Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis

Abstract

Purpose

Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 5 years following resection plus adjuvant gemcitabine (Gem) from outgrowth of occult metastases. We hypothesized that inhibition of the KRAS pathway with the MEK inhibitor trametinib would inhibit the outgrowth of occult liver metastases in a preclinical model.

Methods

Liver metastases harvested from two patients with PDAC (Tumors 608, 366) were implanted orthotopically in mice. Tumor cell lines were derived and transduced with lentiviruses encoding luciferase and injected into spleens of mice generating microscopic liver metastases. Growth kinetics of liver metastases were measured with bioluminescent imaging and time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) were determined.

Results

Trametinib (0.3 mg/kg BID) significantly prolonged OS versus control (Tumor 608: 114 vs. 43 days, p < 0.001; Tumor 366: not reached vs. 167 days, p = 0.0488). In vivo target validation demonstrated trametinib significantly reduced phosphorylated-ERK and expression of the ERK-responsive gene DUSP6. In a randomized, preclinical trial, mice were randomized to: (1) control, (2) adjuvant Gem (100 mg/kg IP, Q3 days) × 7 days followed by surveillance, or (3) adjuvant Gem followed by trametinib. Sequential Gem-trametinib significantly decreased metastatic cell outgrowth and increased TTP and PFS.

Conclusions

Treatment of mice bearing micrometastases with trametinib significantly delayed tumor outgrowth by effectively inhibiting KRAS-MEK-ERK signaling. In a randomized, preclinical, murine trial adjuvant sequential Gem followed by trametinib inhibited occult metastatic cell outgrowth in the liver and increased PFS versus adjuvant Gem alone. An adjuvant trial of sequential Gem-trametinib is being planned in patients with resected PDAC.

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Rechallenge with 5-fluorouracil in a patient who developed encephalopathy caused by 5-fluorouracil for colon cancer

Abstract

We report a case involving a patient with colon cancer who underwent 5-fluorouracil (5-FU) rechallenge and maintained an oncological effect for a long period after encephalopathy caused by 5-FU. Our patient was a 61-year-old man who was diagnosed with adenocarcinoma of the ascending colon with direct liver invasion. He underwent right hemicolectomy with partial liver resection followed by adjuvant chemotherapy with modified FOLFOX6 (mFOLFOX6). Ten months after completion of mFOLFOX6, his carcinoembryonic antigen concentration increased, and ascites was revealed by computed tomography 2 months later. We started FOLFIRI, and he was taken to our hospital by ambulance because of loss of consciousness 10 days after the start of the third cycle of FOLFIRI. Laboratory investigations showed hyperammonemia and elevations of his serum creatinine and blood urea nitrogen concentrations. Brain computed tomography demonstrated no abnormalities. Transfusion of 1500 ml of crystalloid fluid resulted in gradual recovery over the next 12 h. His ammonia concentration decreased to a normal level. Twelve days after onset of the encephalopathy, we restarted FOLFIRI, but the dose of continuous 5-FU was decreased by 20 %. The patient's carcinoembryonic antigen concentration considerably decreased from 376.5 to 19.9 ng/ml, and his ascites disappeared. Nineteen months after the resumption of FOLFIRI, he underwent 34 courses of FOLFIRI and maintained stable disease. The encephalopathy did not recur.

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Frequencies of EGFR single nucleotide polymorphisms in non-small cell lung cancer patients and healthy individuals in the Republic of Serbia: a preliminary study

Abstract

The purpose of this study was to determine the frequencies of EGFR −216G>T, −191C>A, and 181946C>T in Serbian non-small cell lung cancer (NSCLC) patients, as well as to compare it with healthy individuals, in order to assess their potential importance for lung cancer in Serbia. The study involved 56 NSCLC patients and 53 unrelated healthy volunteers, and genotyping was performed on DNA samples obtained from formalin-fixed paraffin-embedded lung tumor tissue and blood, respectively. This was the first time to show genotype frequencies of those single nucleotide polymorphisms for this study group from the territory of the Republic of Serbia. There was very strong evidence of association between age and death due to lung cancer (Pearson chi-square = 43.439, df = 2, p < 0,001), as well as between ever smoking and death due to lung cancer (Pearson chi-square = 31.727, df = 1, p < 0.001). When dominant genetic model (GG vs. GT+TT) was used for −216G>T, we have found significant association (p = 0.012) between −216GG genotype and NSCLC patients within smokers' subgroup. So, carriers of −216GG genotype had higher risk (OR = 4.33, 95 % CI = 1.324–14.179) than noncarriers (GT and TT) for developing non-small cell lung cancer in our patients.

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Low expression of PIDD is associated with cell proliferation and apoptosis in hepatocellular carcinoma

Abstract

p53-induced death domain protein (PIDD) facilitates p53-dependent apoptosis through the interaction with components of the death receptor signaling pathways. However, the role of PIDD in hepatocellular carcinoma (HCC) development remains unknown. In this study, we investigated the expression pattern of PIDD in clinical HCC samples and adjacent non-cancerous tissues using immunohistochemistrical and Western blot analyses. The results showed that PIDD was lowly expressed in HCC tissues and HCC cell lines, compared with the adjacent non-tumorous tissues and LO2 normal hepatocytes. In addition, clinicopathological analysis showed that the expression of PIDD was closely related with multiple clinicopathological variables, such as American Joint Committee on Cancer (AJCC) stage, AFP, and poor prognosis of HCC. Univariate and multivariate survival analyses demonstrated that PIDD could serve as an independent prognostic factor to predict the survival of HCC patients. We used serum starvation-refeeding experiment to explore the involvement of PIDD in HCC cell cycle regulation. We found that PIDD was accumulated in growth-arrested HCC cells and was progressively decreased when cells entered into S phase. Moreover, flow cytometry and cell counting kit-8 (CCK-8) assays indicated that depleting the expression of PIDD could facilitate cell cycle progression and accelerate cell proliferation in HepG2 cells, while overexpression of PIDD could result in cell cycle arrest at G1 phase and hinder the cell proliferation in Hep3B cells. Finally, flow cytometry revealed that overexpression of PIDD slightly increased the apoptosis of HCC cells. Taken together, we concluded that PIDD may be a valuable prognostic marker and promising therapeutic target of HCC.

