Tumor Infiltrative Pattern Predicts Sites of Recurrence After Curative Gastrectomy for Stages 2 and 3 Gastric Cancer

Abstract

Background

In East Asia, the tumor infiltrative pattern (INF) has been routinely evaluated by hematoxylin and eosin-stained sections as a pathologic characteristic of surgically resected specimens.

Methods

The infiltrative pattern of gastric cancer (GC) has been histopathologically classified as INFa (expansive growth), INFb (intermediate type) and INFc (infiltrative growth) according to the Japanese Classification of Gastric Carcinoma. The prognostic value and characteristics of the disease recurrence pattern for each INF type were assessed in 785 patients with various stages of GC and also in 243 patients with stages 2 and 3 GC.

Results

Comparison of the overall survival experienced by patients independently of stage showed that INF was significantly associated with prognosis. Specifically, peritoneal metastasis was present in 91 % of stage 4 patients in the INFc group, whereas hepatic metastasis was present in 39 % of stage 4 patients in the INFa and INFb group. After curative gastrectomy of patients with stages 2 or 3 GC, INF was not significantly associated with survival. The prevalence of peritoneal recurrence was significantly higher in the INFc group than in the INFa and INFb group, whereas the prevalence of hepatic recurrence was significantly higher in the INFa and INFb group than in the INFc group. Multivariate analysis identified INFc as an independent risk factor for peritoneal recurrence after curative gastrectomy. The association of the INF type with the incidence of peritoneal recurrence was observed with all disease stages regardless whether the patient was given adjuvant chemotherapy or not.

Conclusions

Evaluation of the INF type shows promise for its role as a predictor of postoperative recurrence sites in patients with GC.

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Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma

Abstract

Background

Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes.

Methods

A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome.

Results

At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age <61 years, tumor size <10 cm, margin-negative resection, and sporadic-tumor status. At the protein level, loss of cyclin D1 (p = 0.06), pEGFR (p = 0.023), pIGF-1R (p = 0.022), and PTEN (p < 0.001) and overexpression of AXL (p = 0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA, and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS), whereas RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R.

Discussion

Loss of cyclin D1, overexpression of AXL, and loss of PTEN are associated with poor cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and also could explain the aggressive phenotype seen in RA-UPS compared with the sporadic lesions.

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Pilot Study of a New Nonradioactive Surgical Guidance Technology for Locating Nonpalpable Breast Lesions

Abstract

Background

The current technique for locating nonpalpable breast lesions is wire localization (WL). Radioactive seed localization and intraoperative ultrasound were developed to improve difficulties with WL. The SAVI SCOUT surgical guidance system was developed to improve these methods. The SCOUT system is a non-radioactive, FDA-cleared medical device that uses electromagnetic wave technology to provide real-time guidance during excisional breast procedures.

Methods

Consenting patients underwent localization and excision using an implantable electromagnetic wave reflective device (reflector) and a detector handpiece with a console. Using image guidance, the reflector was placed up to 7 days before the surgical procedure. The primary end points of the study were successful reflector placement, localization, and retrieval. The secondary end points were percentage of clear margins, reexcision rates, days of placement before excision, and physician comparison with WL.

Results

This study analyzed 50 patients. The reflectors were placed under mammographic guidance (n = 18, 36 %) or ultrasound guidance (n = 32, 64 %). Of the 50 patients, 10 (20 %) underwent excisional biopsy and 40 (80 %) had a lumpectomy. The lesion and reflector were successfully removed in all 50 patients, and no adverse events occurred. Of the 41 patients who had in situ and/or invasive carcinoma identified, 38 (93 %) had clear margins and 3 (7 %) were recommended for reexcision.

Conclusions

These data suggest that the SCOUT system is safe and effective for guiding the excision of nonpalpable breast lesions and a viable alternative to standard localization options. A larger prospective, multi-institution trial of SCOUT currently is underway to validate these findings.

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Induction and differentiation of adipose-derived stem cells from human buccal fat pads into salivary gland cells

Abstract

Atrophy or hypofunction of the salivary gland because of aging or disease leads to hyposalivation that affects patient quality of life by causing dry mouth, deterioration of mastication/deglutition, and poor oral hygiene status. Current therapy for atrophy or hypofunction of the salivary gland in clinical practice focuses on symptom relief using drugs and artificial saliva; therefore, there is still a need to develop new therapies. To investigate potential novel therapeutic targets, we induced the differentiation of salivary gland cells by co-culturing human adipose-derived stem cells isolated from buccal fat pads (hBFP-ASCs) with human salivary-gland-derived fibroblasts (hSG-fibros). We examined their potential for transplantation and tissue neogenesis. Following the culture of hBFP-ASCs and hSG-fibros, differentiated cells were transplanted into the submandibular glands of SCID mice, and their degree of differentiation in tissues was determined. We also examined their potential for functional tissue reconstitution using a three-dimensional (3D) culture system. Co-cultured cells expressed salivary-glandrelated markers and generated new tissues following transplantation in vivo. Moreover, cell reconstituted glandular structures in the 3D culture system. In conclusion, coculture of hSG-fibros with hBFP-ASCs led to successful differentiation into salivary gland cells that could be transplanted to generate new tissues.

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Imaging hamster model of bile duct cancer in vivo using fluorescent l -glucose derivatives

Abstract

Extrahepatic bile duct cancer (cholangiocarcinoma) has a poor prognosis. Since surgical resection is the only way to prolong the patient's life, it is of critical importance to correctly determine the extent of lesions. However, conventional pre-operative assessments have insufficient spatial resolution for determining the surgical margin. A fluorescent contrast agent might provide a more precise measure to identify anomalies in biliary surface, when combined with probe-based confocal laser endomicroscopy (pCLE). We have previously shown that 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-l-glucose (2-NBDLG), a fluorescent derivative of l-glucose (fLG), is specifically taken up into spheroids consisting of cells showing heterogeneous nuclear-cytoplasm ratio, a feature of malignant cells in clinical settings. In addition, a combined use of 2-TRLG, a membrane-impermeable fLG, with 2-NBDLG visualized membrane integrity as well. We therefore explored in the present study the availability of the fLGs in vivo as a contrast agent for pCLE by using a hamster model of cholangiocarcinoma. Extrahepatic cholangiocarcinoma developed in mid common duct in ~20 % of the animals subjected to cholecystoduodenostomy with the ligation at the distal end of the common duct followed by injection of a carcinogen N-nitrosobis(2-oxopropyl)amine. After infusing bile duct with a solution containing 2-NBDLG and 2-TRLG, the lumen was surgically exposed and examined by pCLE. Fluorescence pattern characterized by bright spots and dark clumps was detected in the areas diagnosed with cholangiocarcinoma in later histopathology, whereas no such pattern was detected in control animals. These findings may form a basis for elucidating a potential availability of fLGs in imaging cholangiocarcinoma by pCLE.

