5th International ACC Symposium: Classification of Adrenocortical Cancers from Pathology to Integrated Genomics: Real Advances or Lost in Translation ?

Abstract

For the clinician, despite its rarity, adrenocortical cancer is a heterogeneous tumor both in term of steroid excess and tumor evolution. For patient management, it is crucial to have an accurate vision of this heterogeneity, in order to use a correct tumor classification. Pathology is the best way to classify operated adrenocortical tumors: to recognize their adrenocortical nature and to differentiate benign from malignant tumors. Among malignant tumors pathology also aims at prognosis assessment. Although progress has being made for prognosis assessment, there is still a need for improvement. Recent studies have established the value of Ki67 for adrenocortical cancer (ACC) prognostication, aiming also at standardization to reduce variability. The use of genomics to study adrenocortical tumors gives a very new insight in their pathogenesis and molecular classification. Genomics studies of ACC give now a clear description of the mRNA (transcriptome) and miRNA expression profile, as well as chromosomal and methylation alterations. Exome sequencing also established firmly the list of the main ACC driver genes. Interestingly, genomics study of ACC also revealed subtypes of malignant tumors with different pattern of molecular alterations, associated with different outcome. This leads to a new vision of adrenocortical tumors classification based on molecular analysis. Interestingly, these molecular classifications meet also the results of pathological analysis. This opens new perspectives on the development and use of various molecular tools to classify, along with pathological analysis, ACC, and guides patient management at the area of precision medicine.

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A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma

Epstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aimed to address how EBV ...

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Late Pseudoprogression in glioblastoma: diagnostic value of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine PET

Purpose: Pseudoprogression (PsP) is characterized by therapy-associated but not tumor growth-associated increases of contrast-enhancing glioblastoma lesions on MRI. Although typically occurring during the first 3 months after radiochemotherapy (RCX), PsP may occur later in the course of the disease and may then be particularly difficult to distinguish from true tumor progression. We explored PET using O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET-PET) to approach the diagnostic dilemma. Experimental Design: Twenty-six patients with glioblastoma that presented with increasing contrast-enhancing lesions later than 3 months after completion of RCX underwent 18F-FET-PET. Maximum and mean tumor/brain ratios (TBRmax, TBRmean) of 18F-FET uptake as well as time-to peak (TTP) and patterns of the time-activity curves were determined. The final diagnosis of true progression vs. latePsP was based on follow-up MRI using RANO criteria. Results: LatePsP occurred in seven patients with a median time from RCX completion of 24 weeks while the remaining patients showed true tumor progression. TBRmax and TBRmean were significantly higher in patients with true progression than in patients with latePsP (TBRmax 2.4±0.1 vs. 1.5±0.2, p=0.003; TBRmean 2.1±0.1 vs. 1.5±0.2, p=0.012) while TTP was significantly shorter (mean TTP 25±2 vs. 40±2 min, p<0.001). ROC analysis yielded an optimal cut-off of 1.9 for TBRmax to differentiate between true progression and latePsP (sensitivity 84%, specificity 86%, accuracy 85%, p=0.015). Conclusions: O-(2-[18F]fluoroethyl)-L-tyrosine PET provides valuable information in assessing the elusive phenomenon of late pseudoprogression.

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A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer

Purpose: Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential. Experimental Design: We report the discovery of a novel, solvent-front ROS1^D2033N mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib-resistance of CD74-ROS1^D2033N was functionally evaluated using cell based assays and structural modelling. Results: In biochemical and cell-based assays, the CD74-ROS1^D2033N mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near complete radiographic response in this patient. Conclusions: These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer.

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The prognostic and predictive value of soluble of type IV collagen in colorectal cancer: A retrospective multicenter study

Purpose: To investigate the prognostic and predictive biomarker value of type IV collagen in colorectal cancer (CRC). Experimental Design: Retrospective evaluation of two independent cohorts of CRC patients included prospectively in 2004-2005 (training set) and 2006-2008 (validation set). Plasma samples were available from 297 (training set) and 482 (validation set) patients. Type IV collagen determinations were performed using an ELISA. From the training set, 222 tumors were available for immunohistochemistry. Clinical and follow-up data were retrieved from patient files and national registries. Results: High levels of type IV collagen showed independent prognostic significance in both cohorts with hazard ratios (HRs) (for a one-unit change on the log base 2 scale) of 2.25 (95% CI: 1.78-2.84, p < 0.0001) and 2.24 (95% CI: 1.75-2.86, p < 0.0001) for the training and validation set, respectively. The prognostic impact was present both in patients with metastatic and non-metastatic disease. The predictive value of the marker was investigated in stage II-III patients. In the training set, type IV collagen was prognostic both in the subsets of patients receiving and not receiving adjuvant anti-neoplastic therapy. However, in the validation set the prognostic effect of the marker vanished when looking at patients who received adjuvant anti-neoplatic therapy (HR 0.90, 95% CI: 0.42-1.93) but was still present in the group not receiving adjuvant chemotherapy (HR 2.88, 95% CI: 1.98-4.21). Conclusions: The results indicate clinical validity of type IV collagen as a prognostic biomarker in CRC, although the suggested predictive role of the marker should be validated.

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Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models identify second line combination therapies

Purpose: To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models. Methods: We established 12 PDX from BRAF inhibitor progressed melanoma patients. Following expansion, PDX were analyzed using targeted sequencing and reverse phase protein arrays (RPPA). By using multi-arm pre-clinical trial designs, we identified efficacious precision medicine approaches. Results: We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDX, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho MAPK predominated, with parallel activation of PI3K in a subset. Second line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib) /MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo. Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/ encorafenib/ binimetinib resulted in complete and sustained tumor regression in all animals. Conclusions: Genomic and proteomic data integration identifies dual core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select patients' personalized therapies and avoid treatment failures.

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From the Editor-in-Chief's Desk

Journal of Adolescent and Young Adult Oncology Dec 2015, Vol. 4, No. 4: 151-151.


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A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma

Abstract

Background

Epstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aimed to address how EBV variations contribute to the risk of NPC.

Methods

Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1, a multi-stage association study was conducted to identify EBV variations associated with NPC risk. A protein degradation assay was performed to characterize the functional relevance of the RPMS1 variations.

Results

Based on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P < 0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71–7.37]. The results were further validated in three independent cohorts from the NPC endemic region (P < 0.001, OR = 5.20, 95% CI 3.18–8.50 in 168 cases vs. 241 controls, and P < 0.001, OR = 5.27, 95% CI 4.06–6.85 in 726 cases vs. 880 controls) and a non-endemic region (P < 0.001, OR = 7.52, 95% CI 3.69–15.32 in 58 cases vs. 612 controls). The combined analysis in 1109 cases and 2052 controls revealed that the SNP G155391A was strongly associated with NPC (P _combined  < 0.001, OR = 5.27, 95% CI 4.31–6.44). Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Furthermore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein.