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FOXR2 contributes to cell proliferation and malignancy in human hepatocellular carcinoma

Abstract

Forkhead box R2 (FOXR2), a member of forkhead box (FOX) family, has been identified as an oncogene in medulloblastoma and breast cancer recently. However, the expression and function of FOXR2 in hepatocellular carcinoma cell (HCC) are still unclear. Here, we report that FOXR2 is frequently upregulated in 25/42 (59.5 %) of HCC specimens compared with neighboring non-cancerous tissues in messenger RNA (mRNA) level and further confirmed by immunohistochemistry analysis in protein level. Cellular function analyses revealed that FOXR2 promoted cell growth and colony formation, whereas knockdown of FOXR2 by RNA inference inhibited cell growth and decreased the growth ability of HCC cells in soft agar. Moreover, we also found FOXR2 overexpression facilitated the development of tumor xenografts in nude mice model. In addition, we validated β-catenin, Skp2, c-Myc, and Gli-1 as the potential downstream effectors of FOXR2 in the regulation of cell proliferation and malignancy by quantitative real-time PCR analysis. Collectively, our data suggest that FOXR2 promotes cell proliferation and malignancy in HCC and could be a novel promising therapeutic target for this disease.

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Isoform 1 of TPD52 (PC-1) promotes neuroendocrine transdifferentiation in prostate cancer cells

Abstract

The tumour protein D52 isoform 1 (PC-1), a member of the tumour protein D52 (TPD52) protein family, is androgen-regulated and prostate-specific expressed. Previous studies confirmed that PC-1 contributes to malignant progression in prostate cancer with an important role in castration-resistant stage. In the present work, we identified its impact in mechanisms leading to neuroendocrine (NE) transdifferentiation. We established for long-term PC-1 overexpression an inducible expression system derived from the prostate carcinoma cell line LNCaP. We observed that PC-1 overexpression itself initiates characteristics of neuroendocrine cells, but the effect was much more pronounced in the presence of the cytokine interleukin-6 (IL-6). Moreover, to our knowledge, this is the first report that treatment with IL-6 leads to a significant upregulation of PC-1 in LNCaP cells. Other TPD52 isoforms were not affected. Proceeding from this result, we conclude that PC-1 overexpression enhances the IL-6-mediated differentiation of LNCaP cells into a NE-like phenotype, noticeable by morphological changes and increased expression of typical NE markers, like chromogranin A, synaptophysin or beta-3 tubulin. Immunofluorescent staining of IL-6-treated PC-1-overexpressing LNCaP cells indicates a considerable PC-1 accumulation at the end of the long-branched neuron-like cell processes, which are typically formed by NE cells. Additionally, the experimentally initiated NE transdifferentiation correlates with the androgen receptor status, which was upregulated additively. In summary, our data provide evidence for an involvement of PC-1 in NE transdifferentiation, frequently associated with castration resistance, which is a major therapeutic challenge in the treatment of advanced prostate cancer.

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Roles of CDKN1A gene polymorphisms (rs1801270 and rs1059234) in the development of cervical neoplasia

Abstract

The CDKN1A gene product is a p53 downstream effector, which participates in cell differentiation, development process, repair, apoptosis, senescence, migration, and tumorigenesis. The objective of our study was investigated the importance of two polymorphisms in the CDKN1A gene, rs1801270 (31C>A) and rs1059234 (70C>T), for the development of cervical lesions in a Southeastern Brazilian population (283 cases, stratified by lesion severity, and 189 controls). CDKN1A genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and/or DNA sequencing. CDKN1A 31A allele presents a genetic pattern of protection for the development of high-grade cervical lesions (CC vs CA genotype: OR = 0.60; 95 % CI = 0.38–0.95; p = 0.029; CA+AA vs CC genotype: OR = 0.60; 95 % CI = 0.39–0.93; p = 0.021). Allele distributions of the CDKN1A 70C>T polymorphism were also different between the two study groups, with the CDKN1A 70T allele being less prevalent among cases. Moreover, the double heterozygote genotype combination 31CA-70CT decreases the chance of developing high-grade squamous intraepithelial lesion (HSIL) and cancer (OR = 0.55; 95 % CI = 0.32–0.93; p = 0.034) by 50 %, representing a protective factor against the development of more severe cervical lesions.

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The clinical and prognostic significance of CD14 + HLA-DR −/low myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy

Abstract

Myeloid-derived suppressor cells (MDSCs) are key player in mediating systemic immunosuppression, and their accumulation and expansion in the periphery and tumor have been iteratively observed in patients with various types of cancer. It has been reported that CD14⁺HLA-DR^−/low MDSCs are increased in hepatocellular carcinoma (HCC) patients; however, the clinical significance of MDSC alteration in HCC patients after treatment is poorly studied. In this study, we examined the frequency of MDSCs in 92 HCC patients, 14 chronic liver disease patients without HCC, and 22 healthy controls by flow cytometric analysis. The associations between the clinical features and the frequency of MDSCs were analyzed. In particular, we further examined the prognostic impact of MDSCs on the overall survival of HCC patients receiving radiation therapy. The frequency of MDSCs in HCC patients was significantly increased and correlated with tumor stage, size, burden, and Child-Pugh classification but not with biochemical parameters of liver function. In HCC patients who received radiation therapy, the frequency of MDSCs after treatment significantly decreased and was inversely correlated with overall survival time. In multivariate analysis, only post-treatment MDSC ratio and Child-Pugh classification were correlated with the prognosis of HCC patients. Patients with a high frequency of MDSCs after radiotherapy should be closely followed, and the inhibition of MDSCs may improve the prognosis of patients.

