Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study

Abstract

Background

This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery is uncertain.

Methods

Data from patients with a diagnosis of hgPNEC determined between 1998 and 2012 were retrospectively registered at 10 Nordic university hospitals. Kaplan–Meier curves were used to compare the overall survival of different treatment groups, and Cox-regression analysis was used to evaluate factors potentially influencing survival.

Results

The study registered 119 patients. The median survival period from the time of metastasis was 23 months for patients undergoing initial resection of localized nonmetastatic disease and chemotherapy at the time of recurrence (n = 14), 29 months for patients undergoing resection of the primary tumor and resection/radiofrequency ablation of synchronous metastatic liver disease (n = 12), and 13 months for patients with synchronous metastatic disease given systemic chemotherapy alone (n = 78). The 3-year survival rate after surgery of the primary tumor and metastatic disease was 69 %. Resection of the primary tumor was an independent factor for improved survival after occurrence of metastatic disease.

Conclusions

Patients with resected localized nonmetastatic hgPNEC and later metastatic disease seemed to benefit from initial resection of the primary tumor. Patients selected for resection of the primary tumor and synchronous liver metastases had a high 3-year survival rate. Selected patients with both localized hgPNEC and metastatic hgPNEC should be considered for radical surgical treatment.

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Impact of Time from Completion of Neoadjuvant Chemotherapy to Surgery on Survival Outcomes in Breast Cancer Patients

Abstract

Background

No studies have examined the impact of the interval from conclusion of neoadjuvant chemotherapy to surgery in breast cancer patients. This study was undertaken to investigate the relationship between time interval from neoadjuvant chemotherapy to surgery and survival outcomes.

Methods

Breast cancer patients diagnosed with stage I–III disease who received neoadjuvant chemotherapy June 1995 to April 2007 were identified. The effect of neoadjuvant chemotherapy to surgery interval, defined as ≤4, 4–6, or >6 weeks, on survival outcomes was examined. Descriptive statistics and Cox proportional hazards models were used.

Results

A total of 1101 patients were identified. Median time to surgery was 33 (range 8–159) days; 335 patients (30.4 %) had surgery within 4 weeks of their last dose of neoadjuvant chemotherapy, 524 (47.6 %) within 4–6 weeks, and 242 (22.0 %) after more than 6 weeks. Median follow-up was 94 (range 3–178) months. The 5-year overall survival (OS) estimates were 79, 87, and 81 % in patients who underwent surgery ≤4, 4–6, and >6 weeks after neoadjuvant chemotherapy, respectively (p = 0.03). The three groups did not differ in 5-year recurrence-free survival (RFS) or locoregional recurrence-free survival (LRFS). In multivariable analysis, compared with an interval of ≤4 weeks, patients who underwent surgery at 4–6 or >6 weeks had equivalent OS, LRFS, and RFS; a sensitivity analysis suggested worse OS in patients who underwent surgery at >8 weeks.

Conclusions

Patients with neoadjuvant chemotherapy to surgery intervals of up to 8 weeks had equivalent OS, RFS, and LRFS.

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Characterization of the expression of the pro-metastatic Mena INV isoform during breast tumor progression

Abstract

Several functionally distinct isoforms of the actin regulatory Mena are produced by alternative splicing during tumor progression. Forced expression of the Mena^INV isoform drives invasion, intravasation and metastasis. However, the abundance and distribution of endogenously expressed Mena^INV within primary tumors during progression remain unknown, as most studies to date have only assessed relative mRNA levels from dissociated tumor samples. We have developed a Mena^INV isoform-specific monoclonal antibody and used it to examine Mena^INV expression patterns in mouse mammary and human breast tumors. Mena^INV expression increases during tumor progression and to examine the relationship between Mena^INV expression and markers for epithelial or mesenchymal status, stemness, stromal cell types and hypoxic regions. Further, while Mena^INV robustly expressed in vascularized areas of the tumor, it is not confined to cells adjacent to blood vessels. Altogether, these data demonstrate the specificity and utility of the anti-Mena^INV-isoform specific antibody, and provide the first description of endogenous Mena^INV protein expression in mouse and human tumors.

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Differences in limb volume trajectories after breast cancer treatment

Abstract

Purpose

Approximately 20 % of patients develop lymphedema (LE) following breast cancer (BC) surgery. An evaluation of distinct trajectories of volume change may improve our ability to diagnose LE sooner. The purposes of this study were to identify subgroups of women with distinct trajectories of limb volume changes following BC surgery and to evaluate for phenotypic differences among these classes.

Methods

In this prospective longitudinal study, 380 women were enrolled prior to unilateral BC surgery. Upper limb bioimpedance was measured preoperatively and serially for 1 year postoperatively. Resistance ratios (RRs) were calculated. A RR of >1 indicates affected limb volume > unaffected limb volume. Latent class growth analysis (LCGA) was used to identify classes of women with distinct postoperative RR trajectories. Differences among classes were evaluated using analyses of variance and chi-square analyses.

Results

Three distinct classes were identified as follows: RR <0.95 (37.9 %), RR ~1.00 (46.8 %), and RR >1.05 (15.3 %). Patients in the RR >1.05 class were more likely to have diabetes (p = 0.036), were more likely to have BC on their dominant side (p < 0.001), had higher RR ratios at the preoperative and 1-month assessments (p < 0.001), and were more likely to be diagnosed with LE (p < 0.001).

Conclusions

LCGA is a useful analytic technique to identify subgroups of women who may be at higher risk for the development of LE, based on trajectories of limb volume change after BC surgery.

Implications for Cancer Survivors

Assessment of preoperative and 1-month bioimpedance RRs may allow for the earlier identification of patients who are at higher risk for the development of LE.

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SEOM clinical guidelines in metastatic breast cancer 2015

Abstract

Metastatic breast cancer is essentially an incurable disease. However, recent advances have resulted in a significant improvement of overall survival. The SEOM guidelines are intended to make evidence-based recommendations on how to manage patients with metastatic breast cancer to achieve the best patient outcomes based on a rational use of the currently available therapies. To assign a level of certainty and a grade of recommendation the United States Preventive Services Task Force guidelines methodology was selected as reference.

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Analysis of surgery for incurable gastric cancer

Abstract

Background

It is important to evaluate the curability of and avoid unnecessary exploratory surgery for gastric cancer preoperatively. However, no related research has been reported until now. The aim of this study was to evaluate the factors influencing surgery for incurable gastric cancer.

Methods

310 cases of T3–4 gastric cancer patients were analyzed retrospectively, including 141 cases with radical surgery and 169 with surgery for incurable gastric cancer. The incurable factors were categorized as T status (unresectable T4 tumor), N status (unresectable lymph node), peritoneal metastasis, and distant metastasis. χ ² test and logistic regression were performed to analyze the associations between curability, T status, N status, peritoneal metastasis, or distant metastasis and clinicopathological data.

Results

Esophageal involvement and T grade were associated with curability. Cardia involvement and Borrmann type were associated with T status. Esophageal involvement and T grade were associated with N status. Gastric body involvement, esophageal involvement, and T grade were associated with peritoneal metastasis. Gastric antrum involvement was associated with distant metastasis.