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ALDH2 polymorphism for the risk of cervical carcinogenesis

Abstract

To investigate the clinical significance of ALDH2 genetic polymorphisms in cervical carcinogenesis. ALDH2 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 195 cervical smear in exfoliated cervical cell samples using Real-Time polymerase chain reaction (PCR) System. The frequency for the AG+AA genotype was seven in the normal group (70.0 %), 16 in the LSIL group (57.1 %), and 27 in the HSIL group (90.0 %). A significant difference was found between the LSIL and HSIL groups (P = 0.0064). Patients with HSIL lesions frequently had high-risk HPV infections and concurrently belonged to the AG+AA group. ALDH2 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population.

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Intensity modulated radiation therapy (IMRT) for sinonasal tumors: a single center long-term clinical analysis

Radiotherapy has a central role in the treatment of sinonasal malignancies, either as postoperative or as primary therapy. To study the efficacy and safety of intensity modulated radiotherapy (IMRT) for sinona...

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Prognostic significance of nuclear or cytoplasmic nucleolin expression in human non-small cell lung cancer and its relationship with DNA-PKcs

Abstract

This study investigated the expression of nucleolin in tissue samples in patients with non-small cell lung cancer (NSCLC). Nucleolin was studied to determine whether it has a prognostic value and if its levels correlate with various clinicopathologic parameters. The relationship between nucleolin and expression of DNA-PKcs was also evaluated. Immunohistochemistry was used for detecting the expression levels of nucleolin and DNA-PKcs in tissues from 225 stage IA to IIIB NSCLC patients who underwent lung surgery. Nucleolin was observed predominantly in the cytoplasm, and some levels were observed in the nucleus. Nucleolin expression was higher in NSCLC tissues than adjacent normal lung tissues. Among 225 NSCLC patients, 117 (52.0 %) had high expression of nucleolin. The expression of nucleolin was significantly associated with pathologic stage (P = 0.013) and T status (P = 0.043). Multivariate analysis revealed that nucleolin, cytoplasmic nucleolin, and nuclear nucleolin expression were independent prognostic factors for both overall survival (OS) (P < 0.001) and disease-free survival (DFS) (P < 0.001). A high level of nuclear nucleolin served as an independent prognostic factor for better survival, while a high level of cytoplasmic nucleolin was closely associated with worse prognosis in NSCLC patients. The expression of nucleolin and cytoplasmic nucleolin positively correlated with DNA-PKcs (P < 0.001). These data suggest that nucleolin could be an effective treatment target and prognostic factor for patients with NSCLC.

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Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China

Abstract

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

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Overexpression of the non-coding SOX2OT variants 4 and 7 in lung tumors suggests an oncogenic role in lung cancer

Abstract

Despite the advances in cancer therapy, lung cancer still remains the most leading cause of cancer death worldwide. The long non-coding RNAs (lncRNAs) are recently introduced as novel regulators of human cancers. SOX2 overlapping transcript (SOX2OT) is a cancer-associated lncRNA gene that encodes different alternatively spliced transcripts. Here, we investigated the alterations in the preferential expression of different SOX2OTs in twenty non-small cell lung cancer (NSCLC) patients by real-time quantitative reverse transcription PCR (qRT-PCR) method. We observed preferential expression of SOX2OT4 and SOX2OT7 in lung tumor tissues. The quantitative gene expression analysis revealed that >30 % of NSCLC tumors express SOX2OT4 (mean = 7.6 times) and SOX2OT7 (mean = 5.9 times) more than normal tissues, with higher expression in squamous cell carcinoma. Further, we observed overexpression of pluripotency-associated transcription factor, SOX2 in 47 % of our samples concordant with SOX2OT (R = 0.62, P value <0.05). Overexpression of OCT4A gene was also observed in 36.8 % of tumor tissues. Then, we investigated the effects of SOX2OT suppression in lung adenocarcinoma cell line, by means of RNAi. Cell characteristics of colony formation, apoptosis, 2-D mobility, and cell cycle progression were measured in control and treated A549 cells. The SOX2OT knockdown significantly reduced the colony formation ability of cancer cells; however, no alterations in the rate of apoptosis were detected. On the other hand, SOX2OT-suppressed cells had elevated accumulation in G2/M phase of cell cycle and exhibited limited mobility. Altogether, our findings support a potential oncogenic role for SOX2OT in non-small cell lung cancer tumor genesis and SOX2OT seems a promising therapeutic candidate for NSCLC.

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The effects and mechanisms of SLC34A2 on tumorigenicity in human non-small cell lung cancer stem cells

Abstract

A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) growth is driven by lung cancer stem cell-like cells (LCSCs), but molecular mechanisms regulating tumorigenic and self-renewal potential of LCSCs are still unclear. Here, we aim to investigate biological function of SLC34A2 in regulating tumorigenicity of LCSCs and its underlying mechanisms. Our findings testified that CD166⁺ cells which were derived from fresh primary NSCLC samples displayed stem cell-like features. Fluorescence-activated cell sorting (FACS) analysis showed the presence of a variable fraction of CD166 cells in 15 out of 15 NSCLC samples. Significantly, CD166⁺ LCSCs from primary NSCLC tumors expressed high level of SLC34A2 which was required for CD166⁺ LCSCs tumorigenic and self-renewal potential. In NSCLC patient cohort, increased SLC34A2 expression correlated with histology, which suggests a potential role of SLC34A2 in CD166⁺ LCSCs. Furthermore, Wnt/β-catenin pathway and Bmi1 were found necessary for tumorigenicity and self-renewal capacity of CD166⁺ LCSCs by a series in vitro and in vivo experiments. Then, our study indicated that SLC34A2 regulated Bmi1 to promote tumorigenic and self-renewal potential of CD166⁺ LCSCs through Wnt/β-catenin pathway. In this study, the characterization of molecular basis of SLC34A2 in CD166⁺ LCSCs not only allows for better understanding of the mechanisms regulating tumorigenicity of this specific population of NSCLC cells but also provides insight into the gradual improvement of more effective cancer therapies against this disease.

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A novel derivative of tetrandrine (H1) induces endoplasmic reticulum stress-mediated apoptosis and prosurvival autophagy in human non-small cell lung cancer cells

Abstract

H1, a bromized derivative of tetrandrine, has been reported to induce apoptosis in human cancer cells. But, the underlying mechanism of apoptosis triggered by H1 is unclear. In the present study, we found that H1 triggered death receptor 5 (DR5)-dependent apoptosis in non-small cell lung cancer (NSCLC) cells. Further study showed that H1 activated ER stress through enforcing the expression of Bip/GRP78, IRE1α, p-eIF2α, and CHOP. Moreover, abrogating CHOP expression blocked DR5 upregulation and subsequent apoptosis, indicating that CHOP was essential for DR5-dependent apoptosis induced by H1. In addition, H1 greatly downregulated cellular FLICE-inhibitory protein (c-FLIP), and enhanced expression of c-FLIP protected cancer cells from apoptosis in spite of H1 therapy. Furthermore, we discovered that H1 induced autophagy in human NSCLC cells. Interestingly, the autophagy induced by H1 played a protective function in NSCLC cells and effectively weakened caspase-mediated apoptosis. In summary, these findings suggest that H1 induces DR5-dependent apoptosis in human NSCLC cells via stimulating ER stress signaling pathway, and pharmacologically inhibiting autophagy will be an efficient approach to synergize H1-caused apoptosis in lung cancer cells.