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Hyperthermotherapy enhances antitumor effect of 5-aminolevulinic acid-mediated sonodynamic therapy with activation of caspase-dependent apoptotic pathway in human glioma

Abstract

Sonodynamic therapy (SDT) has shown great potential as an approach for cancer treatment, and hyperthermotherapy (HT) is also a promising cancer therapy. Here, we investigate whether HT could improve the efficacy of SDT and to make a preliminary exploration on potential mechanism. Xenograft tumor was established in nude mice model, and SNB19 and U87MG glioma cell lines were utilized for in vitro experiment. Alamar blue assay was performed to assess cell viability. Optical microscope was used to characterize the morphology changes of the glioma cells induced by SDT and HT treatments. Apoptotic rate, mitochondrial membrane potential (MMP), and intracellular production of reactive oxygen species (ROS) were examined by flow cytometer. The cell apoptosis of tumor tissues were detected by TUNEL assay. Furthermore, the expression of apoptosis-related proteins was detected with Western blot in vitro and immunohistochemistry in vivo. SDT plus HT group could significantly reduce the cell viability with circular-cell morphological change, compared with SDT group, and cell viability was decreased depending on raise of 5-ALA concentration, ultrasound exposure time, and temperature. The results also indicate that HT increased a conspicuous apoptosis, ROS production, and a remarkable loss in MMP induced by 5-ALA-SDT in vitro. Meanwhile, our data also demonstrated that the combined treatment could significantly induce apoptosis and delay tumor growth in vivo. Furthermore, in both in vitro and in vivo experiments, SDT plus HT group expressed significantly higher protein levels of Bax and cleaved caspase-3, 8, and 9 compared to SDT, HT, and control groups and significantly lower protein level of bcl-2 than the other three groups, while the expression of these proteins was unchanged between HT and control groups. HT may provide an important promotion on 5-ALA-SDT and further propose that SDT in combination with HT is a new potential application for the treatment of human glioma.

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Impact of a 3-Day Introductory Oncology Course on First-Year International Medical Students

Abstract

Although only some medical students will choose cancer as their specialty, it is essential that all students have a basic understanding of cancer and its treatment. The purpose of this study was to evaluate the impact of an introductory clinical oncology course on first-year international medical students. Evaluation of the course involved a quantitative survey designed for this study that was given pre- and post-course completion. Participants included 29 first-year international medical students. Students reported that the course affected them emotionally more than they anticipated it would prior to beginning the course. By the end of the course, students felt more comfortable focusing on how to live with cancer, felt less afraid of dealing with death, and were better able to cope with uncomfortable emotional situations. The course had no significant effect on students' interest in specializing in oncology in the future. Our study provides evidence that an introductory oncology course can increase student comfort with issues related to living with cancer, with confronting and dealing with death and dying, and with coping with uncomfortable emotional situations as related to cancer care. In anticipation of growing shortages in oncology specialists in the coming years, the ability of an early course in oncology to attract more students to the field is of interest. Future research should examine ethnic and cultural differences in uptake of the clinical oncology courses across continents and should use direct observation in addition to self-report in evaluating outcomes.

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Clinical Research Recession: Training Needs Perception Among Medical Students

Abstract

Clinical research is an integrated part of medical education. There is a noticeable decrease in the number of physician-scientists in developing countries, which is reflected by a decrease in research output and publications from these countries. We conducted a survey aiming to identify the gaps in clinical research training from the perspective of medical students. The results can be used to customize future clinical research trainings. The survey tool was divided into six modules which represent the cornerstones of clinical research based on similar surveys done for the same purpose. For each module, questions covered the perceived knowledge of its aspects and how much relevant the responder thought it was to clinical research. Five hundred one candidates have filled the survey. Evidence-based medicine (EBM) had the highest knowledge score of 2.20/4, while "clinical trials execution" knowledge got the lowest score of 1.64/4. Responders perceived EBM as the most relevant aspect of clinical research (3.39/4), while research ethics received the lowest score 3.18/4. "Clinical trials execution" had the largest gap of a difference calculated as 1.60, while EBM had the lowest gap of 1.20. More attention must be paid to clinical research training for medical students in developing countries. These trainings have to be customized to focus on clinical trial execution, research methodology, and biostatistics. In parallel, awareness campaigns targeted toward the medical community emphasizing the importance of the ethics as an aspect of clinical research should be established.

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Impact of Knowledge, Self-Efficacy, and Perceived Importance on Steps Taken Toward Cancer Prevention Among College Men and Women

Abstract

The incidence of skin, most HPV-related, liver, and lung cancers can be reduced through primary prevention. Morbidity from breast and testicular cancers can be reduced through secondary prevention. Thus, it is important to understand the mechanisms that predict engagement in primary and secondary prevention behaviors for these cancers. We investigated the roles of knowledge of cancer prevention, perceived importance of cancer prevention, and self-efficacy to engage in prevention steps in order to predict college students' actual engagement in cancer prevention behaviors (CPB). Participants were 315 undergraduates who completed an online survey to assess these constructs. Hierarchical linear regression analyses were used to model knowledge, self-efficacy, and perceived importance as predictors of CPB for a range of cancers. Self-efficacy predicted CPB similarly across all cancers such that having a higher level of self-efficacy to prevent the cancer predicted having engaged in more CPB. Increase in knowledge predicted an increase in the frequency of CPB for skin and HPV-related cancers. Perceived importance of prevention predicted skin cancer CPB. These findings can be used to tailor cancer prevention programs for undergraduates to achieve greatest impact.

