Progressive delayed hemidystonia following clinically mild traumatic brain injury

A 16-year-old boy presented with progressive left hemidystonia over 3 years. The possibilities of symptomatic hemidystonia due to focal lesions such as infarct (vasculitis), tumours, tuberculoma, arteriovenous malformations or heredodegenerative disorders such as Wilson disease were considered. Imaging showed a peculiar scar involving right basifrontal region extending upto anterior, centromedian and dorsomedial nuclei of thalamus due to blowout fracture of roof of orbit. This scar was responsible for progressive left hemidystonia. On probing the history, it was revealed that patient had sustained a mild traumatic brain injury (mTBI) 3 years ago. Burke-Fahn-Marsden dystonia severity rating scale showed improvement from 19 to 6 after treatment with tablet trihexyphenidyl 16 mg and clonazepam 1 mg. A linear scar reaching upto thalamus due to blowout fracture of roof of orbit following clinically mTBI is unique. Delayed, progressive hemidystonia has been reported following severe head injury, however is less common following clinically mTBI.

http://ift.tt/2EauTuS

Endobronchial metastasis of mixed Mullerian tumour of the uterus

Endobronchial metastasis occurs in only 2%–5% of non-pulmonary cancers. Here we report on an 84-year-old woman who presented with breathlessness and light-headedness while on holiday in Australia, 2 years post-treatment for endometrial cancer. Initial CT pulmonary angiogram identified a soft tissue mass in the left hemithorax. A chest radiograph performed after repatriation was consistent with a large left pleural effusion, but bedside ultrasound showed a lobulated mass involving the left hemidiaphragm. A pleural procedure in the traditional 'triangle of safety' would have resulted in inadvertent puncture of the underlying mass. Serial imaging confirmed the mass was rapidly progressing, and metastatic malignant mixed Mullerian endometrial carcinoma was diagnosed by endobronchial biopsy. A tunnelled intrapleural catheter was inserted for symptom relief, and the patient deteriorated and died at home 2 weeks later. To our knowledge, this is the first case of endobronchial metastasis from malignant mixed Mullerian tumour of the uterus.

http://ift.tt/2pUbtar

Intramural oesophageal haematoma following traumatic neck injury

This case describes a previously well 90-year-old woman who presented with neck pain, swelling, dysphagia and hoarseness following a motor vehicle collision. Oesophageal oedema was visualised on CT of cervical spine and subsequent CT angiography highlighted an actively bleeding intramural oesophageal haematoma (IOH) extending from the cervical oesophagus to the carina. This rare phenomenon (IOH) has been described as a possible consequence of blunt trauma to the neck; however, we found no cases resulting from acceleration/deceleration injury. Although this was a potentially life-threatening injury, our patient made a full recovery with conservative management.

http://ift.tt/2EbWThC

Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects

Abstract

The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran's Q statistic and I² analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25–30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30–1.61; I² = 43.0%). Subjects with BMI ≥ 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24–1.63; I² = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger's regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30–1.58 vs. SOR 1.16, 95% CI 1.07–1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation.

http://ift.tt/2lh5sQn

Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects

Abstract

The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran's Q statistic and I² analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25–30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30–1.61; I² = 43.0%). Subjects with BMI ≥ 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24–1.63; I² = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger's regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30–1.58 vs. SOR 1.16, 95% CI 1.07–1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation.