Conclusions

The influencing factors of surgery for incurable gastric cancer should be analyzed preoperatively. Resectability should be evaluated according to these influencing factors combined with imaging analysis.

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Rapid thyroid nodule growth is not a marker for well-differentiated thyroid cancer

Abstract

Background

Rapid growth of thyroid nodules is described as being associated with thyroid cancer. The objective of the study was to determine how the growth rate of thyroid nodules during follow-up is associated with the risk of thyroid cancer.

Methods

Retrospective analysis of patients undergoing thyroid surgery for nodular disease and a repetitive preoperative ultrasound work-up of at least 6 months was done. Nodule growth was considered relevant when a volume increase >49 % was detected. Growth patterns were described as rapid for a volume increase present over 6 to 24 months.

Results

Of the 297 analysed patients, 226 (76 %) displayed relevant nodule growth and 71 (24 %) no relevant growth. A rapid growth pattern was seen in 73 patients (32 %). Well-differentiated thyroid cancer was diagnosed in 33 patients (11 %; 27 papillary, 6 follicular) with a relevant nodule growth in 2 and no relevant growth in 31 patients. No rapid growth pattern was observed in any case of well-differentiated thyroid cancer. A rapid growth pattern occurred only in benign nodules (70 patients) and in 1 patient each with a lymphoma, a metastasis of a renal cell cancer and a metastasis of a gastric adenocarcinoma. Therapy with levothyroxine and/or iodine was administered to 129 patients (43 %) and was significantly inversely correlated with nodule growth (odds ratio 0.27; CI 95 % 0.14–0.53, p < 0.001).

Conclusions

Thyroid nodule growth alone and especially a rapid growth pattern during follow-up for thyroid nodular disease is not a marker for well-differentiated thyroid cancer and should not be used as a stand-alone argument for thyroid surgery.

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Infective endocarditis and cancer in the elderly

Abstract

Little is known about the magnitude of the association between infective endocarditis and cancer, and about the natural history of cancer patients with concomitant diagnosis of infective endocarditis. We used the SEER-Medicare linked database to identify individuals aged 65 years or more diagnosed with colorectal, lung, breast, or prostate cancer, and without any cancer diagnosis (5 % random Medicare sample from SEER areas) between 1992 and 2009. We identified infective endocarditis from the ICD-9 diagnosis of each admission recorded in the Medpar file and its incidence rate 90 days around cancer diagnosis. We also estimated the overall survival and CRC-specific survival after a concomitant diagnosis of infective endocarditis. The peri-diagnostic incidence of infective endocarditis was 19.8 cases per 100,000 person-months for CRC, 5.7 cases per 100,000 person-months for lung cancer, 1.9 cases per 100,000 person-months for breast cancer, 4.1 cases per 100,000 person-months for prostate cancer and 2.4 cases per 100,000 person-months for individuals without cancer. Two-year overall survival was 46.4 % (95 % CI 39.5, 54.5 %) for stage I–III CRC patients with concomitant endocarditis and 73.1 % (95 % CI 72.9, 73.3 %) for those without it. In this elderly population, the incidence of infective endocarditis around CRC diagnosis was substantially higher than around the diagnosis of lung, breast and prostate cancers. A concomitant diagnosis of infective endocarditis in patients with CRC diagnosis is associated with shorter survival.

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Gold(III) compounds-mediated inhibition of lung cancer cell line proliferation: potential apoptotic effects for its chemotherapeutic effects.

Research on chemotherapeutics for lung cancer is crucial for designing a new therapeutic strategy against malignant lung tumors. Although radiotherapy and chemotherapy, which are not selective for cancer cells and exert toxic effects on healthy cells, have a limited advantage, they are the primary treatment modalities for non-small lung cancer. In addition to cytotoxicity, resistance of chemotherapeutics results in failure of treatment. This is why it is of utmost importance to focus on the creation of new chemotherapeutics without toxicity for the successful treatment and improved survival of cancer patients. New gold(III) and Pt(II) compounds were synthesized with a heterocyclic ligand using 2-phenylimidazo[4,5-f][1,10]phenanthroline as a ligand and bis-1,4-di[([1,10] phenanthroline-5-il)amino]-2-buten as a bridge molecule. The characterization of the compounds was carried out using a variety of spectroscopic methods (1H NMR, IR, MS, and elemental analysis). Their antiproliferative, antitumoral, and apoptotic activities were determined. IR spectra and NMR results confirmed the formation of dinuclear heterocyclic complexes for two metal complexes. Cytotoxicity studies on lung cancer cells (A549) and healthy cells (CHL) showed a marked increase in cytotoxicity with the use of gold(III) complexes, and especially [Au(L)B](PF6)2 showed higher cytotoxic and apoptotic features than cisplatin at lower concentrations in cancer cells. These findings have been supported by results from DAPI staining and colorimetric measurement of the caspase-3 enzyme in both cell lines. Compounds showed selective toxicity on the cancer cells. In the light of the high efficacy of our newly synthesized gold complexes, they might be good and promising anticancer agents compared with cisplatin. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Potential role of targeted therapies in the treatment of triple-negative breast cancer.

Breast cancer is the most common cancer type that affects women and is the major cause of morbidity and mortality. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype and accounts for 10-20% of all breast cancer cases. TNBC is commonly characterized by the absence of estrogen, progesterone, and the Her2/neu receptor and is usually diagnosed by immunohistochemistry. Mutations in the BRCA1 gene, as well as overexpression of oncogenic kinases, such as human epidermal growth factor receptor 2, vascular endothelial growth factor-A, insulin-like growth factor-1 (IGF-1)/IGF-1 receptor, and transforming growth factor-[beta]1, have been found to be correlated with a higher risk of metastasis and poor overall survival in TNBC patients. The current review briefly discusses the various treatment options including chemotherapeutics and targeted therapies that are available currently for the therapy of TNBC patients and highlights their comparative benefits and disadvantages for clinical application. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Lu-177-Labeled Zirconia Particles for Radiation Synovectomy

Cancer Biotherapy & Radiopharmaceuticals Dec 2015, Vol. 30, No. 10: 433-438.


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Expression of Neuropeptide Y and Its Relationship with Molecular and Morphological Changes in Human Pituitary Adenomas

Cancer Biotherapy & Radiopharmaceuticals Dec 2015, Vol. 30, No. 10: 411-419.