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DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia

Abstract

We aimed to investigate the association between dihydropyrimidine dehydrogenase (DPYD) gene polymorphisms and the risk of pediatric acute lymphoblastic leukemia (ALL) and its prognosis after chemotherapy. A total of 147 pediatric ALL patients diagnosed by our hospital between January 2011 and December 2014 were included in the case group, and 102 healthy people who received a physical examination during the same time frame in our hospital were included in the control group. DNA sequencing was applied for site determination and genotyping of the DPYD 85T > C, 2194G > A, 1156G > T, and IVS14 + 1G > A polymorphisms. The genotype and allele frequencies of the two groups were compared. A significant difference was found in the comparison of the mutant gene and allele frequencies of the 85T > C polymorphism between the case and control groups (P < 0.05). The CT and CC genotypes in the 85T > C polymorphism were associated with the risk of the disease (OR = 1.592, 95 % CI = 1.010–2.509), suggesting that the recessive gene (85C) was more likely to lead to the occurrence of ALL compared with the dominant gene (85T) (P < 0.05). Patients carrying the C allele of the 85T > C polymorphism presented higher damage of their liver functions and higher infection rates compared with patients carrying the non-C allele (P < 0.05). A higher proportion of liver function damage and a higher infection rate were found in patients with the GA genotype in the IVS14 + 1G > A polymorphism compared with the GG genotype (P < 0.05). The complete remission (CR) rate in patients with the GG genotype in the IVS14 + 1G > A polymorphism was higher than in patients with the GA genotype (P = 0.020). After 5-fluorouracil/calcium folinate (5-FU/CF)-based chemotherapy, the event-free survival (EFS) rate of patients with the TT genotype was higher than patients with the CT and CC genotypes (P < 0.05). Our results revealed that the C allele of the 85T > C polymorphism might be associated with susceptibility to pediatric ALL. Patients carrying the C allele may have an increased risk of ALL. Thus, the 85T > C polymorphism may be a predictor of CR for pediatric ALL patients.

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Hepatitis B virus X protein reduces the stability of Nrdp1 to up-regulate ErbB3 in hepatocellular carcinoma cells

Abstract

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is the most widespread type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very intricate and HBV-encoded X protein (HBx) has been reported to play a key role in this process. It has been reported that HBx up-regulates the transcription of ErbB3. However, it remains unclear whether HBx can regulate ErbB3 expression at post-translational modification level. In this study, we showed that HBx interacts with ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) and decreases its stability, which results in the up-regulation of ErbB3 and promotion of HCC cells. Moreover, the expression of ErbB3 was almost undetectable in normal liver tissues but was relative abundant in HCC tissues, and the level of ErbB3 and Nrdp1 significantly showed a negative correlation in HCC tissues. Taken together, these findings suggest that HBx promotes the progression of HCC by decreasing the stability of Nrdp1, which results in up-regulation of ErbB3, suggesting that ErbB3 may be a target for HCC therapy.

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Silencing Bag-1 gene via magnetic gold nanoparticle-delivered siRNA plasmid for colorectal cancer therapy in vivo and in vitro

Abstract

Apoptosis disorder is generally regarded as an important mechanism of carcinogenesis. Inducement of tumor cell apoptosis can be an effectual way to treat cancer. Bcl-2-associated athanogene 1 (Bag-1) is a positive regulator of Bcl-2 which is an anti-apoptotic gene. Bag-1 is highly expressed in colorectal cancer, which plays a critical role in promoting metastasis, poor prognosis, especially in anti-apoptotic function, and is perhaps a valuable gene target for colorectal cancer therapy. Recently, we applied a novel non-viral gene carrier, magnetic gold nanoparticle, and mediated plasmid pGPH1/GFP/Neo-Bag-1-homo-825 silencing Bag-1 gene for treating colorectal cancer in vivo and in vitro. By mediating with magnetic gold nanoparticle, siRNA plasmid was successfully transfected into cell. In 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, magnetic gold nanoparticle had no significant cytotoxicity and by which delivered RNA plasmid inhibited cell viability significantly (P < 0.05). Downregulation of Bag-1 promoted cell apoptosis (∼47.0 %) in vitro and significantly decreased tumor growth when the cells were injected into nude mice. Based on the studies in vivo, the relative expression of Bag-1 was 0.165 ± 0.072 at mRNA level and ∼60 % at protein level. In further study, C-myc and β-catenin, mainly molecules of Wnt/β-catenin pathway, were decreased notably when Bag-1 were silenced in nanoparticle plasmid complex-transfected Balb c/nude tumor xenograft. In conclusion, Bag-1 is confirmed an anti-apoptosis gene that functioned in colorectal cancer, and the mechanism of Bag-1 gene causing colorectal cancer may be related to Wnt/β-catenin signaling pathway abnormality and suggested that magnetic gold nanoparticle-delivered siRNA plasmid silencing Bag-1 is an effective gene therapy method for colorectal cancer.

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Manganese-superoxide dismutase (Mn-SOD) overexpression is a common event in colorectal cancers with mitochondrial microsatellite instability

Abstract

Mitochondrial displacement loop (D-loop) is a hot spot for mitochondrial DNA (mtDNA) alterations that effects cellular reactive oxygen species (ROS) generation. Manganese-superoxide dismutase (Mn-SOD) is a major antioxidant enzyme that protects cells from ROS-mediated damage. In the present study, we investigated the relationship between sequence alterations of mitochondrial D-loop and Mn-SOD expression in colorectal cancer (CRC). Genotyping of entire mitochondrial D-loop (1124 bp) was carried out on mtDNA of analogous tumor and normal tissues from 35 CRC patients of south Indian origin by PCR-sequencing analysis. Tumor-specific large-scale mtDNA deletions and Mn-SOD expression was analyzed by PCR and Western blot analysis, respectively. We identified 87 polymorphisms in the D-loop region of tumor and/or control tissues. Polymorphisms were predominantly located in hypervariable region I (67.9 %) than in II (32.1 %) of D-loop. Significantly increased mtDNA microsatellite instability (mtMSI) [310'C' insertion (P = 0.00001) and T16189C (P = 0.0007)] and elevated Mn-SOD expression was observed in tumor tissues compared with controls. Interestingly, mtMSI was significantly high in tumors with Mn-SOD overexpression. Tumor-specific large-scale mtDNA deletions were not observed in CRC tissues. In conclusion, mtMSI and Mn-SOD overexpression are a common event in CRC. The analysis of mtMSI and/or Mn-SOD expression might help to identify patients at high risk for disease outcome, thereby helping to refine therapeutic decisions in CRC.

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Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model

Abstract

Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP⁺ stromal cells which mimicked the FAP⁺ CAF in vivo. We immunized a breast cancer mouse model with FAP⁺ stromal cells to perform immunotherapy against FAP⁺ cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP⁺ stromal cells whose phenotype was CD11b⁺/CD34⁺/Sca-1⁺/FSP-1⁺/MHC class I⁺. Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP⁺ stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4⁺ and CD8⁺ T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP⁺ CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP⁺ stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

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Oncogene swap as a novel mechanism of acquired resistance to EGFR-tyrosine kinase inhibitor in lung cancer

Abstract

Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKIs. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose to describe this phenomenon as "oncogene swap". Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKIs. This possibility should be considered in order to avoid futile inhibition of the original oncogene.