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A retrospective examination of the US Food and Drug Administration’s clinical pharmacology reviews of oncology biologics for potential use of therapeutic drug monitoring

http://ift.tt/2DTkDaj

Appendicular and breast cancers in an old lady: a case report

Abstract

The presence of two or more malignant tumors of different histological entities in an individual is referred to as multiple primary malignant neoplasms (MPMN). These are becoming more frequently encountered and reported in clinical practice nowadays. Majority of MPMN are diagnosed in elderly, where senility might alter the management plan. Despite the increased reporting of MPMN in the literature, only a few elaborated on the management of such cases. Also, the combination of synchronous primary appendicular and breast cancers—to our knowledge—has never been reported. Here we present the first report of an appendicular adenocarcinoma synchronously presenting along with invasive ductal carcinoma of the breast. We highlight the diagnostic essentials and the multidisciplinary management approach including surgical excision and adjuvant therapy.

http://ift.tt/2E7olNE

Endoscopic management of duodeno-ileal fistula secondary to diffuse B-cell lymphoma

Abstract

Lymphoma arising in the gastrointestinal tract is relatively common and can affect multiple sites. The development of a gastrointestinal fistula secondary to lymphoma is very rare and has not previously been reported between the duodenum and ileum. This is the first reported care where a fistula secondary to lymphoma has been treated by an endoscopic covered duodenal stent occluding the defect rather than surgical intervention. This strategy permitted early commencement of curative intent chemotherapy which led to tumour shrinkage and fistula closure.

http://ift.tt/2pTJs2U

Acute cholecystitis in a parastomal hernia causing a small bowel obstruction

Abstract

A parastomal hernia is the abnormal protrusion of intra-abdominal tissue and organs through a defect in the abdominal wall around an ostomy. Commonly, they involve intra-abdominal fat, omentum or bowel. However, there are rare cases that involve other organs. We present the case of an 89-year-old gentleman with a gallbladder in his parastomal hernia. Due to his acute cholecystitis, the distended gallbladder compressed adjacent bowel loops in the parastomal hernia, resulting in a mechanical bowel obstruction. The patient was treated with antibiotics and a nasogastric tube. As his cholecystitis resolved his ostomy function returned.

http://ift.tt/2pW4bDs

Identification of genes highly downregulated in pancreatic cancer through a meta-analysis of microarray datasets: implications for discovery of novel tumor-suppressor genes and therapeutic targets

Abstract

Purpose

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a 5-year survival rate of about 7%. Recent failures of targeted therapies inhibiting kinase activity in clinical trials have highlighted the need for new approaches towards combating this deadly disease.

Methods

In this study, we have identified genes that are significantly downregulated in PC, through a meta-analysis of large number of microarray datasets. We have used qRT-PCR to confirm the downregulation of selected genes in a panel of PC cell lines.

Results

This study has yielded several novel candidate tumor-suppressor genes (TSGs) including GNMT, CEL, PLA2G1B and SERPINI2. We highlight the role of GNMT, a methyl transferase associated with the methylation potential of the cell, and CEL, a lipase, as potential therapeutic targets. We have uncovered genetic links to risk factors associated with PC such as smoking and obesity. Genes important for patient survival and prognosis are also discussed, and we confirm the dysregulation of metabolic pathways previously observed in PC.

Conclusions

While many of the genes downregulated in our dataset are associated with protein products normally produced by the pancreas for excretion, we have uncovered some genes whose downregulation appear to play a more causal role in PC. These genes will assist in providing a better understanding of the disease etiology of PC, and in the search for new therapeutic targets and biomarkers.

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Identification of genes highly downregulated in pancreatic cancer through a meta-analysis of microarray datasets: implications for discovery of novel tumor-suppressor genes and therapeutic targets

Abstract

Purpose

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a 5-year survival rate of about 7%. Recent failures of targeted therapies inhibiting kinase activity in clinical trials have highlighted the need for new approaches towards combating this deadly disease.

Methods

In this study, we have identified genes that are significantly downregulated in PC, through a meta-analysis of large number of microarray datasets. We have used qRT-PCR to confirm the downregulation of selected genes in a panel of PC cell lines.

Results

This study has yielded several novel candidate tumor-suppressor genes (TSGs) including GNMT, CEL, PLA2G1B and SERPINI2. We highlight the role of GNMT, a methyl transferase associated with the methylation potential of the cell, and CEL, a lipase, as potential therapeutic targets. We have uncovered genetic links to risk factors associated with PC such as smoking and obesity. Genes important for patient survival and prognosis are also discussed, and we confirm the dysregulation of metabolic pathways previously observed in PC.