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Silencing of HMGA2 suppresses cellular proliferation, migration, invasion, and epithelial–mesenchymal transition in bladder cancer

Abstract

The high-mobility group protein A2 (HMGA2) is an architectural transcription factor that plays a crucial role in the development and progression of various malignant cancers. However, the function of HMGA2 in bladder cancer remains largely unknown. Therefore, we aim to investigate the effect of HMGA2 on the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of bladder cancer cells. The expression of HMGA2 in human bladder cancer cells was downregulated by small interfering RNA (siRNA). The protein levels of HMGA2 and other related proteins were detected by Western blotting. The cell proliferation and apoptosis were examined by Cell Counting Kit-8 and flow cytometry, respectively. Transwell migration and invasion assays were performed to assess the effect of HMGA2 on the migration and invasion ability of cells. In conclusion, we found that HMGA2 knockdown markedly inhibited cell proliferation; this reduced cell growth was due to the high apoptosis rate of cells, as Bcl-xl was diminished, whereas Bax was upregulated. Moreover, our results showed that silencing of HMGA2 in cancer cells greatly inhibited the cell migration and invasion, decreased the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), and affected the occurrence of EMT. We further found that decreased HMGA2 expression suppressed the transforming growth factor-β (TGF-β)/Smad and Wnt/β-catenin signaling pathway in bladder cancer cells. These results revealed that HMGA2 played an important role in the progression of bladder cancer and might be a novel target for therapy in human bladder cancer.

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Upregulation of connexin43 contributes to PX-12-induced oxidative cell death

Abstract

Thioredoxin (Trx) is a small redox protein that underlies aggressive tumor growth and resistance to chemotherapy. Inhibition of Trx with the chemical inhibitor PX-12 suppresses tumor growth and induces cell apoptosis. Currently, the mechanism underlying the therapeutic actions of PX-12 and the molecules influencing cell susceptibility to PX-12 are incompletely understood. Given that connexin43 (Cx43), a tumor suppressor, regulates tumor cell susceptibility to chemotherapy, we examined the possible involvement of Cx43 in PX-12-induced cell death. Exposure of cells to PX-12 led to a loss of cell viability, which was associated with the activation of oxidative sensitive c-Jun N-terminal kinase (JNK). Inhibition of JNK or supplement of cells with anti-oxidants prevented the cell-killing action of PX-12. The forced expression of Cx43 in normal and tumor cells increased cell sensitivity to PX-12-induced JNK activation and cell death. In contrast, the downregulation of Cx43 with siRNA or the suppression of gap junctions with chemical inhibitors attenuated JNK activation and enhanced cell resistance to PX-12. Further analysis revealed that PX-12 at low concentrations induced a JNK-dependent elevation in the Cx43 protein, which was also preventable by supplementing the cells with anti-oxidants. Our results thus indicate that Cx43 is a determinant in the regulation of cell susceptibility to PX-12 and that the upregulation of Cx43 may be an additional mechanism by which PX-12 exerts its anti-tumor actions.

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Silencing pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer cells to gemcitabine

Abstract

Pancreatic adenocarcinoma upregulated factor (PAUF) is a new oncogene that activates signaling pathways that play a critical role in resistance to gemcitabine. We thus speculated that PAUF also plays a role in resistance to gemcitabine of pancreatic cancer cells. We established BxPC-3 cell lines with stable PAUF knockdown (BxPC-3_shPAUF) and controls (BxPC-3_shCtrl) and evaluated sensitivity to gemcitabine in vitro by MTT and flow cytometry. We established a xenograft model of human pancreatic cancer to examine PAUF function in gemcitabine resistance in vivo. Gene chip microarrays were performed to identify differentially expressed genes in BxPC-3_shPAUF and BxPC-3_shCtrl cells. Silencing PAUF increased the sensitivity of BxPC-3 cells to gemcitabine in vitro and in vivo. PAUF-knockdown BxPC-3 cell lines treated with gemcitabine showed increased proliferation inhibition and apoptosis compared with controls. Gemcitabine exhibited a more pronounced effect on reduction of BxPC-3_shPAUF tumors than BxPC-3_shCtrl tumors. Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assays confirmed a significantly higher apoptotic rate of BXPC-3_shPAUF tumors compared with BXPC-3_shCtrl tumors. Gene array showed that PAUF function in gemcitabine sensitivity might involve MRP2, MRP3, MDR1, PIK3R1, and NFkB2 genes. PAUF could be considered as a key molecular target for sensitizing pancreatic cancer cells to gemcitabine.

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KRAS mutations in pancreatic circulating tumor cells: a pilot study

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCell® filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p < 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS ^mut) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis.

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RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma

Abstract

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK′872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma

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Plasma DNA integrity index as a potential molecular diagnostic marker for breast cancer

Abstract

Plasma DNA integrity index is increased in various malignancies including breast cancer, the most common cancer in women worldwide; early detection is crucial for successful treatment. Current screening methods fail to detect many cases of breast cancer at an early stage. In this study, we evaluated the level of plasma DNA integrity index in 260 females (95 with breast cancer, 95 with benign breast lesions, and 70 healthy controls) to verify its potential value in discriminating malignant from benign breast lesions. The criteria of the American Joint Committee on Cancer were used for staging of breast cancer patients. DNA integrity index was measured by real-time PCR. DNA integrity index was significantly higher in breast cancer than in benign breast patients and healthy subjects (P = <0.001). DNA integrity index is correlated with TNM stage. Given 100 % specificity, the highest sensitivity achieved in detecting cancer group was 85.3 % at 0.55 DNA integrity index cutoff. In conclusion, the plasma DNA integrity index may be a promising molecular diagnostic marker of malignancy in breast lesions.

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Using “residual” FNA rinse and body fluid specimens for next-generation sequencing: An institutional experience

BACKGROUND

Tissue specimens are typically considered optimal for molecular testing; however, in the current era of personalized medicine, cytopathology specimens are increasingly recognized as potential sources for molecular testing. This is often accomplished by using cell block specimens and/or fine-needle aspiration (FNA) smear preparations. In this study, the authors investigated the feasibility, performance, and quality of "residual" FNA rinse and body effusion fluids used for next-generation sequencing (NGS).

METHODS

Sequence data were generated from 17 malignancies in 16 patients from 13 FNA (10 lymph nodes, 1 lung, and 2 bone lesions) and 4 effusion (3 pleural and 1 pericardial) specimens. Malignancies included carcinomas (lung, breast, ovarian, and unknown primary), melanoma, and myeloma. Paired NGS testing was performed in 7 patients who had surgical biopsy or cell block specimens available. Routinely processed residual FNA rinse material and body fluids were used for DNA extraction and NGS (targeted gene panel).

RESULTS

NGS was successfully performed on all 17 specimens. A significant amount of DNA was obtained from the residual FNA rinse (176.3 ng/μL) compared with the paired cell block slides (10.6 ng/μL). Two of the 10 lung adenocarcinomas (20%) demonstrated epidermal growth factor receptor (EGFR) mutations, including 1 leucine-to-arginine substitution at codon 858 (L858R) in exon 21 and 1 codon 2235_2249 deletion (resulting in an in-frame deletion of 5 amino acids from position 746 to 750 [glutamic acid, leucine, arginine, glutamic acid, and alanine]; E746_A750del) in exon 19. Three KRAS [Kirsten rat sarcoma viral oncogene homolog] mutations, 1 BRAF (v-Raf murine sarcoma viral oncogene homolog B1) mutation, and 1 NRAS (neuroblastoma RAS viral oncogene homolog) mutation were identified in the remaining lung adenocarcinomas. Patients who underwent paired testing demonstrated 100% concordant mutations.