This article is protected by copyright. All rights reserved.

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Surgical treatment pattern and outcomes in epithelial ovarian cancer patients from a cancer institute in Kerala, India

P Georgeena, Anupama Rajanbabu, DK Vijaykumar, K Pavithran, KR Sundaram, KS Deepak and MR Sanal

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Technology Access and Smartphone App Preferences for Medication Adherence in Adolescents and Young Adults With Sickle Cell Disease

Background

Hydroxyurea is the only Food and Drug Administration approved medication for sickle cell disease (SCD) with short- and long-term benefits for both morbidity and mortality. However, hydroxyurea underutilization and adherence remain challenges for patients with SCD. The objectives of this study were to determine access to technology among adolescents and young adults (AYA) with SCD and to identify their preferred technology-based strategies for improving medication adherence.

Procedure

A cross-sectional survey was administered in a variety of clinical settings from October 2014 through May 2015 to AYA (12–22 years) with SCD (all genotypes) followed in a Comprehensive Sickle Cell Program.

Results

Eighty of 107 eligible participants completed the survey for a 75% response rate. Participants (51% female, 94% Black) had a mean age of 15.3 ± 2.8 years. Most participants (75%) were on a daily medication with about half on hydroxyurea. Forgetfulness (67%) was the most common barrier to medication adherence. The majority of participants (85%) owned smartphones and either owned or had access to electronic tablets (83%), laptops (72%), or desktops (70%). Of the proposed smartphone app features, daily medication reminders were ranked first most frequently, followed by education about SCD, adherence text prompts, education about SCD medications, and medication log.

Conclusions

The majority of our AYA with SCD owned smartphones and had access to other electronic devices. Our survey results provided valuable insight into the preferred app features and optimal strategies for developing technology-based interventions, such as a multicomponent app, to increase medication adherence for AYA with SCD or other chronic conditions.

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Spinal Epidural Hematoma Following Cupping Glass treatment in an Infant With Hemophilia A

A 6 months old infant, diagnosed with a rare mutation causing severe hemophilia A, presented with spinal epidural hematoma. Parents later admitted the infant had glass cupping therapy performed within 2 weeks of the onset of symptoms. The rare mutation, rare bleeding complication, and the eventual course of therapy applied in this case will be discussed in our case report.

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Impaired Left Ventricular Reserve in Childhood Cancer Survivors Treated With Anthracycline Therapy

Background

Childhood cancer survivors show evidence of diffuse myocardial fibrosis that is related to exercise capacity. The mechanism of reduced exercise tolerance in anthracycline cardiotoxicity remains unclear. We explored the determinants of exercise intolerance by evaluating left ventricular (LV) distensibility and functional reserve.

Methods

Patients (n = 22) and healthy controls (n = 10) underwent two-dimensional echocardiography while supine, upright, and during cycle exercise. LV distensibility was measured as the change in end-diastolic cavity area (EDCA) from supine to the upright position. LV functional reserve was assessed during peak exercise, and measured as the exercise-induced change in systolic circumferential strain rate (SR) and early-diastolic SR (EDSR). The peak rate of oxygen consumption was measured by indirect calorimetry.

Results

Median age of patients was 16 years (range 8–19) and controls 14 years (range 8–19). Median time since anthracycline therapy was 6 years (range 2–16). Peak oxygen consumption was significantly lower in patients compared to controls (35 ml/kg/min [28–60] vs. 45 ml/kg/min [44–53], P = 0.005). Transitioning from the supine position to the upright position caused a similar reduction in LV EDCA, suggesting similar LV distensibility between patients (–22% [–46 to –4]) and controls (–20% [–46 to –3], P = 0.3). However, during exercise, both systolic SR and EDSR reserve were significantly impaired in patients (∆SR: 93% [14–308], ∆EDSR: –4.5% [–88 to 121]) compared to controls (∆SR: 128% [54–230], P = 0.046; ∆EDSR: 74% [22–234], P = 0.02).

Conclusions

Our findings suggest that impaired LV contractility and functional reserve play a role in the reduced exercise capacity in anthracycline cardiotoxicity rather than LV distensibility.

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MicroRNA-761 is upregulated in hepatocellular carcinoma and regulates tumorigenesis by targeting Mitofusin-2

Abstract

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related deaths worldwide. The fate of a cell is determined by the balance between the processes of fission and fusion that constantly occur in the mitochondria of cells. We previously showed that overexpression of Mitofusin-2 can induce apoptosis in HCC cells by triggering an influx of Ca²⁺ into the mitochondria from the ER. The function of Mitofusin-2 has been studied extensively, but the mechanism underlying the post-transcriptional regulation of Mitofusin-2 has not been elucidated. In this study, we aimed to identify the mechanism of Mitofusin-2 regulation in HCC. We demonstrated that Mitofusin-2 is a direct target of miR-761, which was found to be upregulated in HCC tissues. Further, a miR-761 inhibitor impairs mitochondrial function by upregulating Mitofusin-2 and effectively repressed tumor growth and metastasis both in vivo and vitro. Our findings provide new insights into the mechanism underlying Mitofusin-2 regulation and the potential role of miR-761 in HCC, making it a potential candidate for use in HCC therapy in the future.

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Racial difference seen in outcomes for older patients with prostate cancer

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NCI seeks to speed drug development for pediatric cancers: New initiative aims to help prioritize agents with most potential

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New risk score for colorectal cancer, advanced polyps could guide screening tests

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Increasing cancer rates threaten economic stability in low- and middle-income countries

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Pulmonary dose-volume predictors of radiation pneumonitis following stereotactic body radiation therapy

Publication date: Available online 4 February 2016
Source:Practical Radiation Oncology
Author(s): Eileen M. Harder, Henry S. Park, Zhe (Jay) Chen, Roy H. Decker
PurposeRadiation pneumonitis (RP) may be severe after stereotactic body radiation therapy (SBRT). Our purpose was to identify pulmonary and cardiac dosimetric parameters that predicted for post-SBRT Grade ≥2 RP.Methods and Materials335 patients with ≥3 months follow-up were included. Normal pulmonary volume was total lungs minus gross tumor volume. Pulmonary Dmax (maximum dose), MLD (mean lung dose), and Vx (% lung receiving ≥x Gy) for 5-50Gy in 5Gy increments were collected. Cardiac Dmax, mean dose, V0.1, V0.25-V1, and V2.5-V12.5 were recorded. Multivariable logistic regression (LR) with manual backward stepwise elimination was used to identify the best dosimetric predictors of toxicity. Optimal dose-volume cutoffs were isolated with recursive partitioning analysis (RPA).ResultsThe Grade ≥2 RP rate was 18.8%. Pulmonary V5-V50, MLD, and cardiac V0.1-V2.5 were significantly associated with toxicity on univariate analysis. On multivariable LR, V10 was the strongest dosimetric predictor of Grade ≥2 RP (odds ratio 1.052, 95% confidence interval=1.014-1.092, p=0.007). RPA identified a 21.6% risk of Grade ≥2 RP with V10 ≥6.14% (vs. 3.8% with <6.14). MLD was the most significant predictor of Grade ≥3 RP (OR 1.002, 95% CI 1.000-1.003, p=0.031). RPA identified a 25.0% risk of Grade ≥3 RP with MLD ≥7.84Gy (vs. 8.0% when <7.84Gy).ConclusionsWith a Grade ≥2 RP rate of 18.8%, lung V10 was the best predictor of Grade ≥2 toxicity. MLD was the best predictor of Grade ≥3 RP.



