laparoscopic-assisted supra-cervical hysterectomy for uterine fibroids. Patient tolerated the procedure and there were no intra-operative complications. Post operatively she developed hypercarbia, subcutaneous emphysema and pneumomediastinum. She was managed conservatively. This case demonstrates a rare occurrence of subcutaneous emphysema and pneumomediastinum after supra-cervical hysterectomy.

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Pylephlebitis with splenic abscess following transrectal prostate biopsy: rare complications of intra-abdominal infection

Abstract

Pylephlebitis is a rare complication of intra-abdominal infection involving septic thrombosis of the portal system. If the splenic vein is compromised, this can lead to a splenic abscess, an extremely rare complication of pylephlebitis. The pathophysiology behind these clinical entities remains unclear. In both cases, symptoms are highly nonspecific and include fever, malaise and abdominal pain. Here, we discuss a case in which a patient develops both pylephlebitis and a subsequent splenic abscess following a transrectal prostate biopsy. Diagnosis was made by computerized tomography scan; the treatment included broad spectrum antibiotics and laparoscopic splenectomy, after which the patient made a full recovery.

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Salivary duct carcinoma arising from the inferior turbinate

ABSTRACT

Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour, which carries a poor prognosis. SDC affects the major salivary glands, usually occurring in the parotid gland. A 76-year-old male patient presented with right-sided nasal obstruction and rhinorrhoea. A polypoidal mass was seen in the right inferior turbinate mimicking a benign neoplasm. Histological examination following wide excision led to a diagnosis of SDC. There are no therapeutic guidelines and management is based on experience with SDC of the major salivary glands. Given the aggressive nature and poor prognosis of the disease, it is a rare but important differential to consider in patients with unilateral nasal mass.

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Acute GI bleed due to leiomyoma of the jejunum: a case report

Abstract

Neoplasms of the small intestine are rare. Leiomyomas are the one of the benign neoplasms that can be found in the small intestine. These lesions usually remain asymptomatic and are often found incidentally; however, they can become symptomatic if obstruction occurs or the tumor outgrows its blood supply resulting mucosa. Their clinical manifestations can include abdominal pain, diarrhea, melena, a palpable abdominal mass and weight loss. Due to their vague presentation, leiomyomas of the small intestine are typically diagnosed after failed conservative therapy for other pathologies such as duodenal ulcers and diverticulosis. This case report describes a 34-year-old male who developed an acute GI bleed due to a symptomatic leiomyoma of the jejunum. He was initially treated with non-operative conservative management; however, his symptoms remained unresolved and he went on to require surgical intervention.

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Checkpoint Inhibitors for Non-Small Cell Lung Cancer Among Older Adults

Abstract

Non-small cell lung cancer (NSCLC) is mostly a disease of older adults, with its incidence and mortality rates increasing exponentially after the age of 65 years. Immune checkpoint inhibitors (ICIs) have changed the scene of NSCLC treatment after a long and relatively stagnant period of standard treatment regimens. However, little is known about the specific impact of these agents in older adults for whom care is often complicated by a variety of syndromes. This underlines the importance of understanding the dynamics of new cancer treatments in an older patient population. In this paper, we will review ICIs' mechanism of action and data from published clinical trials relevant to older adults. In addition, we will discuss immune aging and treatment-related toxicity as potential challenges facing the use of checkpoint inhibitors in older adults with NSCLC.

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Self-reported shift work, recall bias, and belief about disease causation in a case-control study of breast cancer

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Natalia Lizama, Jane Heyworth, Allyson Thomson, Terry Slevin, Lin Fritschi
BackgroundRecall bias is a potential source of misclassification in case-control studies. Studies have shown that the association between exposure and disease can differ according to participants' beliefs or knowledge about the effect of that exposure on disease. We investigated the association between belief about breast cancer causation and self-reported shift work exposure in a case-control study.MethodsWomen completed a questionnaire asking whether they believed that shift work caused cancer either before or after reporting their history of shift work. We measured: whether belief modified the association between reported shift work and disease; whether belief was associated with reported shift work exposure; and whether being prompted to recall shift work exposure was associated with an increased likelihood of believing that shift work increased breast cancer risk.ResultsThere was a significant association between believing shift work increased breast cancer risk and reporting exposure to shift work. Being prompted to recall shift work was not associated with a belief that shift work increased risk.ConclusionThe association between pre-existing belief about breast cancer risk and reported shift work is likely to be due to exposed individuals believing that exposure increases risk, rather than resulting from recall bias.