Conclusions

While many of the genes downregulated in our dataset are associated with protein products normally produced by the pancreas for excretion, we have uncovered some genes whose downregulation appear to play a more causal role in PC. These genes will assist in providing a better understanding of the disease etiology of PC, and in the search for new therapeutic targets and biomarkers.

http://ift.tt/2ChKafm

Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation

Abstract

Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden.

http://ift.tt/2Ea2PI9

De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype

Abstract

Breast cancer molecular subtypes, categorized jointly by hormone receptors (HR) and human epidermal growth factor-2 (HER2), are utilized to guide systemic therapy. We hypothesized distinct patterns of de novo metastasis and overall survival by molecular subtype using a retrospective cohort of 399,772 women in the National Cancer Database diagnosed with first primary invasive breast cancer between 2010 and 2014, of whom 13,924 were diagnosed with de novo metastasis from 2010 to 2013 and had follow up data. The relationship of molecular subtype with patient and tumor characteristics, including site of de novo metastasis, were examined using Chi-squared tests. Kaplan–Meier and Cox proportional hazards analyses were used to examine overall survival by molecular subtype. Bone was the most frequent de novo metastatic site for all molecular subtypes. Compared to HR+/HER2−, patients with HR−/HER2+ experienced 4.5, 3.0, and 6.0 times the de novo brain, lung, and liver metastasis respectively. In survival analyses of women diagnosed with de novo metastasis, the mortality risk relative to HR+/HER2− was twice as high for triple-negative (hazard ratio = 2.02, 95% CI 1.89–2.16) and modestly lower for HR+/HER2+ (hazard ratio = 0.83, 95% CI 0.78–0.88). The median survival difference between metastatic patients with and without chemotherapy was 28.6 months in HR+/HER2+ and 28.2 months in HR−/HER2+, but only 10.9 months in triple-negative and 5.2 months in HR+/HER2−. In conclusion, despite unfavorable patterns of de novo metastasis, HER2+ breast cancers had relatively better survival in recent years, probably due to treatment differences. Utilizing molecular subtype and site of de novo metastasis may predict prognosis and guide treatment.

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Proposal for Reclassification of N Staging Systems in Penile Cancer Patients: Based on Number of Positive Lymph Nodes

Abstract

In the present study, we aim to compare the rationality of proposed N classification based on the number of metastatic lymph nodes (LNs) with the current one. A total of 509 penile cancer patients at our institute were analyzed. Univariable and multivariable statistical analyses were used to assess cancer-specific survival (CSS) in two staging systems. Harrell's concordance index was applied to evaluate predictive accuracy of the current and proposed N classification in predicting CSS. We propose a new classification: pN1 (metastasis in 1-2 regional LNs), pN2 (metastasis in 3 regional LNs, or three or fewer regional lymph nodes with extranodal extension), and pN3 (metastasis in 4 or more regional LNs). According to the current and proposed N classification, the five-year CSS of penile cancer patients with pN1, pN2 and pN3 was 85.8%, 39.0%, and 19.7%; and with pN1, pN2 and pN3 was 79.8%, 39.3% and 15.3%, which almost all showed significant difference (P < 0.001, P = 0.259) (P < 0.001, P < 0.001). Multivariable predictive accuracy of the proposed and current N staging was 76.48% and 70.92% (5.56% gain; P < 0.001). With a multivariable model of clinical features, both current (hazard ratio [HR], 7.761, 10.612; P < 0.001, P < 0.001) and proposed N stages (HR, 3.792, 3.971; P < 0.001, P < 0.001) exhibited independent effects on survival. The proposed N classification is superior to the current one, which is simpler and provides more accurate prognosis.

This article is protected by copyright. All rights reserved.