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A Pan-Canadian Survey of Peer Review Practices in Radiation Oncology

Publication date: Available online 4 February 2016
Source:Practical Radiation Oncology
Author(s): Amanda Caissie, Julie Rouette, Paul Jugpal, Carol-Anne Davis, Helmut Hollenhorst, Jennifer O'Donnell, Gunita Mitera, Michael D. Brundage
PurposePeer review (PR) of treatment plans has been recognized internationally as a key component of quality care in radiation oncology programs (ROPs). We conducted a survey of Canadian ROPs to describe current PR practices and identify barriers/facilitators to PR optimization.Methods and MaterialsA 42-item e-survey was sent to all Canadian ROPs (n=44). Survey development was guided by expert consensus, literature review, and existing guidelines. One multi-disciplinary response per ROP was requested.ResultsResponse rate was 100.0% (44/44). All ROPs (100.0%) reported conducting some PR and rated its importance as 7/10 or higher (10=extremely important). Half of ROPs (52.3%) peer-reviewed >80% of curative treatment plans. Most ROPs reported performing PR "always/almost always" pre-treatment (38.6%) or before 25% of radiotherapy delivery (52.3%). ROPs reported recommending major plans changes in <5% of plans (88.6%) and documenting findings in the medical record (58.1%). Barriers to PR were radiation oncologist availability (34.1%) and time constraints (27.3%). Facilitators included development of PR standards (97.7%) and education/support (90.9%).ConclusionsROPs perceive PR as highly important, but substantial variation in the extent, timing and documentation of PR exists. The understanding of current PR activities, barriers, and facilitators will inform the development of initiatives to optimize PR in radiation oncology.



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"Asian Pac J Cancer Prev"[jour]; +71 new citations

71 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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CTV: The Third Front

Publication date: Available online 4 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Leonard Kim, Cuihuan Wang, Atif Khan, Mark Pierce




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First clinical investigation of CBCT and deformable registration for adaptive proton therapy of lung cancer

Publication date: Available online 4 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Catarina Veiga, Guillaume Janssens, Ching-Ling Teng, Thomas Baudier, Lucian Hotoiu, Jamie R. McClelland, Gary Royle, Liyong Lin, Lingshu Yin, James Metz, Timothy D. Solberg, Zelig Tochner, Charles B. Simone, James McDonough, Boon-Keng Kevin Teo
PurposeAn adaptive proton therapy workflow using cone-beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT). This may be followed by more accurate offline dose recalculation on the vCT which may trigger a rescan CT (rCT) for replanning.Methods and MaterialsThe workflow was tested retrospectively on twenty consecutive lung cancer patients. A diffeomorphic Morphons algorithm was used to generate the lung vCT, by deforming the average planning CT (pCT) onto the CBCT. An additional correction step was applied to account for anatomical modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated based on water equivalent thickness (WET) and dose statistics, and compared to those obtained on a rCT. The fast dose approximation consisted of warping the initial planned dose onto the vCT based on changes in WET. Potential under/over-ranges were assessed as variation in WET at the target's distal surface.ResultsThe range-corrected dose from the vCT reproduced similar clinical indicators as the rCT. The workflow performed well under different clinical scenarios: atelectasis, lung reinflation and different types of tumor response. Between vCT and rCT, we found a difference in the measured 95% percentile of the over-ranges distribution of 3.4±2.7mm. The limitations of the technique consisted of inherent uncertainties of deformable registration and drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomical or density changes in tumors with complex topology.ConclusionsA proton therapy workflow based on CBCT provided similar clinical indicators as rCT on lung patients with considerable anatomical changes.

Teaser

Accurate patient positioning and routine computed tomography (CT) scans are critical components of proton therapy. Cone-beam CT (CBCT) has recently become available as an alternative to verification CT. This study describes the first clinical investigation of CBCT and deformable registration in adaptive lung proton therapy.


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Comparison of Mammographic Changes Across 3 Different Fractionation Schedules for Early Stage Breast Cancer

Publication date: Available online 4 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sibo Tian, Lina F. Paster, Sinae Kim, Laurie Kirstein, Bruce G. Haffty, Adam Ferro, Judith Amorosa, Sharad Goyal
PurposeAs utilization of hypofractionated breast radiotherapy (RT) grows, so does the need for long-term data on post-RT mammographic changes. The purpose of this study was to longitudinally compare the incidence of common mammographic sequelae seen after breast conserving surgery (BCS) and RT in patients treated with accelerated partial breast irradiation (APBI), hypofractionated whole breast irradiation (HWBI) and conventionally fractionated whole breast irradiation (WBI).Materials and MethodsPatients treated with either APBI or HWBI after BCT and had at least 3 mammograms of the treated breast were identified. They were matched 1:1 on age ±5 years to patients treated with WBI. Mammograms were evaluated for common post-RT breast findings by a mammographer blinded to treatment. Outcomes were analyzed using a cumulative logistic regression model; a p < 0.05 considered statistically significant.ResultsOf 89 patients treated with RT between 2006-2011, 29 received APBI, 30 received HWBI and 30 WBI; their median age was 60 years (range 33-83). A total of 605 mammograms were evaluated with a median follow-up of 48 months. Treatment technique did not affect the severity of architectural distortion when groups were evaluated longitudinally. The likelihood of finding skin thickening decreased with follow-up (OR = 0.6; p < 0.001) adjusted for fractionation schemes. No differences were seen with respect to changes in skin thickening, fluid collections, or calcifications when comparing between treatment groups adjusted for follow-up time. Clinical characteristics, including age, race, T stage and chemotherapy use were not linked to the likelihood of finding several mammographic phenomena over time.ConclusionsAlthough specific post-treatment imaging findings evolved over time, RT fractionation did not alter the relative incidence or severity of architectural distortion, skin thickening, fluid collections or calcifications. These findings are useful to both radiologists and radiation oncologists when counseling patients regarding follow-up studies after RT.

Teaser

The purpose of this study was to longitudinally compare the incidence of common mammographic sequelae seen after breast conserving surgery (BCS) in patients treated with accelerated partial breast irradiation (APBI), hypofractionated whole breast irradiation (HWBI) and conventionally fractionated whole breast irradiation (WBI). We found that RT fractionation and technique did not alter the relative incidence or severity of common mammographic sequelae.