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Pancreatic adenocarcinoma with a germline PTEN p.Arg234Gln mutation

Abstract

A minor fraction of pancreatic ductal adenocarcinoma (PDAC) develops in association with germline mutations of the genes responsible for inherited cancer syndromes. However, the PDAC that has a germline PTEN mutation has not received much attention. Genome-wide whole exome sequencing was performed on germline and somatic DNA from an 82-year-old woman who had developed a solid pancreatic cancer but did not show characteristic findings of PTEN hamartoma tumor syndromes (PHTS). Histology of the resected pancreatic tumor showed unique PDAC findings of primarily dendriform structures and dense fibrous tissue, accompanied by multiple pancreatic intraepithelial neoplasias in the vicinity. The tumor immunohistochemistry revealed a loss of PTEN expression and overexpression of TP53. Exome sequencing revealed a K-ras mutation (p.Gly12Val). Germline exome sequencing revealed a missense mutation of PTEN (p.Arg234Gln), a rare variant with a reported association with cancer development but not with other PHTS phenotypes. To our knowledge, this is the first report of PDAC associated with a germline PTEN mutation, particularly a rare variant (p.Arg234Gln) with cancer risks.

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Prophylactic anticonvulsants in patients with primary glioblastoma

Abstract

Glioblastoma is the most common form of primary brain cancer in adults and one of the deadliest of human cancers. Seizures are one of the most frequent presentations of glioblastoma. The use of anti-epileptic drugs (AEDs) in glioblastoma patients suffering from seizures is well accepted. However, the role of long-term AED use in patients with glioblastoma without a history of seizures is controversial. Here, we performed a review of the literature to identify studies that examined the use of AEDs in seizure-free glioblastoma patients. We identified one randomized controlled study suggesting no clinical benefit of seizure prophylaxis in this population. Three of the four retrospective studies identified in our search recapitulated this finding, while the remaining study suggested a benefit for prophylactic AED use. All identified studies were focused on seizure incidence in the post-operative period, ranging from 1 week to long-term follow up. Implications of these findings are reviewed herein.

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Cancer of childhood in sub-Saharan Africa

Cristina Stefan, Freddie Bray, Jacques Ferlay, D Maxwell Parkin and Biying Liu

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Clinical and molecular characteristics of non-small cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program

Abstract

Background:EGFR mutations cause inconsistent response to EGFR tyrosine kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated NSCLC collected in the Biomarkers France database.Patients and methods: Of 17,664 patients, 1,837 (11%) with EGFR-mutated non-small cell lung cancer (NSCLC) were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 Stage IV patients.Results:EGFR exon 18, 19, 20, and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%), and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type (WT) (exon 19: hazard ratio [HR]=0.51 [95% confidence interval [CI]: 0.41-0.64], p < 0.0001; exon 21: HR = 0.76 [95% CI: 0.61-0.95], p = 0.002; exon 20: HR = 1.56, [95% CI: 1.02-2.38], p = 0.004). EGFR mutation type was prognostic of progression-free survival (PFS) versus WT (exon 19: HR = 0.62 [95% CI: 0.49-0.78], p < 0.0001; exon 20: HR = 1.46 [95% CI: 0.96-2.21], p = 0.07). First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved PFS versus chemotherapy (HR = 0.67 [95% CI: 0.53-0.85], p = 0.001). OS was longer for del19 versus L858R, which was associated with better OS compared to other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.Conclusion:EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

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Chemotherapy-induced toxicity – a secondary effect caused by released DNA?

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The Italian Collaborative Group Sets a Standard for the Treatment of Locally Advanced Head and Neck Cancer

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Mobile DNA in Health and Disease

The completion of the Human Genome Project has enabled the identification of many genes, including variants that cause disease. An important discovery, although less celebrated, is that more than half the human genome is derived from mobile pieces of DNA called transposable elements (colloquially…

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Adjuvant endocrine monotherapy for postmenopausal early breast cancer patients with hormone-receptor positive: a systemic review and network meta-analysis

Abstract

Background

In patients with hormone receptor-positive postmenopausal of early stage breast cancer, adjuvant endocrine monotherapies include letrozole, anastrozole, exemestane, toremifene and tamoxifen. But the optimum regimen remains controversial.