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via IFTTT

De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype

Abstract

Breast cancer molecular subtypes, categorized jointly by hormone receptors (HR) and human epidermal growth factor-2 (HER2), are utilized to guide systemic therapy. We hypothesized distinct patterns of de novo metastasis and overall survival by molecular subtype using a retrospective cohort of 399,772 women in the National Cancer Database diagnosed with first primary invasive breast cancer between 2010 and 2014, of whom 13,924 were diagnosed with de novo metastasis from 2010 to 2013 and had follow up data. The relationship of molecular subtype with patient and tumor characteristics, including site of de novo metastasis, were examined using Chi-squared tests. Kaplan–Meier and Cox proportional hazards analyses were used to examine overall survival by molecular subtype. Bone was the most frequent de novo metastatic site for all molecular subtypes. Compared to HR+/HER2−, patients with HR−/HER2+ experienced 4.5, 3.0, and 6.0 times the de novo brain, lung, and liver metastasis respectively. In survival analyses of women diagnosed with de novo metastasis, the mortality risk relative to HR+/HER2− was twice as high for triple-negative (hazard ratio = 2.02, 95% CI 1.89–2.16) and modestly lower for HR+/HER2+ (hazard ratio = 0.83, 95% CI 0.78–0.88). The median survival difference between metastatic patients with and without chemotherapy was 28.6 months in HR+/HER2+ and 28.2 months in HR−/HER2+, but only 10.9 months in triple-negative and 5.2 months in HR+/HER2−. In conclusion, despite unfavorable patterns of de novo metastasis, HER2+ breast cancers had relatively better survival in recent years, probably due to treatment differences. Utilizing molecular subtype and site of de novo metastasis may predict prognosis and guide treatment.

http://ift.tt/2BQHX7e

The 2-anilino-4-amino-5-aroylthiazole-type compound AS7128 inhibits lung cancer growth through decreased iASPP and p53 interaction

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents become urgent demands for lung cancer treatment. In this study, compound AS7128 was selected from a two-million entry chemical library screening and identified as a candidate drug that against non-small cell lung cancer (NSCLC) in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and thus increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs via disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insights for using iASPP as a therapeutic target for NSCLC treatment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zKnAH5

Exosomes Serve as Nano-particles to Suppress Tumor Growth and Angiogenesis in Gastric Cancer by Delivering HGF siRNA

Abstract

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNAs. HGF is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically down-regulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNAs.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C6Vn3g

C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma

Abstract

In hepatocellular carcinoma (HCC) microenvironment, chemokine receptors have a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis still remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion, and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN up-regulates the expression of CCR1 via activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zKSHlB

Implementation of “Clinical Sequencing” in Cancer Genome Medicine in Japan

Abstract

In oncology, actionable mutations (alterations) in cancer-associated genes are critical in terms of the selection of therapeutic approaches. Next-generation sequencing (NGS) of tumor sample DNA (i.e., clinical sequencing) can guide clinical management by providing diagnostic or prognostic data, and facilitating the identification of potential treatment regimens, such as molecular-targeted and immune checkpoint blockade therapies. In the U.S., a variety of tumor-profiling multiplex gene panels have been developed and implemented for this purpose. In Japan, several academic institutions have now performed detailed investigations of the feasibility and value of clinical sequencing, and cancer societies have issued consensus clinical practice guidelines for NGS-based gene panel tests. These efforts will facilitate the implementation of cancer genome medicine in Japan.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C6HEJr

Cancer Immunotherapy Targeted Glypican-3 or Neoantigens

Abstract

Immune checkpoint inhibitors have ushered a new era in cancer therapy, although other therapies or combinations thereof are still needed for the many patients for whom these drugs are ineffective. In this light, we have identified in glypican-3 an HLA-24, HLA-A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials demonstrating that glypican-3 peptide vaccines induce specific cytotoxic T lymphocytes in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, UMIN000006357,). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zLet90