CONCLUSIONS

Targeted NGS can be performed on residual FNA rinse and body fluid specimens. This approach is particularly important when a paucicellular cell block or biopsy specimen is encountered. Cancer (Cancer Cytopathol) 2015. © 2015 American Cancer Society.

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Consistent gene expression profiles in MexTAg transgenic mouse and wild type mouse asbestos-induced mesothelioma

Abstract

Background

The MexTAg transgenic mouse model of mesothelioma replicates many aspects of human mesothelioma, including induction by asbestos, pathogenicity and response to cytotoxic chemotherapy, despite high levels of the SV40 large T Antigen (TAg) in the mesothelial compartment. This model enables analysis of the molecular events associated with asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out.

Methods

Gene expression of MexTAg mesothelioma cell lines bearing a high or low number of copies of the TAg transgene were compared to wild type mouse mesotheliomas and normal mouse mesothelial cells using Affymetrix microarray. These data were then compared to a similar published human microarray study using the same platform.

Results

The main expression differences between transgenic mouse and wild type mouse mesotheliomas occurred for genes involved in cell cycle regulation and DNA replication, as would be expected from overexpression of the TAg oncogene. Quantitative PCR confirmed that E2F and E2F regulated genes were significantly more upregulated in MexTAg mesotheliomas and MexTAg mesothelial cells compared to wild type mesotheliomas. Like human mesothelioma, both MexTAg and wild type mesotheliomas had more genes underexpressed than overexpressed compared to normal mouse mesothelial cells. Most notably, the cdkn2 locus was deleted in the wild type mouse mesotheliomas, consistent with 80 % human mesotheliomas, however, this region was not deleted in MexTAg mesotheliomas. Regardless of the presence of TAg, all mouse mesotheliomas had a highly concordant set of deregulated genes compared to normal mesothelial cells that overlapped with the deregulated genes between human mesotheliomas and mesothelial cells.

Conclusions

This investigation demonstrates that the MexTAg mesotheliomas are comparable with wild type mouse mesotheliomas in their representation of human mesothelioma at the molecular level, with some key gene expression differences that are attributable to the TAg transgene expression. Of particular note, MexTAg mesothelioma development was not dependent on cdkn2 deletion.

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Serum lipidomic profiling as a useful tool for screening potential biomarkers of hepatitis B-related hepatocellular carcinoma by ultraperformance liquid chromatography–mass spectrometry

Abstract

Background

Chronic hepatitis B (CHB) virus infection is a major cause of hepatocellular carcinoma (HCC), as late diagnosis is the main factor for the poor survival of patients. There is an urgent need for accurate biomarkers for early diagnosis of HCC. The aim of the study was to explore the serum lipidome profiles of hepatitis B-related HCC to identify potential diagnostic biomarkers.

Methods

An ultraperformance liquid chromatography mass spectrometry (UPLC-MS) lipidomic method was used to characterize serum profiles from HCC (n = 32), liver cirrhosis (LC) (n = 30), CHB (n = 25), and healthy subjects (n = 34). Patients were diagnosed by clinical laboratory and imaging evidence and all presented with CHB while healthy controls had normal liver function and no infectious diseases.

Results

The UPLC-MS-based serum lipidomic profile provided more accurate diagnosis for LC patients than conventional alpha-fetoprotein (AFP) detection. HCC patients were discriminated from LC with 78 % sensitivity and 64 % specificity. In comparison, AFP showed sensitivity and specificity of 38 % and 93 %, respectively. HCC was differentiated from CHB with 100 % sensitivity and specificity using the UPLC-MS approach. Identified lipids comprised glycerophosphocolines, glycerophosphoserines and glycerophosphoinositols.

Conclusions

UPLC-MS lipid profiling proved to be an efficient and convenient tool for diagnosis and screening of HCC in a high-risk population.

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Alpha-fetoprotein normalization as a prognostic surrogate in small hepatocellular carcinoma after stereotactic body radiotherapy: a propensity score matching analysis

Abstract

Background

To assess the significance of alpha-fetoprotein (AFP) normalization as a prognostic surrogate after stereotactic body radiotherapy (SBRT) for patients with small hepatocellular carcinoma (HCC).

Methods

Patients who underwent SBRT for primary or recurrent HCC were registered and a database thereof was retrospectively reviewed. Among 165 total registered patients, 77 patients were selected who satisfied the following criteria: (1) their AFP levels were > 20 ng/mL before SBRT, and (2) their AFP levels were checked within three months after SBRT. Propensity score based matching analysis was performed to minimize potential confounding bias. AFP normalization was defined as a reduction of AFP level to ≤ 20 ng/mL. Overall survival (OS) and progression-free survival (PFS) curves were estimated by the Kaplan-Meier method.

Results

Thirty-seven (48.1 %) patients displayed AFP normalization (normalized group), while 40 (51.9 %) patients comprised the non-normalized group. The OS rates at 3-year were 62.0 % and 44.0 % (p = 0.023), and the PFS rates at 3-year were 27.9 % and 12.0 % (p = 0.019), in the normalized and non-normalized groups, respectively. Local control rates were 97.2 % in the normalized group and 94.7 % in the non-normalized group at three years (p = 0.579). In the propensity score matching cohort (25 pairs), OS and PFS were significantly longer in the normalized group than in the non-normalized group (p = 0.017 and 0.049, respectively). The local control rates were 100 % in both matched groups.

Conclusions

AFP normalization within three months after SBRT is a prognostic surrogate for OS and PFS in patients with small HCC. AFP monitoring should be considered a useful tool for HCC patients with an elevated AFP level before SBRT.

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High EGFR protein expression and exon 9 PIK3CA mutations are independent prognostic factors in triple negative breast cancers

Abstract

Background

Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.

Methods

We extensively analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients.

Results

EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p < 0.001). Univariate analysis showed a significant association between relapse-free survival (RFS), T and N stage and exon 9 PIK3CA mutations. Overall survival was significantly associated with T stage, N stage and adjuvant chemotherapy, which was administered to 70.3 % of patients. In multivariate analyses, T stage, N stage, presence of exon 9 PIK3CA mutations and high EGFR protein level were independent poor prognostic factors for RFS, while adjuvant chemotherapy was associated with a better outcome.

Conclusions

High EGFR protein expression and exon 9 PIK3CA activating mutations are independent prognostic factors in TNBC. The efficacy of anti-PI3K targeted therapies needs to be evaluated in this setting.

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The genomic and transcriptomic landscape of anaplastic thyroid cancer: implications for therapy

Abstract

Background

Anaplastic thyroid carcinoma is the most undifferentiated form of thyroid cancer and one of the deadliest of all adult solid malignancies. Here we report the first genomic and transcriptomic profile of anaplastic thyroid cancer including those of several unique cell lines and outline novel potential drivers of malignancy and targets of therapy.