Conclusions

Our study identified an EBV variation specifically and significantly associated with a high risk of NPC. These findings provide insights into the pathogenesis of NPC and strategies for prevention.

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B-Cell Disorders and Curcumin

Clinical studies with patients with early hematological malignancies (ie, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or stage 0/1 chronic lymphocytic leukemia) suggest that early intervention with curcumin, derived from the spice turmeric, may lead to prolonged survival and delay in progressive disease in some of these patients.

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t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders

Abstract

Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1.

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Enhanced therapeutic effect using sequential administration of antigenically distinct oncolytic viruses expressing oncostatin M in a Syrian hamster orthotopic pancreatic cancer model

Abstract

Background

The limited efficacy of current treatments against pancreatic cancer has prompted the search of new alternatives such as virotherapy. Activation of the immune response against cancer cells is emerging as one of the main mechanisms of action of oncolytic viruses (OV). Direct oncolysis releases tumor antigens, and viral replication within the tumor microenvironment is a potent danger signal. Arming OV with immunostimulatory transgenes further enhances their therapeutic effect. However, standard virotherapy protocols do not take full advantage of OV as cancer vaccines because repeated viral administrations may polarize immune responses against strong viral antigens, and the rapid onset of neutralizing antibodies limits the efficacy of redosing. An alternative paradigm based on sequential combination of antigenically distinct OV has been recently proposed.

Methods

We have developed a protocol consisting of sequential intratumor administrations of new Adenovirus (Ad) and Newcastle Disease Virus (NDV)-based OV encoding the immunostimulatory cytokine oncostatin M (OSM). Transgene expression, toxicity and antitumor effect were evaluated using an aggressive orthotopic pancreatic cancer model in Syrian hamsters, which are sensitive to OSM and permissive for replication of both OVs.

Results

NDV-OSM was more cytolytic, whereas Ad-OSM caused higher OSM expression in vivo. Both viruses achieved only a marginal antitumor effect in monotherapy. In addition, strong secretion of OSM in serum limited the maximal tolerated dose of Ad-OSM. In contrast, moderate doses of Ad-OSM followed one week later by NDV-OSM were safe, showed a significant antitumor effect and stimulated immune responses against cancer cells. Similar efficacy was observed when the order of virus administrations was reversed.

Conclusion

Sequential administration of oncolytic Ad and NDV encoding OSM is a promising approach against pancreatic cancer.

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Pathology and oncology in Africa: education and training for the future in cancer research– East African Regional Meeting

Abstract

According to the World Health Organisation (WHO), deaths from non-communicable diseases (NCDs) will increase globally, with the largest increase being on the African continent. On our continent, projections have indicated that deaths from NCDs will exceed all combined communicable, maternal, perinatal and nutritional diseases as the most common causes of death by 2030. Hence, the importance of a functional and improved pathology system in the diagnosis of cancer cannot be debated.

Recently, the African Organization for Research and Training in Cancer (AORTIC) organised its East African regional meeting in Mwanza, Tanzania on 25–26 June 2015, with the focus being 'Pathology and oncology: Education and training for the future in cancer research'. The main themes of the workshop were around improving cancer care and the role of twinning in Eastern Africa, in particular the Mwanza cancer project, telepathology, e-health and biobanking. The outcomes of a 2 day strategic meeting were developing an efficient and effective plan to guide the improvement in pathology training and cancer research in Africa.

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Effect of Thiocyanate on Iodine Status of Pregnant Women

Abstract

The aim of this study was to assess the thyroid status of pregnant women on the basis of biochemical indicators and to evaluate the potential risk of developing iodine deficiency as a result of tobacco smoke exposure by assessing the association between urinary thiocyanate levels and the manifestation of iodine deficiency. The study included 219 pregnant women from the town of Plovdiv and Plovdiv District in Southern Bulgaria. The levels of urinary iodine, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and urinary thiocyanate as indicators of tobacco smoke exposure were measured. Most of the pregnant women (60.1 %) were found to have iodine deficiency, 10.6 % of them had TSH values greater than 4 mIU/L, and 16.4 % had FT4 below 9 pmol/L. There were negative correlations between urinary iodine levels and thiocyanate/creatinine ratio (R = −0.148, р = 0.034) and between thiocyanate/creatinine ratio and FT4 (R = −0.379, p < 0.0001); thiocyanate/creatinine ratio and serum TSH were positively correlated (R = 0.169, p = 0.019). Logistic regression analysis showed that pregnant women in whom the thiocyanate/creatinine ratio was greater than the median value of 3.57 mg/g had a 3.882-fold higher risk of developing iodine deficiency (urinary iodine <150 μg/L) than the pregnant women with lower thiocyanate levels (OR = 3.882, 95 % CI 1.402–10.751, p = 0.009). Higher levels of urinary thiocyanate were found in women exposed to tobacco smoke, and quantification of these ions in urine provided a fast non-invasive method to monitor thiocyanate load. Due to the competitive inhibition of iodine intake by thiocyanates, their levels should be carefully monitored, especially in cases of severe iodine deficiency.

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Transitions in the Prophylaxis, Treatment and Care of Patients with Venous Thromboembolism

Abstract

Introduction

Patients experience numerous transitions, including changes in clinical status, pharmacologic treatment and prophylaxis, and progression through the physical locations of their healthcare setting as they advance through a venous thromboembolism (VTE) clinical experience. This review provides an overview of these transitions and highlights how they can impact clinical care.

Methods

Major public resources (PubMed, MEDLINE, and Google Scholar) were searched using various combinations of the terms: "venous thromboembolism", "deep vein thromboses", "pulmonary embolism", "transitions in care", and "hospital protocols" to identify narrative reviews, professional guidelines, or primary manuscripts reporting protocol development strategies and/or clinical data, published in English from 2010 through January 2015. The studies included in this review were selected on the basis of extensive reading of the literature and the author's clinical expertise.

Results

VTE treatment and prophylaxis is a dynamic process requiring ongoing patient assessments and adjustments to therapeutic strategies as the patient progresses through various hospital and outpatient settings. Throughout these transitions in care, physicians need to be vigilant of any changes in the patient's clinical condition which may impact the patient's risk of VTE, and re-evaluate the intervention(s) employed when such changes occur. A standardized, interdisciplinary VTE clinical pathway developed for medical patients with acute VTE resulted in decreased utilization of hospital resources and healthcare costs, suggesting that further research is warranted in this area.

Conclusion

The prevention and management of VTE can be optimized by the development and local implementation of standardized evidence-based clinical pathways.

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Intramural metastasis of T1 rectal cancer: report of a case report

Abstract

Background

Intramural metastasis (IM) is extremely rare in colorectal cancer, although it often occurred in esophageal cancer.