Proposal for Reclassification of N Staging Systems in Penile Cancer Patients: Based on Number of Positive Lymph Nodes

Abstract

In the present study, we aim to compare the rationality of proposed N classification based on the number of metastatic lymph nodes (LNs) with the current one. A total of 509 penile cancer patients at our institute were analyzed. Univariable and multivariable statistical analyses were used to assess cancer-specific survival (CSS) in two staging systems. Harrell's concordance index was applied to evaluate predictive accuracy of the current and proposed N classification in predicting CSS. We propose a new classification: pN1 (metastasis in 1-2 regional LNs), pN2 (metastasis in 3 regional LNs, or three or fewer regional lymph nodes with extranodal extension), and pN3 (metastasis in 4 or more regional LNs). According to the current and proposed N classification, the five-year CSS of penile cancer patients with pN1, pN2 and pN3 was 85.8%, 39.0%, and 19.7%; and with pN1, pN2 and pN3 was 79.8%, 39.3% and 15.3%, which almost all showed significant difference (P < 0.001, P = 0.259) (P < 0.001, P < 0.001). Multivariable predictive accuracy of the proposed and current N staging was 76.48% and 70.92% (5.56% gain; P < 0.001). With a multivariable model of clinical features, both current (hazard ratio [HR], 7.761, 10.612; P < 0.001, P < 0.001) and proposed N stages (HR, 3.792, 3.971; P < 0.001, P < 0.001) exhibited independent effects on survival. The proposed N classification is superior to the current one, which is simpler and provides more accurate prognosis.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C7pt6L

Regulatory mechanisms of HIF-1 activity: Two decades of knowledge

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors, and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of the oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has revealed that HIF-1α may become stable and active, even under normoxic conditions; e.g. when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of the oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zJqAmS

The new metformin derivative HL156A prevents oral cancer progression by inhibiting the IGF/Akt/mTOR pathways

Summary

Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of this study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose dependent manner. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced ROS levels and apoptotic cells with caspase-3 and -9 activation. HL156A inhibited the expression and activation of IGF-1 and its downstream proteins, AKT, mTOR, and ERK1/2. In addition, HL156A activated AMPK-NF-κB signaling of FaDu and YD-10B cells. A xenograft mouse model further revealed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by downregulated p-IGF-1, p-mTOR, PCNA and promoted p-AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C9cDVu

Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: a phase I study

Summary

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and PK of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/week for 25 weeks; or level 2: 400 mg/week in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m² on day 1) and fluorouracil (1000 mg/m² on days 1 to 4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was administered concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in two patients (grade 3 infection and renal disorder). The maximum tolerated dose was estimated to be at least 200 mg/week and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zKfD4q

The 2-anilino-4-amino-5-aroylthiazole-type compound AS7128 inhibits lung cancer growth through decreased iASPP and p53 interaction

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents become urgent demands for lung cancer treatment. In this study, compound AS7128 was selected from a two-million entry chemical library screening and identified as a candidate drug that against non-small cell lung cancer (NSCLC) in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and thus increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs via disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insights for using iASPP as a therapeutic target for NSCLC treatment.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2zKnAH5
via IFTTT

Exosomes Serve as Nano-particles to Suppress Tumor Growth and Angiogenesis in Gastric Cancer by Delivering HGF siRNA

Abstract

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNAs. HGF is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically down-regulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNAs.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2C6Vn3g
via IFTTT

C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma

Abstract

In hepatocellular carcinoma (HCC) microenvironment, chemokine receptors have a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis still remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion, and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN up-regulates the expression of CCR1 via activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.