Methods

We describe whole genomic and transcriptomic profiles of 1 primary anaplastic thyroid tumor and 3 authenticated cell lines. Those profiles augmented by the transcriptomes of 4 additional and unique cell lines were compared to 58 pairs of papillary thyroid carcinoma and matched normal tissue transcriptomes from The Cancer Genome Atlas study.

Results

The most prevalent mutations were those of TP53 and BRAF; repeated alterations of the epigenetic machinery such as frame-shift deletions of HDAC10 and EP300, loss of SMARCA2 and fusions of MECP2, BCL11A and SS18 were observed. Sequence data displayed aneuploidy and large regions of copy loss and gain in all genomes. Common regions of gain were however evident encompassing chromosomes 5p and 20q. We found novel anaplastic gene fusions including MKRN1-BRAF, FGFR2-OGDH and SS18-SLC5A11, all expressed in-frame fusions involving a known proto-oncogene. Comparison of the anaplastic thyroid cancer expression datasets with the papillary thyroid cancer and normal thyroid tissue transcriptomes suggested several known drug targets such as FGFRs, VEGFRs, KIT and RET to have lower expression levels in anaplastic specimens compared with both papillary thyroid cancers and normal tissues, confirming the observed lack of response to therapies targeting these pathways. Further integrative data analysis identified the mTOR signaling pathway as a potential therapeutic target in this disease.

Conclusions

Anaplastic thyroid carcinoma possessed heterogeneous and unique profiles revealing the significance of detailed molecular profiling of individual tumors and the treatment of each as a unique entity; the cell line sequence data promises to facilitate the more accurate and intentional drug screening studies for anaplastic thyroid cancer.

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Negative effect of cyclin D1 overexpression on recurrence-free survival in stage II-IIIA lung adenocarcinoma and its expression modulation by vorinostat in vitro

Abstract

Background

This study was aimed at identifying prognostic biomarkers for stage II-IIIA non-small cell lung cancer (NSCLC) according to histology and at investigating the effect of vorinostat on the expression of these biomarkers.

Methods

Expression levels of cyclin D1, cyclin A2, cyclin E, and p16 proteins that are involved in the G₁-to-S phase progression of cell cycle were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 372 samples of stage II-IIIA NSCLC. The effect of vorinostat on the expression of these proteins, impacts on cell cycle, and histone modification was explored in lung cancer cells.

Results

Abnormal expression of cyclin A2, cyclin D1, cyclin E, and p16 was found in 66, 47, 34, and 51 % of 372 cases, respectively. Amongst the four proteins, only cyclin D1 overexpression was significantly associated with poor recurrence-free survival (adjusted hazard ratio = 1.87; 95 % confidence interval = 1.12 – 2.69, P = 0.02) in adenocarcinoma but not in squamous cell carcinoma (P = 0.44). Vorinostat inhibited cell cycle progression to the S-phase and induced down-regulation of cyclin D1 in vitro. The down-regulation of cyclin D1 by vorinostat was comparable to a siRNA-mediated knockdown of cyclin D1 in A549 cells, but vorinostat in the presence of benzo[a]pyrene showed a differential effect in different lung cancer cell lines. Cyclin D1 down-regulation by vorinostat was associated with the accumulation of dimethyl-H3K9 at the promoter of the gene.

Conclusions

The present study suggests that cyclin D1 may be an independent prognostic factor for recurrence-free survival in stage II-IIIA adenocarcinoma of lung and its expression may be modulated by vorinostat.

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Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis

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A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel

A prognostic index model was developed, composed of six routinely available and readily assessable factors and categorizing patients with metastatic castration-resistant prostate cancer treated with abiraterone-prednisone into distinct prognostic risk groups. This model could be useful for determining patient prognosis for the purposes of follow-up and monitoring, and may aid in patient stratification for clinical trials.

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Regulation of PD-L1: A novel role of pro-survival signalling in cancer

In this review, we summarize the recent progress in understanding regulation of PD-L1 expression and propose a regulatory model for explanation of commonly observed elevation of PD-L1 in cancer cells. In particular, the significance of multiple pro-survival signal pathways that are aberrantly activated in many types of cancer in PD-1/PD-L1-mediated immune evasion is discussed.

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Phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4)

RECORD-4 prospectively assessed second-line everolimus after initial VEGF-targeted therapy or cytokines in mRCC (N=134), Overall population (N=134), median PFS was 7.8 months (95% CI, 5.7-11.0) and median OS was 23.8 months (95% CI, 17.0-NE), Safety population (n=133), median duration of exposure was 5.8 months; 56% of patients experienced grade 3/4 AEs, regardless of study drug relationship, Results confirm the clinical benefit of second-line everolimus

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Association between PSA kinetics and cancer-specific mortality in patients with localised prostate cancer: analysis of the placebo arm of the SPCG-6 study

With up to 15.6 years follow-up after inclusion in the SPCG-6 study, we found no association between PSA kinetics and prostate cancer mortality in patients with localised prostate cancer and PSA at consent ≤10 ng/mL managed observationally. Our findings indicate that the usefulness of PSA kinetics as a surrogate for tumour aggressiveness depends on baseline PSA level.

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Methanol-based fixation is superior to buffered formalin for next-generation sequencing of DNA from clinical cancer samples

High quality tumour DNA is essential for any personalised treatment strategy based on next generation sequencing (NGS). Here we show that methanol fixation is superior to formalin, greater DNA yield, longer fragment size and more accurate copy number calling using shallow whole genome sequencing. We also show provide a new approach to understand fixation artefacts using non-negative matrix factorization.

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Is it possible to encourage hope in non-advanced cancer patients? We must try

To our knowledge, few studies have been conducted so far with the intent to recognize the oncologist's central role in assessing needs and encouraging the hope of their patients, in daily clinical practices. The purpose of this study was to identify and explore the relationship among hope, physical and emotional symptoms, unmet needs and spirituality/religiosity, in patients on oncologic treatments to target early referrals to interventions of healing, while we care and/or cure . Oncologists should consider expanding theirrole and involve themselves more in the holistic aspects of cancer care. It is possible to help cancer patients to cope with feelings of isolation and hopelessness.

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PROSPECTIVE PHASE II TRIAL OF TRABECTEDIN IN BRCA MUTATED AND/OR BRCAness PHENOTYPE RECURRENT OVARIAN CANCER PATIENTS: THE MITO 15 TRIAL

Trabectedin is particularly active in heavily pretreated, BRCA mutated and/or BRCAness phenotype recurrent ovarian cancer patients. Toxicity profile appear in line with what reported in literature. Trabectedin may represent a valuable option in recurrent platinum sensitive ovarian cancer patients, not willing to receive or not able to receive further platinum-based treatments. In platinum resistant BRCA mutated and/or BRCAness phenotype patients the activity of the drug appears of particular interest and merits further evaluation.

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A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer

This is the first phase II trial in which adding oral leucovorin to S-1 (SL) significantly prolonged progression-free survival (PFS) as compared with S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer (PC). The significantly better PFS and disease control rate with SL than with S-1 monotherapy suggest that the antitumor activity of S-1 is enhanced by leucovorin in advanced PC.