Case Presentation

We report a rare case of T1 rectal cancer with IM which was successfully resected by laparoscopic surgery. A 62-year-old man was admitted to our institution for the treatment of rectal cancer detected by medical examination. Colonoscopy revealed two tumors in the rectum: a type II rectal cancer of 2 cm in diameter located 5 cm proximal to the anal verge and a submucosal tumor of 1 cm in diameter located approximately 1.5 cm proximal to the rectal cancer. Abdominal computed tomography (CT), magnetic resonance imaging (MRI), and transrectal ultrasonography indicated the rectal cancer invaded into the submucosal layer with no metastasis to regional lymph nodes or distant organs. The patient underwent laparoscopic intersphincteric resection.Histopathological analysis revealed that the rectal cancer was moderately differentiated adenocarcinoma (stage I; pT1N0M0 according to the 7th edition of UICC) with severe lymphovascular invasion (ly1, v3) and that the submucosal tumor was composed of moderately differentiated adenocarcinoma proliferating within the muscularis propria. A number of features of the submucosal tumor indicated that this was an IM of the rectal cancer: clearly distinct location from the rectal cancer, growth predominantly within the muscularis propria, similar structural and cellular heterogeneity, and the presence of tumor emboli within vascular vessels. The patient was postoperatively followed for more than 4 years without any sign of recurrence.

Conclusions

To the best of our knowledge, this is the first report of the T1 rectal cancer with IM.

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Selection of Lymph Node–Positive Cases Based on Perirectal and Lateral Pelvic Lymph Nodes Using Magnetic Resonance Imaging: Study of the Japanese Society for Cancer of the Colon and Rectum

Abstract

Purpose

To investigate the optimum cutoff for lymph node size to identify cases positive for perirectal lymph node (PRLN) and lateral lymph node (LPLN) metastasis of lower rectal cancer on magnetic resonance imaging (MRI).

Methods

The subjects were 449 patients who underwent preoperative MRI. Mesorectal excision was performed in all patients (combined with lateral pelvic lymph node [LN] dissection in 324) between 2004 and 2013 at 6 institutes. Cases were classified as cN positive and cN negative on the basis of the short axis of the largest LN being greater than or equal to a cutoff or less than a cutoff, respectively. PRLN and LPLN diagnoses using 5 and 10 mm cutoffs were compared with histologic diagnoses. Of the 449 patients, 55 received preoperative chemoradiotherapy. MRI was only performed after this therapy in all of these patients.

Results

For PRLNs, 5 and 10 mm cutoffs gave area under the curve (AUC) values of 0.6364 and 0.5794, respectively. The 5 mm cutoff gave a significantly higher AUC value (P = 0.0152), with an accuracy of 63.7 %, sensitivity of 72.6 %, and specificity of 54.7 %. For right LPLNs, the respective AUC values were 0.7418 and 0.6326 (P = 0.0034), and the variables (5 mm cutoff) were 77.6, 68.6, and 79.7 %. For left LPLNs, AUC values were 0.7593 and 0.6559, respectively (P = 0.0057), and the variables (5 mm cutoff) were 79.3, 70.8, and 81.0 %.

Conclusions

Identification of LN-positive cases on the basis of PRLN and LPLN sizes was superior at a short-axis 5 mm cutoff. Size-based diagnosis of LN metastasis is simple and useful, but further investigation is needed to clarify whether it is superior to diagnosis based on morphology, such as shape, border, and signal intensity.

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Methylation of the Tumor Suppressor Genes HIC1 and RassF1A Clusters Independently From the Methylation of Polycomb Target Genes in Colon Cancer

Abstract

Background

Methylation changes within tumor suppressor (TS) genes or polycomb group target (PcG) genes alter cell fates. Chromatin associated with PcG targets is bivalent in stem cells, while TS genes are not normally bivalent. PcG target methylation changes have been identified in tumor stem cells, and abnormal methylation is found in TS genes in cancers. If the epigenetic states of genes influence DNA methylation, then methylation of PcG targets and TS genes may evolve differently during cancer development. More importantly, methylation changes may be part of a sequence in tumorigenesis.

Methods

Chromatin and methylation states of 4 PcG targets and 2 TS genes were determined in colon cancer cells. The methylation states were also detected in 100 pairs of colon cancer samples. Principle component analysis (PCA) was used to reveal whether TS methylation or PcG methylation was the main methylation change associated with colon cancers.

Results

Chromatin and methylation states differ in colon cancer cell lines. The methylation states within PcG targets clustered independently from the methylation states in TS genes, a finding we previously reported in liver cancers. PCA in colon cancers revealed the strongest association with methylation changes in 2 TS genes, HIC1 and RassF1A. Loss of HIC1 methylation correlated with decreased tumor migration.

Conclusions

PcG and TS methylation states cluster independently from each other. The deduced principle component correlated better with TS methylation than PcG methylation in colon cancer. Abnormal methylation changes may represent a sequential biomarker profile to identify developing colon cancer.

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Refraining from Smoking for 15 Years or More Reduced the Risk of Tumor Recurrence in Non-muscle Invasive Bladder Cancer Patients

Abstract

Purpose

We investigated whether smoking cessation could have preventative effects against tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC).

Methods

Our study population comprised 634 patients with initially diagnosed NMIBC at Keio University Hospital, Saiseikai Central Hospital, and Saitama Medical University Hospital between 1995 and 2012. We analyzed the relationships between tumor recurrence in NMIBC and patient clinicopathological parameters, including smoking status.

Results

Overall, 181 patients (28.5 %) were classified as current smokers, 154 (24.3 %) as former smokers, and 299 (47.2 %) as non-smokers. Kaplan–Meier curve analysis revealed that the tumor recurrence rate was significantly lower in the non-smoker group than in the current- and former-smoker groups (p < 0.001 and p < 0.001, respectively). In the 154 former smokers, Kaplan–Meier curve analysis revealed that smoking intensity and duration was not associated with tumor recurrence rate; however, patients with a smoking cessation period of 15 years or more had a significantly lower tumor recurrence rate than their counterparts (p < 0.001). A multivariate analysis identified a smoking cessation period of <15 years (hazard ratio [HR] 2.20; p = 0.003) and T1 tumors (HR 1.99; p = 0.013) as independent risk factors for tumor recurrence in the former-smokers subgroup.

Conclusions

A positive smoking history was identified as one of the independent risk factors for bladder tumor recurrence after transurethral resection of the bladder tumor. Furthermore, refraining from smoking for 15 years or more reduced the risk of tumor recurrence in former smokers with NMIBC regardless of the intensity or duration of smoking. Therefore, smoking cessation may reduce the risk of tumor recurrence in patients with NMIBC.