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Implementation of “Clinical Sequencing” in Cancer Genome Medicine in Japan

Abstract

In oncology, actionable mutations (alterations) in cancer-associated genes are critical in terms of the selection of therapeutic approaches. Next-generation sequencing (NGS) of tumor sample DNA (i.e., clinical sequencing) can guide clinical management by providing diagnostic or prognostic data, and facilitating the identification of potential treatment regimens, such as molecular-targeted and immune checkpoint blockade therapies. In the U.S., a variety of tumor-profiling multiplex gene panels have been developed and implemented for this purpose. In Japan, several academic institutions have now performed detailed investigations of the feasibility and value of clinical sequencing, and cancer societies have issued consensus clinical practice guidelines for NGS-based gene panel tests. These efforts will facilitate the implementation of cancer genome medicine in Japan.

This article is protected by copyright. All rights reserved.

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Cancer Immunotherapy Targeted Glypican-3 or Neoantigens

Abstract

Immune checkpoint inhibitors have ushered a new era in cancer therapy, although other therapies or combinations thereof are still needed for the many patients for whom these drugs are ineffective. In this light, we have identified in glypican-3 an HLA-24, HLA-A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials demonstrating that glypican-3 peptide vaccines induce specific cytotoxic T lymphocytes in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, UMIN000006357,). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy.

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Regulatory mechanisms of HIF-1 activity: Two decades of knowledge

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors, and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of the oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has revealed that HIF-1α may become stable and active, even under normoxic conditions; e.g. when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of the oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

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The new metformin derivative HL156A prevents oral cancer progression by inhibiting the IGF/Akt/mTOR pathways

Summary

Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of this study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose dependent manner. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced ROS levels and apoptotic cells with caspase-3 and -9 activation. HL156A inhibited the expression and activation of IGF-1 and its downstream proteins, AKT, mTOR, and ERK1/2. In addition, HL156A activated AMPK-NF-κB signaling of FaDu and YD-10B cells. A xenograft mouse model further revealed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by downregulated p-IGF-1, p-mTOR, PCNA and promoted p-AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer.

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Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: a phase I study

Summary

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and PK of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/week for 25 weeks; or level 2: 400 mg/week in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m² on day 1) and fluorouracil (1000 mg/m² on days 1 to 4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was administered concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in two patients (grade 3 infection and renal disorder). The maximum tolerated dose was estimated to be at least 200 mg/week and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

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Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein–Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma

According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients wi...

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Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein–Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma

According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients wi...

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METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification

Publication date: Available online 28 December 2017
Source:Cell Stem Cell
Author(s): Hengyou Weng, Huilin Huang, Huizhe Wu, Xi Qin, Boxuan Simen Zhao, Lei Dong, Hailing Shi, Jennifer Skibbe, Chao Shen, Chao Hu, Yue Sheng, Yungui Wang, Mark Wunderlich, Bin Zhang, Louis C. Dore, Rui Su, Xiaolan Deng, Kyle Ferchen, Chenying Li, Miao Sun, Zhike Lu, Xi Jiang, Guido Marcucci, James C. Mulloy, Jianhua Yang, Zhijian Qian, Minjie Wei, Chuan He, Jianjun Chen
N⁶-methyladenosine (m⁶A), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here, we report that METTL14, a key component of the m⁶A methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21) and is downregulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells and inhibits AML cell survival/proliferation. METTL14 is required for development and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through m⁶A modification, while the protein itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis and highlight the critical roles of METTL14 and m⁶A modification in normal and malignant hematopoiesis.

Graphical abstract

Teaser

The role of N⁶-methyladenosine (m⁶A) modification in normal and malignant hematopoiesis remains elusive. Weng et al. report the essential role of METTL14, a key component of the m⁶A methyltransferase complex, in self-renewal and differentiation of hematopoietic/leukemic stem cells and reveal the SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis.