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Rechallenge with 5-fluorouracil in a patient who developed encephalopathy caused by 5-fluorouracil for colon cancer

Abstract

We report a case involving a patient with colon cancer who underwent 5-fluorouracil (5-FU) rechallenge and maintained an oncological effect for a long period after encephalopathy caused by 5-FU. Our patient was a 61-year-old man who was diagnosed with adenocarcinoma of the ascending colon with direct liver invasion. He underwent right hemicolectomy with partial liver resection followed by adjuvant chemotherapy with modified FOLFOX6 (mFOLFOX6). Ten months after completion of mFOLFOX6, his carcinoembryonic antigen concentration increased, and ascites was revealed by computed tomography 2 months later. We started FOLFIRI, and he was taken to our hospital by ambulance because of loss of consciousness 10 days after the start of the third cycle of FOLFIRI. Laboratory investigations showed hyperammonemia and elevations of his serum creatinine and blood urea nitrogen concentrations. Brain computed tomography demonstrated no abnormalities. Transfusion of 1500 ml of crystalloid fluid resulted in gradual recovery over the next 12 h. His ammonia concentration decreased to a normal level. Twelve days after onset of the encephalopathy, we restarted FOLFIRI, but the dose of continuous 5-FU was decreased by 20 %. The patient's carcinoembryonic antigen concentration considerably decreased from 376.5 to 19.9 ng/ml, and his ascites disappeared. Nineteen months after the resumption of FOLFIRI, he underwent 34 courses of FOLFIRI and maintained stable disease. The encephalopathy did not recur.

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Journal of Experimental & Clinical Cancer Research reviewer acknowledgement 2015

The editors of Journal of Experimental & Clinical Cancer Research would like to thank all our reviewers who have contributed their time and expertise to the journal in Volume 34 (2015).

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Reply to specific gene patterns and molecular pathways related to human carcinogenesis in different populations among various geographic locations

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Specific gene patterns and molecular pathways related to human carcinogenesis in different populations among various geographic locations

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Satisfaction with cancer care among underserved racial-ethnic minorities and lower-income patients receiving patient navigation

BACKGROUND

Patient navigation is a barrier-focused program of care coordination designed to achieve timely and high-quality cancer-related care for medically underserved racial-ethnic minorities and the poor. However, to the authors' knowledge, few studies to date have examined the relationship between satisfaction with navigators and cancer-related care.

METHODS

The authors included data from 1345 patients with abnormal cancer screening tests or a definitive cancer diagnosis who participated in the Patient Navigation Research Program to test the efficacy of patient navigation. Participants completed demographic questionnaires and measures of patient satisfaction with cancer-related care (PSCC) and patient satisfaction with interpersonal relationship with navigator (PSN-I). The authors obtained descriptive statistics to characterize the sample and conducted regression analyses to assess the degree of association between PSN-I and PSCC, controlling for demographic and clinical factors. Analyses of variance were conducted to examine group differences controlling for statistically significant covariates.

RESULTS

Statistically significant relationships were found between the PSCC and PSN-I for patients with abnormal cancer screening tests (1040 patients; correlation coefficient (r), 0.4 [P<.001]) and those with a definitive cancer diagnosis (305 patients; correlation coefficient, 0.4 [P<.001]). The regression analysis indicated that having an abnormal colorectal cancer screening test in the abnormal screening test group and increased age and minority race-ethnicity status in the cancer diagnosis group were associated with a higher satisfaction with cancer care (P<.01).

CONCLUSIONS

Satisfaction with navigators appears to be significantly associated with satisfaction with cancer-related care. Information regarding the patient-navigator relationship should be integrated into patient navigation programs to maximize the likelihood of reducing caner disparities and mortality for medically underserved racial-ethnic minorities and the poor. Cancer 2016. © 2016 American Cancer Society.

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Involved-field radiotherapy for esophageal squamous cell carcinoma: theory and practice

Esophageal carcinoma (EC) is characterized by a high rate of lymph node metastasis and its spread pattern is not always predictable. Chemoradiotherapy has an important role in the treatment of EC in both the i...

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Diffuse Large B-Cell Lymphoma Version 1.2016

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

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Impact of Prostate Cancer Diagnosis on Noncancer Hospitalizations Among Elderly Medicare Beneficiaries With Incident Prostate Cancer

Objectives: The purpose of this study was to analyze the impact of cancer diagnosis on noncancer hospitalizations (NCHs) by comparing these hospitalizations between the precancer and postcancer periods in a cohort of fee-for-service Medicare beneficiaries with incident prostate cancer. Methods: A population-based retrospective cohort study was conducted using the SEER-Medicare linked database for 2000 through 2010. The study cohort consisted of 57,489 elderly men (aged ≥67 years) with incident prostate cancer. NCHs were identified in 6 periods (t₁–t₆) before and after the incidence of prostate cancer. Each period consisted of 120 days. For each period, NCHs were defined as inpatient admissions with primary diagnosis codes not related to prostate cancer, prostate cancer–related procedures, or bowel, sexual, and urinary dysfunction. Bivariate and multivariate comparisons on rates of NCHs between the precancer and postcancer periods accounted for the repeated measures design. Results: The rate of NCHs was higher during the postcancer period (5.1%) compared with the precancer period (3.2%). In both unadjusted and adjusted models, elderly men were 37% (odds ratio [OR], 1.37; 95% CI, 1.32, 1.41) and 38% (adjusted OR, 1.38; 95% CI, 1.33, 1.46) more likely to have any NCHs during the postcancer period compared with the precancer period. Conclusions: Elderly men with prostate cancer had a significant increase in the risk of NCHs after the diagnosis of prostate cancer. This study highlights the need to design interventions for reducing the excess NCHs after prostate cancer diagnosis among elderly men.