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Table_of_Contents

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Cover

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Editorial_Board

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Ex Vivo Expansion or Manipulation of Stem Cells to Improve Outcome of Umbilical Cord Blood Transplantation

Abstract

The outcome of umbilical cord blood transplantation for adult patients with hematologic malignancies now rivals that of matched unrelated donor transplantation. However, delayed hematopoietic and immunologic recovery remains a source of significant morbidity and mortality. Multiple strategies are now being studied to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit prior to transplantation. A second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Such a strategy may also address the problem of slow hematopoietic recovery as well as the increased risk of graft failure. Many of these strategies are now being tested in late phase multi-center clinical trials. If proven cost-effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.

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Application of an M13 bacteriophage displaying tyrosine on the surface for detection of Fe 3+ and Fe 2+ ions

Abstract

Ferric and ferrous ion plays critical roles in bioprocesses, their influences in many fields have not been fully explored due to the lack of methods for quantification of ferric and ferrous ions in biological system or complex matrix. In this study, an M13 bacteriophage (phage) was engineered for use as a sensor for ferric and ferrous ions via the display of a tyrosine residue on the P8 coat protein. The interaction between the specific phenol group of tyrosine and Fe³⁺ / Fe²⁺ was used as the sensor. Transmission electron microscopy showed aggregation of the tyrosine-displaying phages after incubation with Fe³⁺ and Fe²⁺. The aggregated phages infected the host bacterium inefficiently. This phenomenon could be utilized for detection of ferric and ferrous ions. For ferric ions, a calibration curve ranging from 200 nmol/L to 8 µmol/L with a detection limit of 58 nmol/L was acquired. For ferrous ions, a calibration curve ranging from 800 nmol/L to 8 µmol/L with a detection limit of 641.7 nmol/L was acquired. The assay was specific for Fe³⁺ and Fe²⁺ when tested against Ni²⁺, Pb²⁺, Zn²⁺, Mn²⁺, Co²⁺, Ca²⁺, Cu²⁺, Cr³⁺, Ba²⁺, and K⁺. The tyrosine displaying phage to Fe³⁺ and Fe²⁺ interaction would have plenty of room in application to biomaterials and bionanotechnology.

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Conserved termini and adjacent variable region of Twortlikevirus Staphylococcus phages

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing cause of serious infection, both in the community and hospital settings. Despite sophisticated strategies and efforts, the antibiotic options for treating MRSA infection are narrowing because of the limited number of newly developed antimicrobials. Here, four newly-isolated MRSA-virulent phages, IME-SA1, IMESA2, IME-SA118 and IME-SA119, were sequenced and analyzed. Their genome termini were identified using our previously proposed "termini analysis theory". We provide evidence that remarkable conserved terminus sequences are found in IME-SA1/2/118/119, and, moreover, are widespread throughout Twortlikevirus Staphylococcus phage G1 and K species. Results also suggested that each phage of the two species has conserved 5' terminus while the 3' terminus is variable. More importantly, a variable region with a specific pattern was found to be present near the conserved terminus of Twortlikevirus S. phage G1 species. The clone with the longest variable region had variable terminus lengths in successive generations, while the clones with the shortest variable region and with the average length variable region maintained the same terminal length as themselves during successive generations. IME-SA1 bacterial infection experiments showed that the variation is not derived from adaptation of the phage to different host strains. This is the first study of the conserved terminus and variable region of Twortlikevirus S. phages.

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Molecular characterization of DENV-3 circulating during the post-monsoon period of 2013–14 in Delhi, India

Abstract

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HIV-1 Vpr protein activates the NF-κB pathway to promote G2/M cell cycle arrest

Abstract

Viral protein R (Vpr) plays an important role in the replication and pathogenesis of Human immunodeficiency virus type 1 (HIV-1). Some of the various functions attributed to Vpr, including the induction of G2/M cell cycle arrest, activating the NF-?B pathway, and promoting viral reverse transcription, might be interrelated. To test this hypothesis, a panel of Vpr mutants were investigated for their ability to induce G2/M arrest and to activate the NF-κB pathway. The results showed that the Vpr mutants that failed to activate NF-κB also lost the activity to induce G2/M arrest, which suggests that inducing G2/M arrest via Vpr depends at least partially on the activation of NF-κB. This latter possibility is supported by data showing that knocking down the key factors in the NF-κB pathway–p65, RelB, IKKa, or IKKβ–partially rescued the G2/M arrest induced by Vpr. Our results suggest that the NF-κB pathway is probably involved in Vpr-induced G2/M cell cycle arrest.

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The prevalence and clinical profiles of FLT3-ITD, FLT3-TKD, NPM1, C-KIT, DNMT3A, and CEBPA mutations in a cohort of patients with de novo acute myeloid leukemia from southwest China

Abstract

While a substantial amount of data on gene mutations related to acute myeloid leukemia (AML) prognosis from western and other populations have been reported, these studies largely describe one or two genes. Additionally, in southwest China, only insufficient data exist regarding FLT3-ITD, FLT3-TKD, NPM1, C-KIT, DNMT3A, and CEBPA mutations have been widely used in clinical settings. Therefore, a comprehensive study about these mutations of clinical importance in the prognosis of AML in western China is necessary. In a cohort of 255 patients with de novo AML, we retrospectively analyzed the prevalence of the six gene mutations, and then we assessed the results in conjunction with clinical characteristics and treatment responses. As for the frequencies of these mutations, the NPM1 mutation occurred most frequently (17.7 %; 42/237), followed by the CEBPA mutation (15.0 %; 19/127) and the FLT3-ITD mutation (10.2 %; 25/244). The frequencies of the FLT3-TKD, DNMT3A, and C-KIT mutations were 3.7 % (9/234), 4.0 % (9/225) and 4.2 % (10/238), respectively. These mutations were closely related to clinical characteristics including FAB classification, gender and age, hemogram, blasts (%), fusion genes, and immunophenotypes. Additionally, a higher complete remission (CR) rate was found in NPM1-mutated patients. The occurrence of these mutations is variable among different countries and regions worldwide, which may provide clues to the etiology of AML. Besides, we identified new clinical characteristics that advance our understanding of these mutations and further clarify the involvement of these mutations in the development of leukemia.

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Circadian rhythm influences genome-wide transcriptional responses to 131 I in a tissue-specific manner in mice

Abstract

Background

Circadian variation of gene expression is often neglected when ionizing radiation-induced effects are studied, whether in animal models or in cell culture. This study characterized diurnal variation of genome-wide transcriptional regulation and responses of potential biomarkers and signature genes in normal mouse tissues at 24 h after i.v. administration of ¹³¹I.