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Reconstruction of the Human Colon Epithelium In Vivo

Publication date: Available online 28 December 2017
Source:Cell Stem Cell
Author(s): Shinya Sugimoto, Yuki Ohta, Masayuki Fujii, Mami Matano, Mariko Shimokawa, Kosaku Nanki, Shoichi Date, Shingo Nishikori, Yoshihiro Nakazato, Tetsuya Nakamura, Takanori Kanai, Toshiro Sato
Genetic lineage tracing has revealed that Lgr5⁺ murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium. Xenografted organoids formed crypt structures distinctively different from surrounding mouse crypts, reflecting their human origin. Lineage tracing using CRISPR-Cas9 to engineer an LGR5-CreER knockin allele demonstrated self-renewal and multipotency of LGR5⁺ CoSCs. In contrast to the rapidly cycling properties of mouse Lgr5⁺ CoSCs, human LGR5⁺ CoSCs were slow-cycling in vivo. This organoid-based orthotopic xenograft model enables investigation of the functional behaviors of human CoSCs in vivo, with potential therapeutic applications in regenerative medicine.

Graphical abstract

Teaser

Sugimoto et al. established an orthotopic xenotransplantation system for human normal colon organoids. Using LGR5-CreER knockin organoids for genetic lineage tracing, they demonstrated the self-renewal and multipotency of LGR5⁺ colon stem cells in mouse colon. Interestingly, human LGR5⁺ colon stem cells showed slower cycling than those of mice in vivo.


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COX-2/sEH Dual Inhibitor PTUPB Potentiates the Anti-tumor Efficacy of Cisplatin

Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in anti-tumor activity, and has organ protective effects. The goal of this study was to determine the anti-tumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single agent treatment as assessed by body weight, histochemical staining of major organs, blood counts and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared to controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the anti-tumor activity of cisplatin-based treatment without increasing toxicity in vivo, and has potential for further development as a combination chemotherapy partner.

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COX-2/sEH Dual Inhibitor PTUPB Potentiates the Anti-tumor Efficacy of Cisplatin

Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in anti-tumor activity, and has organ protective effects. The goal of this study was to determine the anti-tumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single agent treatment as assessed by body weight, histochemical staining of major organs, blood counts and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared to controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the anti-tumor activity of cisplatin-based treatment without increasing toxicity in vivo, and has potential for further development as a combination chemotherapy partner.

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Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein–Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma

Abstract

Background

According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients with N1 NPC are relatively under-researched, and the metastasis risk of this group is not well-stratified. This study aimed to evaluate the prognostic values of gross tumor volume of metastatic regional lymph node (GTVnd) and pretreatment serum copy number of Epstein–Barr virus (EBV) DNA in predicting distant metastasis of patients with N1 NPC, and to develop an integrated prognostic model that incorporates GTVnd and EBV DNA copy number for this group of patients.

Methods

The medical records of 787 newly diagnosed patients with nonmetastatic, histologically proven N1 NPC who were treated at Sun Yat-sen University Cancer Center between November 2009 and February 2012 were analyzed. Computed tomography-derived GTVnd was measured using the summation-of-area technique. Blood samples were collected before treatment to quantify plasma EBV DNA. The receiver operating characteristic (ROC) curve analysis was used to evaluate the cut-off point for GTVnd, and the area under the ROC curve was used to assess the predicted validity of GTVnd. The survival rates were assessed by Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model.

Results

The 5-year distant metastasis-free survival (DMFS) rates for patients with GTVnd > 18.9 vs. ≤ 18.9 mL were 82.2% vs. 93.2% (P < 0.001), and for patients with EBV DNA copy number > 4000 vs. ≤ 4000 copies/mL were 83.5% vs. 93.9% (P < 0.001). After adjusting for GTVnd, EBV DNA copy number, and T category in the Cox regression model, both GTVnd > 18.9 mL and EBV DNA copy number > 4000 copies/mL were significantly associated with poor prognosis (both P < 0.05). According to combination of GTVnd and EBV DNA copy number, all patients were divided into low-, moderate-, and high-risk groups, with the 5-year DMFS rates of 96.1, 87.4, and 73.8%, respectively (P < 0.001). Multivariate analysis confirmed the prognostic value of this model for distant metastatic risk stratification (hazard ratio [HR], 4.17; 95% confidence interval [CI] 2.34–7.59; P < 0.001).