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Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes

High-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers using the DNA and RNA of tumor shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification, and treatment monitoring, precluding the need for direct tumor sampling.

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Concurrent or sequential letrozole with adjuvant breast radiotherapy: Final results of the CO-HO-RT phase II randomized trial

Long-term follow-up of the COHORT phase II trial showed that letrozole can safely be delivered concomitantly with adjuvant breast radiotherapy. Translational sub-studies which aimed at identifying patients at risk of radiation-induced subcutaneous fibrosis (RISF) confirmed that high values of radiation-induced lymphocyte apoptosis were correlated with patients without RISF whatever concomitant or sequential adjuvant hormonotherapy.

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Adjuvant bisphosphonates in early breast cancer: Consensus guidance for clinical practice from a European Panel

A panel of European experts in breast cancer and bone health convened in a face to face meeting to discuss the available evidence and draft guidance on how bisphosphonates should be used, in addition to standard adjuvant therapy, in early breast cancer. Our manuscript provides a thorough review of the clinical randomised trial evidence evaluating the use of bisphosphonates to a) prevent cancer therapy induced bone loss and b) prevent metastases and improve cancer outcomes. We detail and summarise recommendations to aid clinicians on the use of adjuvant bisphosphonates in this context.

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The GILDA trial finds no survival benefit from intensified screening after primary resection of colorectal cancer: the PulMiCC trial tests the survival benefit of pulmonary metastasectomy for detected asymptomatic lung metastases

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Bone morphogenetic protein 4 regulates microRNA expression in breast cancer cell lines in diverse fashion

Bone morphogenetic protein 4 (BMP4) is a remarkably powerful inhibitor of breast cancer cell proliferation, but it is also able to induce breast cancer cell migration in certain cellular contexts. Previous data demonstrate that BMP4 controls the transcription of a variety of protein-coding genes, but not much is known about microRNAs (miRNA) regulated by BMP4. To address this question, miRNA expression profiles following BMP4 treatment were determined in one mammary epithelial and seven breast cancer cell lines using microarrays. While the analysis revealed an extensive variation in differentially expressed miRNA across cell lines, four miRNAs (miR-16-5p, miR-106b-5p, miR-23a-3p, and miR-23b-3p) were commonly induced in a subset of breast cancer cells upon BMP4 treatment. Inhibition of their expression demonstrated an increase in BT-474 cell number, indicating that they possess tumor suppressive properties. However, with the exception of miR-106b-5p, these effects were independent of BMP4 treatment. Scratch assay with miR-16-5p and miR-106b-5p inhibitors on BMP4-treated MDA-MB-231 cells resulted in enhanced cell migration, suggesting that these miRNAs are engaged in BMP4-induced motility. Taken together, we have for the first time characterized the BMP4-induced miRNA expression profiles in breast cancer cell lines, showing that induced miRNAs contribute to the fine-tuning of proliferation and migration phenotypes. © 2015 Wiley Periodicals, Inc.

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Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes

Gene fusions have been described in approximately one-third of soft tissue tumors (STT); of the 142 different fusions that have been reported, more than half are recurrent in the same histologic subtype. These gene fusions constitute pivotal driver mutations, and detailed studies of their cellular effects have provided important knowledge about pathogenetic mechanisms in STT. Furthermore, most fusions are strongly associated with a particular histotype, serving as ideal molecular diagnostic markers. In recent years, it has also become apparent that some chimeric proteins, directly or indirectly, constitute excellent treatment targets, making the detection of gene fusions in STT ever more important. Indeed, pharmacological treatment of STT displaying fusions that activate protein kinases, such as ALK and ROS1, or growth factors, such as PDGFB, is already in clinical use. However, the vast majority (52/78) of recurrent gene fusions create structurally altered and/or deregulated transcription factors, and a small but growing subset develops through rearranged chromatin regulators. The present review provides an overview of the spectrum of currently recognized gene fusions in STT, and, on the basis of the protein class involved, the mechanisms by which they exert their oncogenic effect are discussed. © 2015 Wiley Periodicals, Inc.

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Contribution of changes in demography and in the risk factors to the predicted pattern of cancer mortality among Spanish women by 2022

Publication date: February 2016
Source:Cancer Epidemiology, Volume 40
Author(s): Ramon Clèries, Maria Buxó, José M. Martínez, Josep A. Espinàs, Tadeusz Dyba, Josep M. Borràs
BackgroundChanges in the burden of cancer mortality are expected to be observed among Spanish women. We predict those changes, in Spain, for breast cancer (BC), colorectal cancer (CRC), lung cancer (LC) and pancreatic cancer (PC) from 2013 to 2022.MethodsBayesian age–period–cohort modeling was used to perform projections of the cancer burden in 2013–2022, extrapolating the trend of cancer mortality data from 1998 to 2012. We assessed the time trends of the crude rates (CRs) during 1998–2012, and compared the number of cancer deaths between the periods 2008–2012 and 2018–2022 to assess the contribution of demographic changes and changes in the risk factors for cancer.ResultsDuring 1998–2012, CRs of cancer decreased for BC (0.3% per year) and increased for LC (4.7%), PC (2%) and CRC (0.7%). During 2013–2022, CRs might level off for CRC, whereas the time trends for the remaining cancers might continue at a similar pace. During 2018–2022, BC could be surpassed by CRC as the most frequent cause of cancer mortality among Spanish women, whereas LC could be the most common cause of cancer mortality among women aged 50–69 years (N/year=1960 for BC versus N/year=1981 for LC). Comparing 2018–2022 and 1998–2012, changes in the risk factors for cancer could contribute 37.93% and 18.36% to the burden of LC and PC, respectively, and demographic shifts – mainly due to ageing (19.27%) – will drive the burden of CRC.ConclusionsDuring 2018–2022, demographic changes (ageing) and changes in risk factors could have a different impact on the lifetime risk of cancer among Spanish women.



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Socio-demographic disadvantage and distant summary stage of cancer at diagnosis—A population-based study in New South Wales

Publication date: February 2016
Source:Cancer Epidemiology, Volume 40
Author(s): Hanna E. Tervonen, Richard Walton, David Roder, Hui You, Stephen Morrell, Deborah Baker, Sanchia Aranda
BackgroundPast studies generally indicate that socio-demographic disadvantage is associated with lower cancer survival but evidence of an association with stage of cancer at diagnosis has been less consistent. This study examines the associations between distant summary stage and remoteness, socio-economic status and country of birth in New South Wales for invasive cancers overall and by cancer site.MethodsThe population-based New South Wales Central Cancer Registry was used to obtain data on all cases diagnosed in 1980–2009 (n=699,382). Logistic regression models were used to compute odds ratios (ORs) with 95% confidence intervals (CIs) for odds of distant summary stage at diagnosis.ResultsA higher likelihood of being diagnosed with distant cancer was detected for those living in the most socio-economically disadvantaged areas compared with the least disadvantaged areas (OR 1.27, 95% CI 1.24–1.30) and for those born in other English and non-English speaking countries compared with Australian-born (OR 1.10, 95% CI 1.07–1.12 and OR 1.12, 95% CI 1.10–1.14, respectively) after adjusting for age, sex, diagnostic period, remoteness, socio-economic status and country of birth. Cases living in inner (OR 0.90, 95% CI 0.88–0.91) and outer regional (OR 0.92, 95% CI 0.89–0.94) areas were less likely to be diagnosed with distant stage than cases living in major cities. Odds of distant stage increased over time for those living in socio-economically disadvantaged areas. In cancer site-specific analyses, living in socio-economically disadvantaged areas was generally a stronger predictor of distant stage than remoteness or country of birth.ConclusionOur results highlight the importance of lower socio-economic status as a predictor of distant stage at diagnosis. Socio-demographic disadvantage patterns varied for specific cancers, but in general, policy actions are recommended that emphasize earlier detection of cancers in people from lower socio-economic areas.