Methods

Female BALB/c nude mice were i.v. injected with 90 kBq ¹³¹I at 9:00 a.m., 12:00 p.m., or 3:00 p.m. and killed after 24 h (n = 4/group). Paired control groups were mock-treated (n = 3–4/group). The kidneys, liver, lungs, spleen, and thyroid were excised, snap-frozen, and stored at −80 °C until extraction of total RNA. RNA microarray technology was used for genome-wide expression analysis. Enriched biological processes were categorized after cellular function. Signature genes for ionizing radiation and thyroid hormone-induced responses were taken from the literature. Absorbed dose was estimated using the Medical Internal Radiation Dose (MIRD) formalism.

Results

The thyroid received an absorbed dose of 5.9 Gy and non-thyroid tissues received 0.75–2.2 mGy over 24 h. A distinct peak in the total number of significantly regulated transcripts was observed at 9:00 a.m. in the thyroid, but 3 h later in the kidney cortex, kidney medulla, and liver. Transcriptional regulation in the lungs and spleen was marginal. Associated cellular functions generally varied in quality and response strength between morning, noon, and afternoon. In the thyroid, 25 genes were significantly regulated at all investigated times of day, and 24 thereof showed a distinct pattern of pronounced down-regulation at 9:00 a.m. and comparatively weak up-regulation at later times. Eleven of these genes belonged to the species-specific kallikrein subfamily Klk1b. Responses in signature genes for thyroid hormone-induced responses were more frequent than for ionizing radiation, and trends persisted irrespective of time of day.

Conclusion

Diurnal variation of genome-wide transcriptional responses to 90 kBq ¹³¹I was demonstrated for the thyroid, kidney cortex and medulla, and liver, whereas variation was only marginal in the lungs and spleen. Overall, significant detection of potential biomarkers and signature genes was validated at each time of day, although direction of regulation and fold-change differed between morning, noon, and afternoon. These findings suggest that circadian rhythm should be considered in radiation research and that biological and analytical endpoints should be validated for circadian robustness.

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Influence of a novel, versatile bifunctional chelator on theranostic properties of a minigastrin analogue

Abstract

Background

6-[Bis(carboxymethyl)amino]-1,4-bis(carboxymethyl)-6-methyl-1,4-diazepane (AAZTA ) is a promising chelator with potential advantages over 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radiopharmaceutical applications. Its mesocyclic structure enables fast radiolabelling under mild conditions with trivalent metals including not only ⁶⁸Ga for positron emission tomography (PET) but also ¹⁷⁷Lu and ¹¹¹In for single-photon emission computed tomography (SPECT) and radionuclide therapy. Here, we describe the evaluation of a bifunctional AAZTA derivative conjugated to a model minigastrin derivative as a potential theranostic agent.

Methods

An AAZTA derivative with an aliphatic C₉ chain as linker was coupled to a minigastrin, namely [AAZTA⁰, D-Glu¹, desGlu^2–6]-minigastrin (AAZTA-MG), and labelled with ⁶⁸Ga, ¹⁷⁷Lu and ¹¹¹In. The characterisation in vitro included stability studies in different media and determination of logD (octanol/PBS). Affinity determination (IC₅₀) and cell uptake studies were performed in A431-CCK2R cells expressing the human CCK2 receptor. μPET/CT and ex vivo biodistribution studies were performed in CCK2 tumour xenograft-bearing nude mice and normal mice.

Results

AAZTA-MG showed high radiochemical yields for ⁶⁸Ga (>95 %), ¹⁷⁷Lu (>98 %) and ¹¹¹In (>98 %). The logD value of −3.7 for both [⁶⁸Ga]- and [¹⁷⁷Lu]-AAZTA-MG indicates a highly hydrophilic character. Stability tests showed overall high stability in solution with some degradation in human plasma for [⁶⁸Ga]- and transchelation towards DTPA for and [¹⁷⁷Lu]-AAZTA-MG. An IC₅₀ value of 10.0 nM was determined, which indicates a high affinity for the CCK2 receptor. Specific cell uptake after 60 min was >7.5 % for [⁶⁸Ga]-AAZTA-MG and >9.5 % for [¹⁷⁷Lu]-AAZTA-MG, comparable to other DOTA-MG-analogues. μPET/CT studies in CCK2 receptor tumour xenografted mice not only revealed high selective accumulation in A431-CCK2R positive tumours of ⁶⁸Ga-labelled AAZTA-MG (1.5 % ID/g in 1 h post injection) but also higher blood levels as corresponding DOTA-analogues. The ¹¹¹In-labelled peptide had a tumour uptake of 1.7 % ID/g. Biodistribution in normal mice with the [¹⁷⁷Lu]-AAZTA-MG showed a considerable uptake in intestine (7.3 % ID/g) and liver (1.5 % ID/g).

Conclusion

Overall, AAZTA showed interesting properties as bifunctional chelator for peptides providing mild radiolabelling conditions for both ⁶⁸Ga and trivalent metals having advantages over the currently used chelator DOTA. Studies are ongoing to further investigate in vivo targeting properties and stability issues and the influence of spacer length on biodistribution of AAZTA.

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Some options in studying side effects of drugs taken during pregnancy

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Pilomyxoid astrocytomas with rare rosenthal fibers

Abstract

Pilomyxoid astrocytomas (PMAs) were first officially described in 2007. Since then, intermediate pilomyxoid tumors with histopathological features typical of both PMAs and pilocytic astrocytomas (PAs) have been described. However, we found evidence of tumors that are histologically like PMAs but contain rare Rosenthal fibers, which have been reported in PAs but not in PMAs. We retrospectively analyzed four such cases involving a 16-year-old adolescent with a 3-cm recurring suprasellar tumor, an 11-year-old boy with a nonrecurring 3-cm mass in the left cerebellum, an 18-year-old adolescent with a mass in the suprasellar cistern who died 2 days after total tumor resection, and a 26-year-old woman with a nonrecurring 2-cm mass in the right temporal lobe. Microscopically, the tumors were a monomorphous population of small bipolar cells in a prominent myxoid/mucoid background with rare Rosenthal fibers. The tumor cells infiltrated the adjacent brain parenchyma. Findings for glial fibrillary acidic protein and oligodendrocyte transcription factor were positive, and the Ki-67 protein proliferation index was about 2 %. Our findings document the existence of tumors that are histologically like PMAs but also have Rosenthal fibers. Studies of more such cases are needed for clarification of such tumors' clinical features.

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A mixed choroid plexus papilloma and ependymoma

Abstract

We report a novel case of a mixed choroid plexus papilloma (CPP) and ependymoma with cartilaginous differentiation. This kind of mixed tumor has not been previously reported in the English literature. The patient was a 5-year-old girl, who presented with a 1-week history of fever and numbness of the right lower limb. Magnetic resonance imaging of the brain with gadolinium revealed a heterogeneously enhancing mass in the occipital horn of the left lateral ventricle. Histologically, the tumor showed an intermixed CPP area and a low-grade papillary ependymoma-like area, which was studded with cartilage islands and psammoma bodies. In many foci, direct transition of CPP and ependymoma was observed, but there were no high-grade features. We report this novel case, describe the unique microscopic and immunohistochemical features, and speculate on the pathogenesis.