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Real Personalized Medicine

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A Nomogram to Predict Distant Metastases After Multimodality Therapy for Patients With Localized Esophageal Cancer

Background: Among patients with localized esophageal cancer (LEC), 35% or more develop distant metastases (DM) as first relapse, most in the first 24 months after local therapy. Implementation of novel strategies may be possible if DM can be predicted reliably. We hypothesized that clinical variables could help generate a DM nomogram. Patients and Methods: Patients with LEC who completed multimodality therapy were analyzed. Various statistical methods were used, including multivariate analysis to generate a nomogram. A concordance index (c-index) was established and validated using the bootstrap method. Results: Among 629 patients analyzed (356 trimodality/273 bimodality), 36% patients developed DM as first relapse. The median overall survival from DM was only 8.6 months (95% CI, 7.0–10.2). In a multivariate analysis, the variables associated with a higher risk for developing DM were poorly differentiated histology (hazard ratio [HR], 1.76; P<.0001), baseline T3/T4 primary (HR, 3.07; P=.0006), and baseline N+ LEC (HR, 2.01; P<.0001). Although variables associated with a lower risk for DM were age of 60 years or older (HR, 0.75; P=.04), squamous cell carcinoma (HR, 0.54; P=.013), and trimodality therapy (HR, 0.58; P=.0001), the bias-corrected c-index was 0.67 after 250 bootstrap resamples. Conclusions: Our nomogram identified patients with LEC who developed DM with a high probability. The model needs to be refined (tumor and blood biomarkers) and validated. This type of model will allow implementation of novel strategies in patients with LEC.

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Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

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Put Us Out of Business--Please!

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The Authors Respond

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Oncology Research Program

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Evaluating the Impact of Provincial Implementation of Screening for Distress on Quality of Life, Symptom Reports, and Psychosocial Well-Being in Patients With Cancer

Background: Although a number of accreditation agencies and professional societies recommend routine screening for distress (SFD) for patients with cancer, it has been integrated very slowly into clinical practice. Objectives: This evaluation investigated the impact of a large-scale SFD intervention on patients' quality of life, symptom reports, and psychosocial well-being. The SFD intervention involved (1) completion of the SFD tool by patients, (2) discussion between patient and provider about the concerns indicated, and (3) provision of appropriate assessments/interventions based on priority concerns. Patients and Methods: This quality improvement work included a pre-evaluation and postevaluation of the impact of implementation on patients' well-being. Patients in cohort 1 (N=740) were surveyed before implementation, whereas patients in cohort 2 (N=534) were surveyed 10 months after the implementation at 17 clinics province-wide. As part of the implementation, providers received training on assessing and responding to patient priority concerns with the standardized tool. Results: No differences were seen in total score of quality of life between the cohorts. Fewer patients in cohort 2 than in cohort 1 reported health problems, including tiredness, drowsiness, poor appetite, nausea, anxiety, and poor well-being. Similarly, significantly fewer patients in cohort 2 endorsed problems relating to emotional, practical, informational, spiritual, social, and physical aspects of well-being. Conclusions: Results showed significantly improved psychological and physical symptoms and psychosocial well-being after routine SFD was implemented, suggesting that a large-scale SFD intervention is beneficial for patients when it is integrated into existing clinical practice and community resources.

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Re: "The Impact of Insurance Status on Tumor Characteristics..."

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The Impact of Electromagnetic Navigational Bronchoscopy on a Multidisciplinary Thoracic Oncology Program

Background: The Leo W. Jenkins Cancer Clinic has adopted a programmatic, multidisciplinary approach to thoracic tumors, which has involved the implementation of new therapeutic and diagnostic approaches. In 2012 we began using electromagnetic navigational bronchoscopy (ENB) as a new diagnostic tool. ENB uses a guidance system that combines CT imaging with magnetic field–guided spatial information to allow tissue sampling or placement of fiducial markers to guide radiation therapy. Methods: The numbers of early-stage (I and II) and late-stage (III and IV) lung cancers were compared before and after the introduction of ENB. We also examined the number of cases of fiducial marker placement using bronchoscopy versus interventional radiology before and after ENB was introduced. Fisher's exact test was used to compare the early- versus late-stage lung cancers found at diagnosis pre- and post-ENB introduction, fiducial marker placements using interventional radiology versus bronchoscopy pre- and post-ENB introduction, and pneumothorax rates. Results: More early-stage cancers were diagnosed after ENB introduction (67 of 286 cases vs 116 of 290; P<.0001). Bronchoscopy was also used more frequently to place fiducial markers post-ENB (53 of 86 pre-ENB vs 105 of 117 post-ENB; P<.0001) and had a lower pneumothorax rate (4% vs 22%) than fiducial placement in interventional radiology (P<.001). Conclusions: The addition of ENB to a multidisciplinary thoracic oncology program may permit the diagnosis of lung cancer at an earlier stage and offers the ability to safely place fiducial markers for therapeutic purposes, such as radiation therapy, within the same procedure, potentially improving safety and decreasing time to treatment.