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History of gonorrhea and prostate cancer in a population-based case–control study in Mexico

Publication date: February 2016
Source:Cancer Epidemiology, Volume 40
Author(s): Ruth Argelia Vázquez-Salas, Luisa Torres-Sánchez, Lizbeth López-Carrillo, Martín Romero-Martínez, Hugo A. Manzanilla-García, Carlos Humberto Cruz-Ortíz, Fernando Mendoza-Peña, Miguel Ángel Jiménez-Ríos, Francisco Rodríguez-Covarrubias, Narciso Hernández-Toríz, Othón Moreno-Alcázar
We evaluated the association between a history of sexually transmitted diseases (STDs) and the risk for prostate cancer (PC) among Mexican males.MethodsPC incident cases (n=402) that were identified at six public hospitals in Mexico City were matched by age (±5 years) with 805 population controls with no history of PC. By face-to-face interview, we obtained information about sexual history, previous STDs, sociodemographic characteristics, and familial history of PC. An unconditional logistic regression model was used to estimate the risk for PC.ResultsA total of 16.6% of men reported having had at least one previous STD, and the most frequently reported STD was gonorrhea (10.5%). After adjusting by PC familial history, the history of STD was associated with a two-fold greater risk of PC: odds ratio (OR)=2.67; 95% confidence interval (95% CI=1.91–3.73). When each STD was evaluated separately, only gonorrhea was associated with a significant increase in PC risk (OR=3.04; 95% CI=1.99–4.64). These associations were similar when we stratified by low-risk PC (Gleason <7) and high-risk PC (Gleason ≥7).ConclusionThese results confirm that STDs, and particularly gonorrhea, may play an etiological role in PC among Mexican males, which is consistent with a previous report from a multiethnic cohort.



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Socioeconomic status, human papillomavirus, and overall survival in head and neck squamous cell carcinomas in Toronto, Canada

Publication date: February 2016
Source:Cancer Epidemiology, Volume 40
Author(s): K.P. Chu, S. Habbous, Q. Kuang, K. Boyd, M. Mirshams, F.-F. Liu, O. Espin-Garcia, W. Xu, D. Goldstein, J. Waldron, B. O'Sullivan, S.H. Huang, G. Liu
BackgroundDespite universal healthcare in some countries, lower socioeconomic status (SES) has been associated with worse cancer survival. The influence of SES on head and neck cancer (HNC) survival is of immense interest, since SES is associated with the risk and prognostic factors associated with this disease.Patients and methodsNewly diagnosed HNC patients from 2003 to 2010 (n=2124) were identified at Toronto's Princess Margaret Cancer Centre. Principal component analysis was used to calculate a composite score using neighbourhood-level SES variables obtained from the 2006 Canada Census. Associations of SES with overall survival were evaluated in HNC subsets and by p16 status (surrogate for human papillomavirus).ResultsSES score was higher for oral cavity (n=423) and p16-positive oropharyngeal cancer (OPC, n=404) patients compared with other disease sites. Lower SES was associated with worse survival [HR 1.14 (1.06–1.22), p=0.0002], larger tumor staging (p<0.001), current smoking (p<0.0001), heavier alcohol consumption (p<0.0001), and greater comorbidity (p<0.0002), but not with treatment regimen (p>0.20). After adjusting for age, sex, and stage, the lowest SES quintile was associated with the worst survival only for OPC patients [HR 1.66 (1.09–2.53), n=832], primarily in the p16-negative subset [HR 1.63 (0.96–2.79)]. The predictive ability of the prognostic models improved when smoking/alcohol was added to the model (c-index 0.71 vs. 0.69), but addition of SES did not (c-index 0.69).ConclusionSES was associated with survival, but this effect was lost after accounting for other factors (age, sex, TNM stage, smoking/alcohol). Lower SES was associated with greater smoking, alcohol consumption, comorbidity, and stage.



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Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma

Abstract

Programmed cell death protein-1 (PD-1) inhibitor may be therapeutic in patients with relapsed or refractory classical Hodgkin's lymphoma (cHL). This study examined the prognostic significance of PD-1 and two PD-1 ligands (PD-L1 and PD-L2) in uniformly treated cHL. Diagnostic tissues from 109 cHL patients treated with a doxorubicin, bleomycin, vinblastine, and dacarbazine regimen were evaluated retrospectively by immunohistochemical analysis of PD-L1, PD-L2, and PD-1 expressions. The median follow-up time was 4.91 years (range, 0.17–17.33 years). Thirteen patients (11 %) expressed PD-1 protein in the peritumoral microenvironment, which was associated with poor overall survival (OS) (P = 0.017). PD-L1 or PD-L2 expression was not associated with OS. There was no correlation between PD-L1 and PD-1 expression or between PD-L2 and PD-1 expression. Multivariate analysis identified PD-1 protein as an independent prognostic factor for OS (P = 0.019). Subgroup analysis according to the Ann Arbor stage of cHL showed that PD-1 protein expression had a prognostic value in limited-stage cHL (P = 0.048). PD-1 is an independent prognostic factor in cHL and may allow the identification of a subgroup of patients with limited-stage cHL who require more intensive therapy and who may benefit from anti-PD-1 agents.

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The tumor-to-breast volume ratio (TBR) predicts cancer-specific survival in breast cancer patients who underwent modified radical mastectomy

Abstract

Breast cancer is the most common cancer in women globally, and tumor size measured as the largest diameter of the tumor focus is currently used in tumor–lymph node–metastasis (TNM) staging for prognosis and treatment decisions. The present study utilized the tumor-to-breast volume ratio (TBR) to evaluate the relative tumor size and determined the prognostic impact of TBR on survival in patients with breast cancer. Two thousand twenty-five consecutive breast cancer patients who underwent modified radical mastectomy between January 2002 and December 2008 at Sun Yat-Sen University Cancer Center were enrolled in this retrospective study. Kaplan–Meier analysis was used to assess the prognostic effect of TBR on cancer-specific survival (CSS), and univariate log-rank test and multivariate Cox proportional hazards regression model were performed to identify independent prognostic factors. The optimal cutoff value of TBR was determined to be 1.70 %, and 1473 and 552 patients were categorized to low-TBR and high-TBR groups, respectively. In the whole patient cohort, CSS was significantly shorter in the high-TBR group (110.2 vs 128.5 months, P < 0.001). Univariate and multivariate analyses revealed that TBR was an independent prognostic factor of CSS in breast cancer patients (hazard ratio (HR) 1.489, 95 % CI 1.130–1.961, P = 0.005). High TBR was independently associated with poor prognosis in breast cancer patients. This variable may serve as a valuable parameter to predict the outcomes of breast cancer.