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Treatment of resectable intrathoracic sarcomas: a single institution experience over twenty years

Abstract

Background

There are very few published data on the management of primary intrathoracic sarcoma, defined as sarcomas arising from the lung, pleura, and mediastinum, excluding the chest wall. Therefore, the aim of this study was to evaluate the outcome of patients with intrathoracic sarcoma treated at an academic referral center over a 21-year period.

Methods

A retrospective search was performed to identify patients with intrathoracic sarcomas treated with surgical resection from January 1990 to November 2011 at the University of Washington Medical Center. Local control and overall survival were analyzed in relation to the treatment received.

Results

Thirty-five patients were identified. Hazard ratios for local control, adjusted for tumor margin status, at 5 years were 0.74 (95 % CI [0.21, 2.58]) for the addition of chemotherapy (CT) to surgery, 0.57 (95 % CI [0.15, 2.23]) with the addition of (radiation therapy) RT, and 0.50 (95 % CI [0.06, 4.03]) with the addition of both CT and RT. At 7 years, the ratios for local control were 0.69 (95 % CI [0.20, 2.36]) for CT added to surgery, 0.58 (95 % CI [0.15, 2.27]) for RT, and 0.41 (95 % CI [0.05, 3.33]) with the addition of both CT and RT. Hazard ratios for overall survival, adjusted for sarcoma stage, at 5 years were 0.61 (95 % CI [0.16, 2.39]) for the addition of CT to surgery, 1.03 (95 % CI [0.26, 4.08]) for the addition of RT, and 0.54 (95 % CI [0.11, 2.69]) for the addition of both CT and RT. The 7-year hazard ratios for overall survival were 0.77 (95 % CI [0.23, 2.60]) for CT added to surgery, 0.99 (95 % CI [0.25, 3.84]) for the addition of RT, and 0.42 (95 % CI [0.09, 2.05]) for both CT and RT with surgery. At 10 years, hazard ratios for overall survival were 0.71 (95 % CI [0.21, 2.38]) for added CT, 0.81 (95 % CI [0.21, 3.08]) for added RT, and 0.33 (95 % CI [0.07, 1.65]) for the addition of both CT and RT to surgery.

Conclusions

Our series is the largest published study of intrathoracic sarcoma which focuses on the survival benefit of adding RT, chemotherapy or both to surgery in resectable intrathoracic sarcoma. Our data suggest a potential benefit in local control and survival from adjuvant therapy, with the greatest benefit likely to come from combined CT and RT, though none of the results achieved statistical significance. As intrathoracic sarcomas are rare and histologically heterogeneous, larger collaborative studies are necessary to determine treatment efficacy and elucidate which histologic subtypes are likely to benefit most from adjuvant therapy.

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Radiation emergencies: radiation-related brain and lung injury

Abstract

Background

The advent of modern radiation techniques, such as intensity modulated and stereotactic ablative radiation therapy, has permitted increasingly accurate delivery of radiation, with ability to shape distribution of dose specifically to the tumor. These techniques limit dose to surrounding normal tissue in an effort to reduce toxicity; however, despite such improvements, potentially serious side effects related to treatment may occur, requiring urgent management.

Objective

Radiation-related brain or lung injury in previously irradiated patients may present in the acute or late post-treatment setting. Patients initially present with non-specific symptoms associated with the organ in question, representing a diagnostic challenge in the emergency room. Here, we review potential complications that may occur following radiation therapy to two commonly treated sites: brain and thorax.

Conclusions

We provide a guideline of the presentation, diagnosis, and management of these complications to function as a useful resource for healthcare providers. Furthermore, we review thedosimetric and volumetric parameters associated with such adverse events.

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Damage-inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter

Wild-type TP53 exons 5–8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2). We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild-type polypeptide. Expression of CpG-enriched TP53 constructs selectively reduced production of the full-length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription. 450K methylation comparison of normal (TP53-wildtype) and cancerous (TP53-mutant) human cells and tissues revealed focal cancer-associated declines in CpG methylation near the P1 transcription start site, accompanied by rises near the alternate exon 5 start site. These data confirm that site-specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage-inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression. © 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

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Grand multiparity and reproductive cancer in the Jerusalem Perinatal Study Cohort

Abstract

Objectives

Grand multiparity is associated with reduced mortality from reproductive cancers. We aimed to separate the components of mortality, by measuring incidence of and survival after reproductive cancer onset in grand multiparous compared to other parous women.

Study design

We linked data from the population-based Jerusalem Perinatal Study Cohort, which included women aged 13–55 who delivered 1964–1976, with Israel's National Cancer Registry. We compared breast and gynecologic cancer risk and all-cause survival following a cancer diagnosis, among grand multiparae (GMPs = parity 5+, n = 8,246) versus women with parity 1–4 (n = 19,703), adjusting for reproductive and demographic variables.

Results

Grand multiparae were at significantly lower risk of breast cancer than others (adjusted hazard ratio (HR_adj) = 0.62, 95 % confidence interval (CI) 0.54–0.71), after controlling for age at first birth, education, and other covariates. This reduction was greater among GMPs whose first birth occurred after age 30 (p-interaction = 0.0001) and for cancer occurring before age 50 years (p = 0.002). In contrast, GMPs were at greater risk of death than women with parity <5, following a breast cancer diagnosis (HR_adj = 1.69, CI 1.39–2.1). Ovarian, uterine, and cervical cancer incidence did not differ between the groups, but survival was reduced for GMPs with uterine cancer (HR_adj = 2.48, CI 1.22–5.03).

Conclusion

Reduced reproductive cancer mortality reported among GMPs masks two opposing phenomena: decreased breast cancer risk and poorer survival after breast and uterine cancers. The latter unfavorable outcome suggests that tumors in GMPs may be particularly aggressive, having perhaps escaped protective mechanisms conferred by parity. This finding calls for heightened clinical attention in this group.

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Erratum: Attenuation measurements show that the presence of a TachoSil surgical patch will not compromise target irradiation in intra-operative electron radiation therapy or high-dose-rate brachytherapy

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Prospective study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer

Abstract

Background

Radio-chemotherapy is one of the steps of multidisciplinary management in locally advanced pancreatic cancer. The Epidermal Growth Factor Receptor (EGFR) plays an important role in the disease pathway. The purpose of this prospective study is to evaluate the feasibility and the efficacy of radiotherapy in combination with gemcitabine and EGFR targeting therapy for patients with locally advanced disease.