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A Comparative Evaluation of Normal Tissue Doses for Patients Receiving Radiation Therapy for Hodgkin Lymphoma on the Childhood Cancer Survivor Study and Recent Children’s Oncology Group Trials

Publication date: Available online 4 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Rachel Zhou, Angela Ng, Louis S. Constine, Marilyn Stovall, Gregory T. Armstrong, Joseph P. Neglia, Debra L. Friedman, Kara Kelly, Thomas J. FitzGerald, David C. Hodgson
PurposeSurvivors of pediatric Hodgkin Lymphoma (HL) are recognized to be at increased risk for delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to out-dated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with patients treated on recent Children's Oncology Group (COG) trials (enrolled 2002-2012).MethodsRT treatment planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to CT planning datasets to reconstruct normal tissue dosimetry. For comparison, normal tissue dosimetry was obtained for all 191 patients with full CT-based volumetric RT planning on COG protocols AHOD0031 and AHOD0831.ResultsFor early stage patients, mean female breast dose in the COG patients was on average 83.5% lower than CCSS patients, with an absolute reduction of 15.5Gy; for advanced stage patients mean breast dose decreased on average by 70% (11.6Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9Gy (68.6%), and 17.6Gy (56.8%) for early and advanced stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients on COG trials than CCSS participants. Reduction in prescribed dose was a major contributor to this dose reduction.ConclusionsThese are the first data quantifying the significant reduction in normal tissue dose based on actual rather than hypothetical treatment plans for children with HL. The findings provide some useful information when counselling families regarding the risks of contemporary RT.

Teaser

The Childhood Cancer Survivors Study (CCSS) is a major source of information regarding late effects among pediatric Hodgkin lymphoma (HL) survivors. In this comparison of children with HL who received radiation therapy, patients treated from 2002-2012 on Children's Oncology Group trials had normal tissue doses typically 55%-80% lower than those registered 1970-1986 on the CCSS. This finding suggests contemporary treatment should significantly reduce RT-related late toxicity compared to treatments given to patients registered in CCSS.


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Feasibility and initial dosimetric findings for a randomized trial using dose painted Multi-parametric-MRI Defined targets in Prostate Cancer

Publication date: Available online 4 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Elizabeth L. Bossart, Radka Stoyanova, Kiri Sandler, Matthew Studenski, Amber Orman, Matthew Abramowitz, Alan Pollack
Purpose/ObjectiveTo compare dosimetric characteristics to multi-parametric MRI identified imaging tumor volume (GTV), prostate CTV and PTV, and organs at risk (OARs) for two treatment techniques representing two arms of an institutional phase III randomized trial of Hypofractionated External Beam Image-Guided Highly Targeted (HEIGHT) radiotherapy (RT).Methods and MaterialsGroup I (n=20) patients were treated prior to the trial inception with the standard dose prescription. Each patient had an additional treatment plan generated per the experimental arm. A total of 40 treatment plans were compared (20 plans for each technique). Group II (n=15) consists of patients currently accrued to the HEIGHT trial. Plans were created as per treatment arm with additional plans for 5 of the Group II experimental arm with a 3mm expansion in the imaging GTV (GTV).ResultsFor all plans in both patient groups, PTV coverage ranged from 95% to 100%; GTV coverage of 89.3Gy for the experimental treatment plans ranged from 95.2% to 99.8%. For both group I and II, the percent volumes of rectum/anus and bladder receiving 40Gy, 65Gy and 80Gy were smaller in the experimental plans than the standard plans. The percent volume at 1Gy per fraction and 1.625Gy per fraction were compared between the standard and the experimental arm, and these were found to be equivalent.ConclusionsThe dose per fraction to the OARs can be made equal even when giving a large simultaneous integrated boost to the GTV. The data suggests that a GTV margin may be added without significant dose effects on the OARs.

Teaser

Dosimetric characteristics for multi-parametric (MP-) MRI identified imaging tumor volume (ImTV), prostate CTV and PTV, and organs at risk (OARs) for two treatment techniques representing two arms of an institutional phase III randomized trial of Hypofractionated External Beam Image-Guided Highly Targeted (HEIGHT) radiotherapy (RT) are given. The MP-MRI protocols are detailed.


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Cone-Beam Computed Tomography (CB-CT) internal motion tracking should be used to validate 4-Dimensional CT for abdominal radiotherapy patients

Publication date: Available online 2 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Leith Rankine, Hanlin Wan, Parag Parikh, Nichole Maughan, Per Poulsen, Todd DeWees, Eric Klein, Lakshmi Santanam
Purpose/Objective(s)Although 4-Dimensional Computed Tomography (4DCT) is often used for motion management in radiation therapy, research shows it does not adequately predict on-table tumor motion for abdominal radiotherapy. In this study, we demonstrate that tumor motion should be measured using fiducial tracking during pre-treatment Cone-Beam CT (CBCT) and used to validate the 4DCT margins before treatment.Materials/MethodsFor 31 patients with abdominal tumors and implanted fiducial markers, tumor motion was measured daily with CBCT and fluoroscopy for 202 treatment fractions. Fiducial tracking and maximum-likelihood algorithms extracted three-dimensional fiducial trajectories from CBCT projections. The daily internal margin (IM), i.e, range of fiducial motion, was calculated for CBCT and fluoroscopy as the 5^th-95^th percentiles of displacement in each cardinal direction. The planning IM from simulation 4DCT (IM4DCT) was considered adequate when within ±1.2mm (AP, LR) and ±3mm (SI) of the daily measured IM. We validated CBCT fiducial-tracking as an accurate predictive measure of intrafraction motion by comparing the daily measured IMCBCT to the daily IM measured by pre-treatment fluoroscopy (IMpre-fluoro); these were compared to pre- and post-treatment fluoroscopy (IMfluoro) to identify those patients who could benefit from imaging during treatment.Results4DCT could not accurately predict intrafractional tumor motion for ≥80% of fractions in 94% (IMCBCT), 97% (IMpre-fluoro), and 100% (IMfluoro) of patients. IMCBCT was significantly closer to IMpre-fluoro than IM4DCT (p<0.01). For patients with median treatment time t<7.5min, IMCBCT agreed with or exceeded IMfluoro for 97.3% of fractions (superior-inferior), compared to 82.3% for the t>7.5min group, demonstrating the need for patient-specific intra-treatment imaging.ConclusionTumor motion determined from 4DCT-simulation does not accurately predict the daily motion observed on CBCT or fluoroscopy. CBCT could replace fluoroscopy for pre-treatment verification of simulation IM4DCT, reducing patient setup time and imaging dose. Patients with treatment time t>7.5min could benefit from the addition of intra-treatment imaging.

Teaser

The intrafractional tumor motion of 31 patients with abdominal tumors was measured over 202 treatment fractions by fiducial marker tracking in cone-beam computed tomography (CBCT) projections. Tumor motion from CBCT was compared to pre- and post- treatment kV fluoroscopy and to the corresponding 4-dimensional computed tomography (4DCT) simulation. In >90% of patients, tumor motion measured from the planning 4DCT did not accurately predict intrafractional tumor motion observed during CBCT and fluoroscopy in ≥80% of fractions. Tumor motion observed during CBCT more accurately reflects the motion observed on fluoroscopy, indicating that CBCT fiducial tracking could replace fluoroscopy for on-treatment verification of tumor motion.