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What Happens When Imatinib Goes Generic?

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NCCN News

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Temporal Heterogeneity of Estrogen Receptor Expression in Bone-Dominant Breast Cancer: 18F-Fluoroestradiol PET Imaging Shows Return of ER Expression

Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using ¹⁸F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging.

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Persistent Peripheral Neuropathy Increases Fall Risk among Cancer Survivors

Many women cancer survivors have problems with mobility and other physical functioning as a result of persistent peripheral neuropathy caused by chemotherapy treatment, according to a new study. The problems with physical functioning were associated with a substantial increase in the women's risk for injurious falls.

The study findings were presented on January 11 at the 2016 Cancer Survivorship Symposium in San Francisco.

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Immunotherapy for pancreatic cancer

Abstract

Introduction

Pancreatic cancer is among the most lethal malignancies resistant to conventional therapies. The vast majority of patients is diagnosed with advanced/metastatic disease and consequently has grim prognosis. Despite the available options with nab-paclitaxel and gemcitabine or 5-fluorouracil/leucovorin/oxaliplatin, chemotherapy offers a modest survival benefit. Targeted therapy in combination with chemotherapy has not shown significant improvement in treatment outcomes. The urgent need for new therapies has turned the spotlights on immunotherapy. Immunotherapy in pancreatic cancer recruits and activates T cells which recognize tumor-specific antigens.

Results

Preclinical models have demonstrated that chemotherapy or targeted therapy works synergistically with immunotherapy. A growing body of evidence has already been gathered regarding the efficacy of checkpoint inhibitors, vaccines, adoptive T cell therapy, monoclonal antibodies, and cytokines in patients with pancreatic cancer.

Conclusions

Many ongoing trials are aiming to identify treatments which could combine efficacy with limited toxicity. In this article, we review the available data concerning multiple aspects of immunotherapy in pancreatic cancer.

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Cancer Imaging reviewer acknowledgement 2015

Contributing reviewers

The Editor of Cancer Imaging would like to thank all reviewers who have contributed their time and expertise to the journal in Volume 15 (2015).

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Impact of Reduced Renal Function on the Glucose-Lowering Effects of Luseogliflozin, a Selective SGLT2 Inhibitor, Assessed by Continuous Glucose Monitoring in Japanese Patients with Type 2 Diabetes Mellitus

Abstract

Introduction

We investigated the impact of reduced renal function on 24-h glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM) treated with luseogliflozin.

Methods

In this double-blind, placebo-controlled, crossover study, 37 Japanese patients with T2DM [glycated hemoglobin (HbA1c) 7.0–10.0%] and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m² were randomized into two groups in which patients first received luseogliflozin then placebo, or vice versa, for 7 days each. Twenty-four-hour glucose variability was measured on day 7 in each period and was compared among patients divided into three groups according to their baseline eGFR (mL/min/1.73 m²): normal (≥90; n = 13; normal group), normal-to-mildly reduced renal function (≥75 to <90; n = 12; normal–mild group), and mild-to-moderately reduced renal function (<75; n = 9; mild–moderate group).

Results

The mean [95% confidence interval (CI)] placebo-subtracted 24-h cumulative urinary glucose excretion (g) was 82.1 (72.7, 91.5), 82.5 (73.4, 91.5), and 62.2 (51.2, 73.3); the placebo-subtracted 24-h mean glucose concentration (mg/dL) was −24.39 (−32.53, −16.26), −28.28 (−39.35, −17.22), and −11.53 (−23.93, 0.86); and the placebo-subtracted peak postprandial glucose (mg/dL) was −26.9 (−46.9, −6.9), −38.1 (−59.6, −16.6), and 1.5 (−25.5, 28.4) in the normal, normal–mild, and mild–moderate groups, respectively. The mean lowest glucose concentrations (placebo vs. luseogliflozin, mg/dL) decreased to similar levels in the normal (115.4 vs. 93.4), normal–mild (121.0 vs. 97.9), and mild–moderate (104.0 vs. 91.1) groups.

Conclusion

This post hoc subanalysis revealed that although mild-to-moderately reduced renal function attenuated the glucose-lowering effects of luseogliflozin on peak postprandial glucose, it did not attenuate the effects of luseogliflozin on fasting glucose. These findings may explain the smaller increase in urinary glucose excretion in these patients relative to patients with normal renal function or normal-to-moderately reduced renal function. Further studies may be needed to examine these findings in large populations of patients with T2DM and reduced renal function.

Trial registration

JapicCTI-142548.

Funding

Taisho Pharmaceutical Co., Ltd.

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Methotrexate and Rheumatoid Arthritis: Current Evidence Regarding Subcutaneous Versus Oral Routes of Administration

Abstract

Methotrexate (MTX) is still considered the drug of choice in rheumatoid arthritis (RA) management. Comparing subcutaneous (MTX SC) and oral (MTX OR) routes of administration is important to optimize the everyday therapeutic strategy in the real-life setting. This review summarizes scientific evidence currently available on this topic. As shown by pharmacokinetic studies, at the same dose level, bioavailability of MTX SC is significantly higher and less variable than that of MTX OR. This difference is even more pronounced for medium-to-high dosages (i.e., >15 mg/week). With regard to clinical response (Disease Activity Score-28, American College of Rheumatology Criteria), randomized, double-blind studies and retrospective or longitudinal analyses in real-life settings showed that MTX SC is more effective than MTX OR. This is true both in MTX-naive patients with early RA, and in patients who switch from MTX OR to MTX SC due to previous treatment failure, lack of efficacy and/or adverse events. Finally, MTX SC has a better tolerability profile than MTX OR, with fewer gastroenterological side effects. Delaying the use of more expensive biological therapies by switching from MTX OR to MTX SC in non-responders might provide cost savings, with relevant implications in the management of patients with RA.