Materials and methods

From November 2008 through January 2012, 34 patients were included in this study. In all cases an accurate pre-treatment staging including CT scan, Endoscopic Ultra-Sonography (EUS), 18F - fluorodeoxyglucose (18F-FDG) PET-CT and laparoscopy with peritoneal washing was performed. External beam radiation was delivered with a total dose of 50.4 Gy (1.8 Gy per fraction). Patients were treated using 3D- conformal radiotherapy, and the clinical target volume was the primary tumor and involved lymph nodes. Gemcitabine 300 mg/m² and Cetuximab were given weekly during radiation therapy.

Results

Ten patients (29.4 %) were excluded from the protocol because of the evidence of metastatic disease at the pre-treatment staging. Three patients refused radiochemotherapy. Twenty-one patients completed the therapy protocol. During the combined therapy grade 3–4 toxicities observed were only haematological (leukopenia 47,6 %, trombocytopenia 4.8 %, elevated gamma-GT 23.8 %, elevated alkaline phosphatase 4,8 %). Non-haematological toxicity grade 3–4 was never reported. Post-treatment workup showed partial response in five patients (24 %), stable disease in 11 patients (52 %) and disease progression in 5 patients (24 %). Two-year Local Control was 49 % (median, 18.6 months), 2-year Metastases Free Survival was 24 % (median, 10.8 months). One and two-year Overall Survival were 66 % and 28 % respectively, with a median survival time of 15.3 months.

Conclusions

The combination of cetuximab and gemcitabine with concurrent radiation therapy provides a feasible and well tolerated treatment for locally advanced pancreatic cancer. Patients' selection is crucial in order to treat patients appropriately.

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SEOM guidelines for the management of Malignant Melanoma 2015

Abstract

All melanoma patients must be confirmed histologically and resected according to Breslow. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon must be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 therapy. Up to 10 years follow up is recommended for melanoma patients with dermatologic examinations and physical exams.

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SEOM clinical guidelines for diagnosis and treatment of metastatic colorectal cancer 2015

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer dead in Spain. About half the patients will eventually develop distant metastases. However, as treatment options are expanding, prognosis has steadily improved over the last decades. Management of advanced CRC should be discussed within an experienced multidisciplinary team to select the most appropriate systemic treatment (chemotherapy and targeted agents) and to integrate surgical or ablative procedures when indicated. Disease site and extent, resectability, tumor biology and gene mutations, clinical presentation, patient preferences, and comorbidities are key factors to design a customized treatment plan. The aim of these guidelines is to provide synthetic recommendations for managing advanced CRC patients.

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SEOM clinical guidelines in Hereditary Breast and ovarian cancer

Abstract

Approximately, 7 % of all breast cancers (BC) and 11–15 % of ovarian cancers (OC) are associated with inherited predisposition, mainly related to germline mutations in high penetrance BRCA1/2 genes. Clinical criteria for genetic testing are based on personal and family history to estimate a minimum 10 % detection rate. Selection criteria are evolving according to new advances in this field and the clinical utility of genetic testing. Multiplex panel testing carries its own challenges and we recommend inclusion of genes with clinical utility. We recommend screening with annual mammography from age 30 and breast MRI from age 25 for BRCA1 and BRCA2 mutation carriers. Bilateral salpingo-oophorectomy should be offered to women with a BRCA1 or BRCA2 mutation, between 35 and 40 years and after completion of childbearing, or individualise based on the earliest age of ovarian cancer diagnosed in the family. Bilateral risk-reducing mastectomy is an option for healthy BRCA1 and BRCA2 mutation carriers, as well as contralateral mastectomy for young patients with a prior BC diagnosis. BRCA genetic testing in patients with BC and OC may influence their locoregional and systemic treatment.

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Vγ9Vδ2 T cells and zoledronate mediate antitumor activity in an orthotopic mouse model of human chondrosarcoma

Abstract

Chondrosarcoma (CS) is a cartilaginous malignant neoplasm characterized by resistance to conventional adjuvant therapy. The prognosis of unresectable or metastatic CS is poor. Therefore, it is imperative to explore novel therapeutic approaches to improve the treatment efficacy for those CS patients. Emerging data has implicated the synergistic antitumor activity of zoledronate (ZOL) and Vγ9Vδ2 T cells. However, whether ZOL-stimulated Vγ9Vδ2 T cells could infiltrate bone sarcoma and inhibit tumor growth has not been thoroughly answered yet. In this study, Vγ9Vδ2 T cells from healthy donors and CS patients were expanded in the presence of ZOL (1 μM) and IL-2 (400 IU/ml). The antitumor activity of Vγ9Vδ2 T cells to ZOL-pretreated human CS was examined both in vitro and in vivo. ZOL pretreatment substantially enhanced the cytotoxicity of Vγ9Vδ2 T cells to SW1353 and primary CS cells. ZOL potentiated the migration and cytotoxicity of Vγ9Vδ2 T cells to SW1353 in dose- and time-dependent manner. Moreover, weekly intravenous ZOL followed by Vγ9Vδ2 T cells inhibited subcutaneous xenograft growth. Thus, Vγ9Vδ2 T cells were able to infiltrate bone tumor and significantly suppressed the development of orthotopic SW1353 xenografts. Altogether, the study raises the possibility of combining ZOL with Vγ9Vδ2 T cells for CS treatment.

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Hyperoside induces apoptosis and inhibits growth in pancreatic cancer via Bcl-2 family and NF-κB signaling pathway both in vitro and in vivo

Abstract

Although advanced surgical operation and chemotherapy have been under taken, pancreatic cancer remains one of the most aggressive and fatal human malignancies with a low 5-year survival rate of less than 5 %. Therefore, novel therapeutic strategies for prevention and remedy are urgently needed in pancreatic cancer. This present research aimed to investigate the anti-cancer effects of hyperoside in human pancreatic cancer cells. Our in vitro results showed that hyperoside suppressed the proliferation and promoted apoptosis of two different human pancreatic cancer cell lines, which correlated with up-regulation of the ratios of Bax/Bcl-2 and Bcl-xL and down-regulation of levels of nuclear factor-κB (NF-κB) and NF-κB's downstream gene products. What's more, using an orthotopic model of human pancreatic cancer, we found that hyperoside also inhibited the tumor growth significantly. Mechanically, these outcomes could also be associated with the up-regulation of the ratios of Bax/Bcl-2 and Bcl-xL and down-regulation of levels of NF-κB and NF-κB's downstream gene products. Collectively, our experiments indicate that hyperoside may be a promising candidate agent for the treatment of pancreatic cancer.

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The role of microRNAs in the adrenocortical carcinomas

Abstract

MicroRNAs (miRNAs) are a group of small, non-protein-coding RNAs that inhibit gene expressions through binding their 3′-UTR regions. Each miRNA can regulate a number of target genes and play crucial roles in a lot of biological processes including organogenesis, hematopoiesis, cell development, proliferation, and invasion. Deregulated expression of miRNAs has been found to be associated with initiation and development of tumors. Increasing evidences showed that miRNAs play a crucial role in adrenocortical carcinomas (ACCs). Aberrant miRNA expression may contribute to ACC carcinogenesis, and it can act as tumor-suppressive or oncogenic miRNAs. In this review, we reviewed the recent studies available on ACC-associated miRNAs. We try to summarize the contribution of miRNAs to the initiation and development of ACCs.