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Seed placement in permanent breast seed implant brachytherapy: Are concerns over accuracy valid?

Publication date: Available online 2 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daniel Morton, Michelle Hilts, Deidre Batchelar, Juanita Crook
PurposeTo evaluate seed placement accuracy in permanent breast seed implant brachytherapy (PBSI) in order to identify any systematic errors and evaluate their effect on dosimetry.Materials and MethodTreatment plans and post-implant CT scans for 20 PBSI patients were spatially registered and used to evaluate differences between planned and implanted seed positions, termed seed displacements. For each patient, the mean total and directional seed displacements were determined in both standard room coordinates and in needle coordinates relative to needle insertion angle. Seeds were labelled according to their proximity to the anatomy within the breast in order to evaluate the influence of anatomical regions on seed placement. Dosimetry within an ETV (seroma+5mm), skin, breast, and ribs was evaluated to determine the impact of seed placement on the treatment.ResultsThe overall mean difference between implanted and planned positions was 9 ± 5 mm for the aggregate seed population. No significant systematic directional displacements were observed for this whole population. However, for individual patients, systematic displacements were observed, implying intra-patient offsets occur during the procedure. Mean displacements for seeds in the different anatomical areas were not found to be significantly different from the mean for the entire seed population. However, small directional trends were observed within the anatomy, potentially indicating some bias in the delivery. Despite observed differences between the planned and implanted seed positions, the median (range) V90 for the 20 patients was 97% (66–100%), and acceptable dosimetry was achieved for critical structures.ConclusionsNo significant trends or systematic errors were observed in the placement of seeds in PBSI, including seeds implanted directly into the seroma. Recorded seed displacements may be related to intra-patient setup adjustments. Despite observed seed displacements, acceptable post-implant dosimetry was achieved.

Teaser

Permanent breast seed implant brachytherapy is an attractive treatment option for early stage breast cancer patients. In order to improve the accuracy and confidence in the procedure, uncertainties in the delivery must be identified. This study evaluates the accuracy of seed placement within the breast in order to identify any systematic errors in the delivery and evaluate the impact of seed placement on the treatment.


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Is superior tibiofibular joint resection necessary in extraarticular knee resection for sarcomas? A systematic review

Abstract

Background

Sarcomas infiltrating the knee joint require extraarticular resection to achieve wide margins. Opinions differ as to whether the superior tibiofibular joint (STFJ) is part of the knee joint and should be removed in the course of extraarticular resection. Thus, we investigated the frequency of communication between the tibiofemoral joint (TFJ) and the STFJ, and the reported local recurrence rates (LRR) following extraarticular knee resection.

Methods

A systematic literature review on STFJ and TFJ communication and local recurrence rates following extraarticular knee resections was undertaken.

Results

Cadaver studies detected communication between the TFJ and STFJ in 10–64 % of the cases. Direct arthrography with physical loading verified a 100 % communication rate. Regarding the extent of extraarticular knee resection, two institutions where the STFJ was resected had a LRR of 4–8 %, while studies from another three where the STFJ was not routinely resected reported a LRR of 0–21 %.

Conclusions

Since the literature reports about a 100 % communication rate between the TFJ and the STFJ, resection of the STFJ in patients with sarcomas involving the knee joint would seem to be indicated, although it is not clear whether resection of the STFJ reduces local recurrence rates.

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Epithelioid angiosarcoma arising in schwannoma of the kidney: report of the first case and review of the literature

Abstract

Background

Schwannoma and angiosarcoma are infrequent pathologies that have been rarely reported in the kidney. Angiosarcoma is an uncommon malignant tumor presenting a recognizable vascular differentiation. It can develop in any site but the most common locations include the skin, soft tissues, breast, bone, liver, and spleen while renal localization has been very rarely reported in the literature. Schwannoma is a benign peripheral nerve sheath tumor composed of cells with the immunophenotype and ultrastructural features of differentiated Schwann cells. It has a wide anatomical distribution but the most frequent locations include subcutaneous tissues of the extremities and the head and neck region and the retroperitoneal and mediastinal soft tissues. The occurrence of an angiosarcoma in a pre-existing schwannoma is an extremely rare event with <20 cases reported in worldwide literature. In the present study, a renal case of angiosarcoma arising in schwannoma is presented with a detailed review of the pertinent literature.

Case Presentation

A 56-year-old man was admitted with a few days history of lower back pain and hematuria. Abdominal ultrasound showed a mass inside the left renal medulla. Subsequent imaging investigations with computed tomography and magnetic resonance confirmed the presence of the lesion and showed a pulmonary metastasis.

Conclusions

The final histopathological examination led to the diagnosis of epithelioid angiosarcoma arising in a schwannoma. The patient came to death a few months later due to a massive hemothorax. To the best of our knowledge, the present is the first case of an angiosarcoma arising in a schwannoma of the kidney.

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The Role of Risk-Reducing Surgery in Hereditary Breast and Ovarian Cancer

Hereditary breast and ovarian cancer is a syndrome that involves an increased predisposition to breast cancer, ovarian cancer, or both and an autosomal dominant pattern of transmission. The numbers of breast-cancer diagnoses, the ages of patients at diagnosis, and the occurrence of ovarian cancer…

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Does microscopically involved margin increase disease recurrence after curative surgery in papillary thyroid carcinoma?

Background

The prognostic significance of microscopically involved margin in papillary thyroid carcinoma (PTC) following curative surgery remains unclear. We aimed to evaluate the impact of an involved margin and its location (anterior vs. posterior) on disease recurrence.

Methods

Of the 638 eligible patients, 538 (85.9%) did not have an involved margin (group I) while 100 (14.1%) did (group II). The latter group was further classified according to its location relative to the surface of the thyroid gland (anterior or posterior). A multivariate analysis was conducted to identify independent factors for recurrence risk.

Results

After a mean of 130.1 ± 93.5 months, 22 patients had disease recurrence. The 10-year disease-free survival (DFS) was significantly worse in group II (95.0% vs. 97.0%, P = 0.011). After adjusting other significant factors, involved margin was not an independent risk factor for disease recurrence (P = 0.358). Compared to a negative margin, an anterior involved margin did not pose increased recurrence risk (HR = 1.21, 95%CI = 0.93–500.00, P = 0.368), whereas a posterior involved margin had almost 23 times higher recurrence risk (HR = 22.95; 95%CI = 4.33–121.70, P < 0.001).

Conclusions

Overall, a microscopically involved margin was not an independent factor for DFS. However, although an anterior involved margin itself did not increase disease recurrence, a posterior involved margin did. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Identification of breast cancer margins using intraoperative near-infrared imaging

Background and Objectives

Current methods of intraoperative breast cancer margin assessment are labor intensive, not fully reliable, and time consuming; therefore novel strategies are necessary. We hypothesized that near infrared (NIR) intraoperative molecular imaging using systemic indocyanine green (ICG) would be helpful in discerning tumor margins.