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Inhibition of CXCR4 and CXCR7 for reduction of cell proliferation and invasion in human endometrial cancer

Abstract

As one of the most common malignant cancers in female reproductive tract, endometrial cancer accounts for 20–30 % of the most frequent gynecological malignancy, which is originated from endometrial epithelial. The molecular mechanisms for the generation of endometrial cancer are up to now unclear, hindering the development of corresponding therapy. CXCR4 and CXCR7 were receptors of CXCL12 chemokine ligand, which could regulate critical procedures of neoplastic transformation, including proliferation, invasion, and apoptosis of the cells. The messenger RNA (mRNA) and protein expression levels of CXCR4 and CXCR7 in human endometrial adenocarcinoma cancer, as well as in Ishikawa and HEC-1-A cell line, were analyzed by using reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting. In order to explore the biological function of CXCR4 and CXCR7 in endometrial tumor, small interference RNAs of CXCR4 and CXCR7 fragments were designed, synthesized, and transfected into Ishikawa and HEC-1-A by using Lipofectamine2000. The influence of RNA interference (RNAi)-mediated silencing CXCR4 and CXCR7 on the cell proliferation was investigated under CCK-8. The invasion assay was performed transwell, and cell apoptosis was tested by FCM. Higher mRNA and protein expression levels of CXCR4 and CXCR7 were investigated in endometrial adenocarcinomas. The expression levels of CXCR4 and CXCR7 could be inhibited by RNA interference, reducing the cell proliferation, invasion in Ishikawa and HEC-1-A cells. In this study, we also observed that treated with CXCR4 and CXCR7 small interfering RNA (siRNA) arrested cells in S phase. CXCL12/CXCR4 and CXCL12/CXCR7 receptor ligand systems affect the invasion of endometrial carcinoma cell line into Ishikawa and HEC-1-A. CXCR4 and CXCR7 were silenced by RNAi, which can inhibit the invasion of Ishikawa and HEC-1-A cell lines. Hence, CXCR4 and CXCR7 are expected to become two target genes for the treatment of endometrial carcinoma.

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MicroRNA-9 promotes proliferation of leukemia cells in adult CD34-positive acute myeloid leukemia with normal karyotype by downregulation of Hes1

Abstract

Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies sustained by leukemic stem cells (LSCs) that can resist treatment. Previously, we found that low expression of Hes1 was a poor prognostic factor for AML. However, the activation status of Hes1 and its regulation in LSCs and leukemic progenitors (LPs) as well as normal hematopoietic stem cells (HSCs) in Hes1-low AML patients have not been elucidated. In this study, the expression of Hes1 in LSCs and LPs was analyzed in adult CD34⁺ Hes1-low AML with normal karyotype and the upstream microRNA (miRNA) regulators were screened. Our results showed that the level of either Hes1 or p21 was lower in LSCs or LPs than in HSCs whereas the level of miR-9 was highest in LPs and lowest in HSCs. An inverse correlation was observed in the expression of Hes1 and miR-9. Furthermore, we validated miR-9 as one of the regulators of Hes1 by reporter gene analysis. Knockdown of miR-9 by lentivirus infection suppressed the proliferation of AML cells by the induction of G0 arrest and apoptosis in vitro. Moreover, knockdown of miR-9 resulted in decreased circulating leukemic cell counts in peripheral blood and bone marrow, attenuated splenomegaly, and prolonged survival in a xenotransplant mouse model. Our results indicate that the miR-9 plays an important role in supporting AML cell growth and survival by downregulation of Hes1 and that miR-9 has potential as a therapeutic target for treating AML.

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Overexpression of interleukins IL-17 and IL-8 with poor prognosis in colorectal cancer induces metastasis

Abstract

Current evidences indicated that a group of soluble mediators called chemokines is involved in tumor growth and metastasis. The association of IL-8 with tumor cell migration was previously found, and its expression was related to angiogenesis, tumor progression, and metastasis in many kinds of carcinomas in human and animal models. Furthermore, it has been showed that IL-17 plays its role as either a proteome of tumor progression or antitumor indifferent cancer models. To investigate the messenger RNA (mRNA) expressions of IL-8 and IL-17 in patients with colorectal cancer (CRC) and non-tumor tissue, quantitative real-time PCR was used in the study. Our results showed that expression of IL-8 mRNA was significantly increased in tumor tissues (mean ± SD 3.84 ± 0.08) compared with adjacent normal mucosa (mean ± SD 1.17 ± 0.75, P = 0.001). Furthermore, a higher expression of IL-17 mRNA was found in tumor tissues (mean ± SD 2.73 ± 0.69) when compared with normal tissues (mean ± SD 1.06 ± 0.07, P = 0.001). Our findings indicated that advanced tumor-node-metastasis (TNM) stage (P = 0.024) and histological grade (poorly differentiated, P = 0.013) and distant metastasis (P = 0.001) were correlated with expression of IL-8. Moreover, high expression of IL-17 showed significant association with early stage CRC (TNM) (P = 0.038). In conclusion, the expression of IL-8 and IL-17 mRNAs was significantly increased in tumor tissues compared with adjacent normal tissues. We found that advanced TNM stage and histological grade and distant metastasis were correlated with expression of IL-8, while high expression of IL-17 showed significant association with early stage CRC (TNM) stage and overexpression of IL-8 may be associated with progression of CRC.

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Tumor-suppressive microRNA-34a inhibits breast cancer cell migration and invasion via targeting oncogenic TPD52

Abstract

The tumor protein D52 (TPD52) is an oncogene overexpressed in breast cancer. Although the oncogenic effects of TPD52 are well recognized, how its expression and the role in migration/invasion is still not clear. This study tried to explore the regulative role of microRNA-34a (miR-34a), a tumor suppressive miRNA, on TPD52 expression in breast cancer. The expression of miR-34a was found significantly decreased in breast cancer specimens with lymph node metastases and breast cancer cell lines. The clinicopathological characteristics analyzed showed that lower expression levels of miR-34a were associated with advanced clinical stages. Moreover, TPD52 was demonstrated as one of miR-34a direct targets in human breast cancer cells. miR-34a was further found significantly repress epithelial-mesenchymal transition (EMT) and inhibit breast cancer cell migration and invasion via TPD52. These findings indicate that miR-34a inhibits breast cancer progression and metastasis through targeting TPD52. Consequently, our data strongly suggested that oncogenic TPD52 pathway regulated by miR-34a might be useful to reveal new therapeutic targets for breast cancer.

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