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Γ-Ionizing radiation-induced activation of the EGFR–p38/ERK–STAT3/CREB-1–EMT pathway promotes the migration/invasion of non-small cell lung cancer cells and is inhibited by podophyllotoxin acetate

Abstract

Here, we report a new intracellular signaling pathway involved in γ-ionizing radiation (IR)-induced migration/invasion and show that podophyllotoxin acetate (PA) inhibits the IR-induced invasion and migration of A549 cells (a non-small cell lung cancer (NSCLC) cell line). Our results revealed that IR increased the invasion/migration of A549 cells, and this effect was decreased by 10 nM PA treatment. PA also inhibited the expressions/activities of matrix metalloprotase (MMP) -2, MMP-9, and vimentin, suggesting that PA could block the IR-induced epithelial-mesenchymal transition (EMT). The IR-induced increases in invasion/migration were associated with the activation of EGFR-AKT, and PA inhibited this effect. P38 and p44/42 ERK were also involved in IR-induced invasion/migration, and combined treatments with PA plus inhibitors of each MAPK synergistically blocked this invasion/migration. In terms of transcription factors (TFs), IR-induced increases in cyclic AMP response element-binding protein-1 (CREB-1) and signal transducer and activator of transcription 3 (STAT3) increased invasion/migration and EMT. PA also inhibited these transcription factors and then blocked IR-induced invasion/migration. Collectively, these results indicate that IR induces cancer cell invasion/migration by activating the EGFR–p38/ERK–CREB-1/STAT3–EMT pathway and that PA blocks this pathway to inhibit IR-induced invasion/migration.

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The prediction of survival of patients with gastric cancer with PD-L1 expression using contrast-enhanced ultrasonography

Abstract

Gastric cancer is the one of the most common cancers around the world. The prognosis of gastric cancer remains poor, due to the biological characteristics of the primary tumor as well as the recurrence after treatment. Accumulating evidence suggests the implication of programmed death ligand-1 (PD-L1) in the pathogenesis and prognosis of cancer. This study aimed to explore the CEUS as a valuable tool to improve the assessment of the therapeutic effect of the PD-L1 blocker in the treatment of gastric cancer. A total number of 105 patients with gastric cancer were enrolled in this study from June 2008 to December 2011 in our hospital. The association of PD-L1 expression level (105 cases) and CEUS parameters (100 cases) with the prognosis of gastric cancer was examined. The results showed that PD-L1-positive staining was associated with the depth of invasion, differentiation, and poor prognosis of patients with gastric cancer. The CEUS intensity (positive) exhibited poor prognosis compared to the negative counterpart. Moreover, PD-L1 and CEUS co-positivity was significantly related to a poor prognosis. The characteristic of ultrasonography images correlated with the expression of PD-L1 (r = 0.46, P = 0.0003). Collectively, the mean intensity of contrast-enhanced ultrasonography is a useful predictor in the PD-L1 expression in gastric cancer. The ultrasonography and CEUS parameter could be considered as the predictor of response to PD-L1 blocker treatment in the clinical practice.

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Bayesian Cure Rate Modeling of Local Tumor Control: Evaluation in Stereotactic Body Radiotherapy for Pulmonary Metastases

Publication date: Available online 15 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Rainer J. Klement, Michael Allgäuer, Nicolaus Andratschke, Oliver Blanck, Judit Boda-Heggemann, Karin Dieckmann, Marciana Duma, Iris Ernst, Michael Flentje, Ute Ganswindt, Peter Hass, Christoph Henkenberens, Detlef Imhoff, Henning K. Kahl, Robert Krempien, Fabian Lohaus, Ursula Nestle, Meinhard Nevinny-Stickel, Cordula Petersen, Vanessa Schmitt, Sabine Semrau, Florian Sterzing, Jan Streblow, Thomas G. Wendt, Andrea Wittig, Matthias Guckenberger
BackgroundThe majority of radiobiological models about prediction of tumor control probability (TCP) does not account for the fact that many events could remain unobserved because of censoring.Methods and MaterialsWe applied two fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiotherapy at German, Austrian and Swiss institutions: (i) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); (ii) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution while in the BG model only one dominant recurrence-competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age and pre-treatment chemotherapy were used as covariates for regression.ResultsMean follow-up time was 15.5 months (range 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (114-188) Gy10 in the CIS99 and 133 (101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (≳20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model.ConclusionsBiologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term.

Teaser

We apply two Bayesian cure rate models to a sample of 770 pulmonary metastases treated with stereotactic body radiotherapy in order to predict tumor control probability while accounting for censored observations. Both models yielded stable posterior model parameter estimates, indicating their identifiability. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term.


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Surgical techniques to prevent reflux esophagitis in proximal gastrectomy reconstructed by esophagogastrostomy with preservation of the lower esophageal sphincter, pyloric and celiac branches of the vagal nerve, and reconstruction of the new His angle for early proximal gastric cancer

Abstract

Purpose

This article describes the surgical techniques to prevent reflux esophagitis (RE) after proximal gastrectomy reconstructed by esophagogastrostomy (PGE) preservation of the lower esophageal sphincter (LES) and both pyloric and celiac branches of the vagal nerve (PCVN), and reconstruction of the new His angle (HA) for early proximal gastric cancer (PGC).

Methods

Twenty patients after PGE were divided into 2 groups (group A: 10 patients without preserved LES and PCVN for advanced PGC; group B: 10 patients with preserved LES and PCNV and the addition of a new HA for early PGC). A postoperative interview on gastroesophageal reflux disease (GERD) and satisfaction with this procedure and the collection of endoscopic findings for RE and stasis of the remnant stomach (SRS) were conducted 1 year after PGE in groups A and B.

Results

The rates of proton pump inhibitor administration and the symptoms of GERD, RE and SRS in group A were significantly higher than those in group B (p = 0.0433, p = 0.0190, p = 0.0253, p = 0.0190, respectively). Seven out of 10 patients in group A voiced dissatisfaction. Patients in group B were significantly more satisfied with this procedure than those in group A (p = 0.0010).

Conclusion

This method is useful for preventing postoperative GERD including RE in early PGC patients.

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Erratum: Attenuation measurements show that the presence of a TachoSil surgical patch will not compromise target irradiation in intra-operative electron radiation therapy or high-dose-rate brachytherapy

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Prospective study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer

Radio-chemotherapy is one of the steps of multidisciplinary management in locally advanced pancreatic cancer. The Epidermal Growth Factor Receptor (EGFR) plays an important role in the disease pathway. The pur...

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