Funding

Alfa Wassermann.

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Adolescent Diet and Breast Cancer Risk

Abstract

Although breast cancer risk increases with age, the importance of early events on breast cancer development is increasingly recognized. Compared to the plethora of studies on adult dietary exposures and breast cancer risk, the field of adolescent diet and breast cancer risk is still in its infancy. We review the data on breast cancer risk and diet during adolescence (defined as between ages 11 and 19) with a focus on the dietary exposures that have been investigated most in adult diet. The current literature suggests possible associations with dietary intake of soy and red meat and breast cancer risk. However, the lack of strong associations for other exposures may be due to methodological issues regarding precise measurement and a paucity of published studies. Overall, the area of early life exposures and cancer risk deserves more research and increased resources to advance the field.

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Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial

Abstract

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m², days 1–21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

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Proteomic and Metabolic Signatures of Esophageal Squamous Cell Carcinoma.

Proteomic and Metabolic Signatures of Esophageal Squamous Cell Carcinoma.

Curr Cancer Drug Targets. 2016 Feb 2;

Authors: Karagoz K, Lehman HL, Stairs DB, Sinha R, Arga KY

Abstract
Esophageal squamous cell carcinoma (ESCC), which is the most common subtype of esophageal cancers, is the sixth leading cause of cancer death worldwide with a five-year survival rate of 19%. Identification of efficient biomarkers for early detection and better understanding of the molecular mechanisms of ESCC may offer reduced mortality. However, proper biomarkers for clinical diagnosis and prognosis have not been defined yet. In the presented study, we employed a systematic and integrative 'omics' strategy to reconstruct networks of transcriptional regulation and protein-protein interaction to identify novel biomarkers, potential molecular targets, and mechanisms of transcriptional control in ESCC. Towards this end, we revealed 30 down-regulated and 21 up-regulated genes as ESCC specific biomarkers since these were differentially expressed between 91 ESCC tumor samples compared to normal tissues in five different datasets. We report the association of ACPP, C2orf54, DYNLT3, ENDOU, FMO2, and KANK1 (down-regulated genes) and COL10A1, FNDC3B, HOMER3, MARCKSL1, and RFC4 (up-regulated genes) to ESCC for the first time. Further, the ESCC driven molecular pathways were also constructed to elucidate the molecular mechanism of the disease; specifically several metabolic pathways were down-regulated while the signaling pathways were up-regulated. Additionally, reporter metabolites for ESCC were analyzed and metabolic dysfunction was ascertained in arachidonic acid metabolism and steroid hormone biosynthesis pathways. The multi-omics network strategy presented here may enable discovery of novel biomarkers and targets for personalized medicine in ESCC patients.

PMID: 26845434 [PubMed - as supplied by publisher]

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BRCA1-associated triple-negative breast cancer and potential treatment for ruthenium-based compounds.

BRCA1-associated triple-negative breast cancer and potential treatment for ruthenium-based compounds.

Curr Cancer Drug Targets. 2016 Feb 2;

Authors: Hongthong K, Ratanaphan A

Abstract
Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). The clinicopathological characteristics of TNBC include a high grading, a high rate of cell proliferation and a greater degree of chromosomal rearrangement. Patients with triple-negative breast cancer are more likely to be drug resistant and more difficult to treat, and are also frequently BRCA1 mutants. Methylation of the BRCA1 promoter region is associated with a reduction of the BRCA1 mRNA level. TNBC patients with a methylated BRCA1 had a better disease-free survival compared with those with non-methylated BRCA1. From a therapeutic perspective, the expression level of BRCA1 has been a major determinant of the responses to different classes of chemotherapy. BRCA1-dysfunctional tumors are hypersensitive to DNA damaging chemotherapeutic agents like platinum drugs. Although platinum based drugs are currently widely used as conventional chemotherapeutic drugs in breast cancer chemotherapy, their use has several disadvantages. It is therefore of interest to seek out alternative therapeutic metal-based compounds that could overcome the limitations of these platinum based drugs. Ruthenium-based compounds could be the most promising alternative to the platinum drugs. This review highlights the use of BRCA1 as a predictive marker as well as for a potential drug target for anticancer ruthenium compounds.

PMID: 26845433 [PubMed - as supplied by publisher]

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miR-137 suppresses the phosphorylation of AKT and improves the dexamethasone sensitivity in multiple myeloma cells via targeting MITF.

miR-137 suppresses the phosphorylation of AKT and improves the dexamethasone sensitivity in multiple myeloma cells via targeting MITF.

Curr Cancer Drug Targets. 2016 Feb 2;

Authors: Zhang B, Ma L, Wei J, Hu J, Zhao Z, Wang Y, Chen Y, Zhao F

Abstract
Multiple myeloma (MM), a clonal B cell malignancy characterized by the proliferation of plasma cells within the bone marrow, is still an incurable disease, and therefore, finding new therapeutic targets is urgently required. Although micro RNA-137 (miR-137), which is involved in a variety of cellular processes, has been reported to be under-expressed in many types of solid tumors, its role in MM is less known. In this study, the target gene and the potential effect of miR-137 in MM were investigated. The results showed significantly downregulated expression of miR-137 in MM cell lines and in the CD138+ bone marrow mononuclear cells of MM patients. A dual luciferase reporter gene analysis revealed that MITF is a direct target of miR-137. The overexpression of miR-137 or transfection of MITF-shRNA had no significant effect on the expression of serine/threonine protein kinase (AKT), but the expression of MITF, c-MET, p-AKT, and its phosphorylated substrate protein decreased significantly, which was accompanied by an increase in p53 expression. In addition, the overexpression of miR-137 or MITF-shRNA significantly improved the 36-hour inhibition rate and apoptosis rate in multiple myeloma cells treated with dexamethasone. The overexpression of MITF could counteract the biological effect of miR-137 in multiple myeloma cells. We conclude that MITF is a direct target of miR-137. The miR-137 can improve the dexamethasone sensitivity in multiple myeloma cells by reducing the c-MET expression and further decreasing the AKT phosphorylation via targeting MITF.