Methods

PubMed, Cochrane Database and ClinicalTrials.gov were systematically reviewed of abstract for randomized-controlled trials (RCTs) to assess the efficacy of tamoxifen, letrozole, exemestane, anastrozle and toremifene for postmenopausal patients with hormone-receptor positive (HR+), who have not received prior therapy for early stage breast cancer. The outcomes were measured by disease-free survival (DFS) and overall survival (OS). We evaluated relative hazard ratios (HRs) for death of different therapies by combination hazard ratios for death of included trials. The SUCRA values were used to evaluate the rankings of efficacy for these monotherapies.

Results

A total of fourteen studies including 19,517 patients in our research were absorbed and estimated. The superiority of efficacy for DFS were 5-year letrozole and 10-year tamoxifen (SUCRA values 0.743/0.657) in all comparisons. A more efficient SUCRA values for OS were 5-year Exemestane, 5-year letrozole and 10-year tamoxifen (0.756/0.677/0.669).

Conclusions

Clinically important differences exist between commonly prescribed different adjuvant endocrine monotherapy regimens for both efficacy and acceptability in favor of exemestane and letrozole. 10-year tamoxifen for early breast cancer patients is noninferior to 5-year anastrozle, and might be the best choice where aromatase inhibitors (AIs) are not easy to acquire.

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Erratum to: Sarcopenia, but not visceral fat amount, is a risk factor of postoperative complications after major hepatectomy

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Cancers, Vol. 9, Pages 97: Localization of VEGF to Vascular ECM Is an Important Aspect of Tumor Angiogenesis

Cancers, Vol. 9, Pages 97: Localization of VEGF to Vascular ECM Is an Important Aspect of Tumor Angiogenesis

Cancers doi: 10.3390/cancers9080097

Authors: Weon-Kyoo You William Stallcup

Our research has identified several examples in which reduced VEGF-A binding to deficient vascular extracellular matrix leads to deficits in tumor vascularization and tumor growth: (1) germline ablation of collagen VI in the stroma of intracranial B16F10 melanomas; (2) knockdown of the Tks5 scaffolding protein in MDA-MB-231 mammary tumor cells; (3) germline ablation of NG2 proteoglycan in the stroma of MMTV-PyMT mammary tumors; and (4) myeloid-specific ablation of NG2 in the stroma of intracranial B16F10 melanomas. Tumor hypoxia is increased in each of the four types of experimental mice, accompanied by increases in total VEGF-A. However, while VEGF-A is highly associated with tumor blood vessels in control mice, it is much more diffusely distributed in tumors in all four sets of experimental mice, likely due to reduced extent of the vascular extracellular matrix. In parallel to lost VEGF-A localization, tumor vessels in each case have smaller diameters and are leakier than tumor vessels in control mice. Tumor growth is decreased as a result of this poor vascular function. The fact that the observed vascular changes occur in the absence of alterations in vascular density suggests that examination of vessel structure and function is more useful than vascular density for understanding the importance of angiogenesis in tumor progression.

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Targeting B Cell Signaling in Chronic Lymphocytic Leukemia

Abstract

In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development.

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Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies

Publication date: Available online 27 July 2017
Source:Cancer Cell
Author(s): Marco Mina, Franck Raynaud, Daniele Tavernari, Elena Battistello, Stephanie Sungalee, Sadegh Saghafinia, Titouan Laessle, Francisco Sanchez-Vega, Nikolaus Schultz, Elisa Oricchio, Giovanni Ciriello
Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response.

Graphical abstract

Teaser

Using an algorithmic approach that they design, Mina et al. construct a pan-cancer map of oncogenic dependencies and find several co-dependent alterations that modify drug response. These results provide a framework to improve cancer therapy by anticipating drug resistance and proposing alternative strategies.


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CAR T cells targeting solid tumors: carcinoembryonic antigen (CEA) proves to be a safe target

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