Methods

A mammary cancer cell line, 4T1, was used to establish tumors in mouse flanks (n = 60). Tumors were excised 24 hr after intravenous ICG. Assessment of residual tumor in the wound bed was performed using a combination of NIR imaging and traditional method (by visual inspection and palpation) versus traditional method alone. Next we performed a clinical trial to evaluate the role of NIR imaging after systemic ICG for the margin assessment of 12 patients undergoing breast-conserving surgery.

Results

Traditional margin assessment identified 30% of positive margins while NIR imaging identified 90% of positive margins. In our clinical trial, all tumors were detected by NIR imaging and there was fluorescent evidence of residual tumor in the tumor bed in 6 of the 12 patients. None of these patients had positive margins on pathology.

Conclusions

Systemic ICG reliably accumulates in breast cancers in murine models as well as human breast cancer. While NIR imaging is helpful for detection of retained tumor margins in our animal model, intraoperative imaging for precise margin detection will need further refinement before clinical value can be obtained. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Colorectal cancer surgery for obese patients: Financial and clinical outcomes of a Dutch population-based registry

Background and Objectives

The objective of this study was to explore the association among adverse events, body mass index (BMI), and hospital costs after colorectal cancer surgery in a country with an intermediate BMI distribution.

Methods

All colorectal cancer procedures in 29 Dutch hospitals listed in a 2010–2012 population-based database and with a BMI > 18.5 were included (n = 8687). Hospital costs were measured uniformly and based on time-driven activity-based costing. The BMI classification of the World Health Organization was used.

Results

Patients in obesity classes 1 (23.6% [after risk-adjustment OR 1.245, CI 1.064–1.479, P = 0.007]) and ≥2 (28.1% [after risk-adjustment OR 1.816, CI 1.382–2.388, P < 0.001]) were associated with more severe complications and higher hospital costs (€14,294, +9.6%, after risk-adjustment +7.9%, P < 0.001; and €15,913 +22.0%, after risk-adjustment +21.2%, P < 0.001, respectively) than normal weight patients (20.8% and €13,040, respectively). Pre-obese patients had significantly lower mortality rates (2.7%, after risk-adjustment, OR 0.756, CI 0.577–0.991, P = 0.042) than normal-weight patients (3.9%).

Conclusions

Obese surgical colorectal cancer patients in a country with an intermediate BMI distribution are associated with a significant increase in hospital costs because these patients suffer from more severe complications. This is the first study to provide evidence for the "obesity-paradox" for mortality in colorectal cancer surgery. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Is Hormone Replacement Therapy Safe in Women With a BRCA Mutation?: A Systematic Review of the Contemporary Literature.

Objectives: Women with a BRCA1 or BRCA2 mutation are recommended to undergo prophylactic (or risk reducing) bilateral salpingo-oophorectomy (BSO) before age 40, resulting in surgical menopause. Given the concerns of estrogen deprivation on overall health, hormone therapy (HT) is often discussed, yet safety concerns persist. Materials and Methods: We performed a systematic literature review of the safety of HT in women with a BRCA mutation undergoing prophylactic BSO. Results: Although there remains a paucity of data on this topic, as evidenced by this systematic review of the contemporary literature, these patients do benefit from treatment, especially as it relates to menopausal symptoms without an apparently increased risk of breast cancer. Conclusions: Decisions regarding the use of HT in women who undergo BSO after detection of a BRCA mutation must be individualized based on careful consideration of the risks and benefits. However, the risks of a subsequent cancer diagnosis appear small, particularly in regards to the benefits of treatment afforded by HT. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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The Cancer Experience: The Doctor, The Patient, The Journey. Roy B. Sessions. Rowman & Littlefield Publishers, Inc., Lanham, Maryland, 2012. No. of pages: 205. Price: $59.95 (US) ISBN: 978-1442216211.

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Issue Information

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Correlates of quality of life in overweight or obese breast cancer survivors at enrollment into a weight loss trial

Abstract

Objective

The purpose of this analysis was to examine the correlates of the physical and psychosocial domains of quality of life (QOL) in a cohort of breast cancer survivors participating in a weight loss intervention trial.

Methods

Correlates of QOL and psychosocial functioning were examined in 692 overweight or obese breast cancer survivors at entry into a weight loss trial. QOL was explored with three measures: Short-form 36 (SF-36), Impact of Cancer scale (IOC), and the Breast Cancer Prevention Trial (BCPT) symptom scales. Available data included information on weight and physical activity, as well as demographic and medical characteristics. Multivariate analyses were used to identify associations adjusted for other characteristics.

Results

In multivariate analysis, younger age was associated with higher negative impact scores (p < 0.0001). Hispanic, African-American, and Asian women had higher positive IOC impact scores compared with White non-Hispanic women (p < 0.01). Increased number of comorbidities was associated with lower physical and mental QOL scores (p < 0.01). Body mass index was not independently associated with QOL measures. Physical activity was directly associated with physical and mental QOL and IOC positive impact, and inversely related to IOC negative impact and Breast Cancer Prevention Trial symptom scales.

Conclusions

Quality-of-life measures in breast cancer survivors are differentially associated with demographic and other characteristics. When adjusted for these characteristics, degree of adiposity among overweight or obese women does not appear to be independently associated with QOL. Among overweight or obese breast cancer survivors, higher level of physical activity is associated with higher QOL across various scales and dimensions. Copyright © 2015 John Wiley & Sons, Ltd.

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Assessing the utility of a telephonically delivered psychoeducational intervention to improve health-related quality of life in African American breast cancer survivors: a pilot trial

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Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas

Intraocular medulloepithelioma (IO-MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. Little is known about the cytogenetics, molecular biology, and pathogenesis of this tumor. In the present study we investigated the mutational landscape of 19 IO-MEPL using targeted next-generation sequencing. Routinely prepared paraffin-embedded samples were assessed with high-coverage genome sequencing on the Illumina NextSeq 500 platform using a customized gene panel set covering the coding region of 130 genes. This revealed several notable genomic alterations, including mutations of DICER1 (6 tumors) and KMT2D (also known as MLL2; 5 tumors)—which are frequently recurrent and mutually exclusive molecular events for IO-MEPL. Non-recurrent mutations in the cancer-associated genes BRCA2, BRCA1, NOTCH2, CDH1, and GSE1 were also identified. IO-MEPL samples harboring a DICER1 mutation disclosed few chromosomal alterations and formed a separate DNA methylation cluster, indicating potential differences in genetic and epigenetic events arising perhaps from the presence of this aberration in the tumor genome. The high proportion of recurrent somatic DICER1 and KMT2D mutations in this series of sporadic IO-MEPL points to their likely important roles in the molecular pathogenesis of these rare embryonal tumors, and perhaps suggests the existence of distinct molecular variants of IO-MEPL. Although the precise role of these recurrent mutations in the development of IO-MEPL, and their relationship to pro-oncogenic molecular mechanisms, have yet to be determined, unraveling their roles could eventually be exploited for nonsurgical therapies of these neoplasms. © 2016 Wiley Periodicals, Inc.

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