PMID: 26845432 [PubMed - as supplied by publisher]

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Open Access publizieren in „memo – magazine of european medical oncology“

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Frederick W. Alt received the 2015 Szent-Györgi Prize for Progress in Cancer Research

Abstract

The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)—a leading cancer research charitable organization in the United States that is committed to supporting scientific research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, significant research to the fight against cancer, and whose accomplishments have helped improve treatment options for cancer patients. The Prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the pioneering work led by the 2015 Prize winner, Dr. Frederick Alt. Dr. Alt's work in the area of cancer genetics over four decades has helped to shape the very roots of modern cancer research. His work continues to profoundly impact the approaches that doctors around the globe use to diagnose and treat cancer. In particular, his seminal discoveries of gene amplification and his pioneering work on molecular mechanisms of DNA damage repair have helped to usher in the era of genetically targeted therapy and personalized medicine.

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Trastuzumab use during pregnancy: long-term survival after locally advanced breast cancer and long-term infant follow-up.

Here, we describe the case of a patient diagnosed with locally advanced breast cancer 8 years ago. Her treatment course was neoadjuvant chemotherapy, followed by mastectomy and then adjuvant radiotherapy and trastuzumab (TTZ). During the use of adjuvant targeted therapy, an incidental pregnancy was diagnosed. Four years later, she developed bone and cerebral metastases, and since then, she has received courses of TTZ, capecitabine, lapatinib, and radiotherapy with intermittent control of the disease. Her 7-year-old son presents a normal physical and long-term neurological developmental curve according to specialized evaluation. This case is unique for several reasons: the patient received the highest dose of TTZ yet described during pregnancy (4400 mg); there has been a long period of disease-free survival after treatment for locally advanced breast cancer and long overall survival despite successive disease progressions during the metastatic phase of the disease (97 months), and there was a monitored pediatric follow-up period (7 years). Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Reduced folate and serum vitamin metabolites in patients with rectal carcinoma: an open-label feasibility study of pemetrexed with folic acid and vitamin B12 supplementation.

The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m2, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1faivrI. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib.

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis

Previous studies have investigated the sustained aberrantly activated Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for pancreatic cancer growth a...

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Efficacy of limb salvage with primary tumor resection simultaneously for solitary bone metastasis in limbs

Abstract

Background

This study aims to evaluate the efficacy of limb salvage with primary tumor resection on patients with solitary bone metastasis.

Methods

A retrospective treatment outcome review was performed on 20 patients with solitary bone metastasis as the primary clinical symptom who were admitted to the hospital between 2006 and 2010. With primary tumor resection, 18/20 patients received limb salvage surgery simultaneously. Pain scoring was assessed using the 0 to 10 numerical rating scale. The quality of life scoring was performed before and 3 months after surgery using the SF-30 scoring system. In addition, limb function was assessed 3 months after the operation using the Scoring System of American Musculoskeletal Tumor Society system (MSTS).

Results

The pain symptom was significantly ameliorated after the operation (t = 26.653, P < 0.001), and the quality of life dramatically improved (t = −20.581, P < 0.001). The postoperative MSTS scores ranged from 18 to 27. The average score was 23.10 ± 2.36. The Kaplan-Meier analysis showed that no significant differences (χ2 = 1.589, P = 0.207) were observed in the tumor-free survival time between the wide and marginal resections.

Conclusions

The application of the wide or marginal excision for the primary lesion and bony metastasis focus, based on the principles of primary bone tumors, can significantly relieve the pain and improve the quality of life and limb function of patients whose solitary bone metastasis was manifested as the first sign.

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Expression of HIF-1α and HIF-2α correlates to biological and clinical significance in papillary thyroid carcinoma

Abstract

Background

The aim of this study was to detect the expression of hypoxia-inducible factor (HIF)-1α and HIF-2α in papillary thyroid carcinoma (PTC) compared with normal thyroid tissues.

Methods

The mRNA levels and protein levels of HIF-1α and HIF-2α were detected by real-time PCR and Western blot separately in 30 pairs of PTCs and normal thyroid cases. The protein levels were also detected by immunohistochemistry (IHC) using 92 samples of PTC group and 46 normal samples as control group for analyzing the biological and clinical significance of the expression of HIF-1α/HIF-2α.

Results

Real-time PCR results showed the mRNA level of HIF-1α and HIF-2α were significantly higher in PTC than normal group (P < 0.001). Also, significantly higher positive rates (73 %/65 %) of HIF-1α and HIF-2α were observed in PTC compared with the control group (27 %/35 %) by IHC (P < 0.01); the consistent results were gotten with Western blot. Although we did not find a significant correlation between the expression of HIF-1α and HIF-2α with gender, age, calcification, or Hashimoto's disease in the present study (P > 0.05), both of their expressions were correlated to lymph node metastasis (P < 0.05), capsular invasion (P < 0.05), and TNM stage (P < 0.05).

Conclusions

Overexpression of HIF-1α and HIF-2α are associated with the carcinogenesis of PTC, served as potential biomarkers of PTC.

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