Conclusions

GTVnd and serum EBV DNA copy number are independent prognostic factors for predicting distant metastasis in NPC patients with N1 disease. The prognostic model incorporating GTVnd and EBV DNA copy number may improve metastatic risk stratification for this group of patients.

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Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein–Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma

Abstract

Background

According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients with N1 NPC are relatively under-researched, and the metastasis risk of this group is not well-stratified. This study aimed to evaluate the prognostic values of gross tumor volume of metastatic regional lymph node (GTVnd) and pretreatment serum copy number of Epstein–Barr virus (EBV) DNA in predicting distant metastasis of patients with N1 NPC, and to develop an integrated prognostic model that incorporates GTVnd and EBV DNA copy number for this group of patients.

Methods

The medical records of 787 newly diagnosed patients with nonmetastatic, histologically proven N1 NPC who were treated at Sun Yat-sen University Cancer Center between November 2009 and February 2012 were analyzed. Computed tomography-derived GTVnd was measured using the summation-of-area technique. Blood samples were collected before treatment to quantify plasma EBV DNA. The receiver operating characteristic (ROC) curve analysis was used to evaluate the cut-off point for GTVnd, and the area under the ROC curve was used to assess the predicted validity of GTVnd. The survival rates were assessed by Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model.

Results

The 5-year distant metastasis-free survival (DMFS) rates for patients with GTVnd > 18.9 vs. ≤ 18.9 mL were 82.2% vs. 93.2% (P < 0.001), and for patients with EBV DNA copy number > 4000 vs. ≤ 4000 copies/mL were 83.5% vs. 93.9% (P < 0.001). After adjusting for GTVnd, EBV DNA copy number, and T category in the Cox regression model, both GTVnd > 18.9 mL and EBV DNA copy number > 4000 copies/mL were significantly associated with poor prognosis (both P < 0.05). According to combination of GTVnd and EBV DNA copy number, all patients were divided into low-, moderate-, and high-risk groups, with the 5-year DMFS rates of 96.1, 87.4, and 73.8%, respectively (P < 0.001). Multivariate analysis confirmed the prognostic value of this model for distant metastatic risk stratification (hazard ratio [HR], 4.17; 95% confidence interval [CI] 2.34–7.59; P < 0.001).

Conclusions

GTVnd and serum EBV DNA copy number are independent prognostic factors for predicting distant metastasis in NPC patients with N1 disease. The prognostic model incorporating GTVnd and EBV DNA copy number may improve metastatic risk stratification for this group of patients.

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Low-virulent Babesia venatorum infection masquerading as hemophagocytic syndrome

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Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Abstract

Background

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS).

Methods

Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation.

Results

OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n ≤ 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n ≤ 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n ≤ 3).

Conclusions

In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n ≤ 3).

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Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Abstract

Background

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS).

Methods

Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation.

Results

OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n ≤ 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n ≤ 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n ≤ 3).

Conclusions

In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n ≤ 3).

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The effect of selective internal radiation therapy with yttrium-90 resin microspheres on lung carbon monoxide diffusion capacity

Abstract

Background

Selective internal radiation therapy (SIRT) with embolization of branches of the hepatic artery is a valuable therapeutic tool for patients with hepatic malignancies; however, it is also associated with lung injury risk due to shunting. Diffusion capacity of the lungs for carbon monoxide (DLCO) is a clinically significant lung function test, and worsening in DLCO is suggested to reflect a limited gas exchange reserve caused by the potential toxicity of chemoradiotherapy or it may be a marker of related lung injury. This study aimed to examine the changes in DLCO during SIRT with resin microspheres in newly treated and retreated patients. Forty consecutive patients who received SIRT for a variety of malignant conditions were included. All subjects were treated with Yttrium-90 labelled resin microspheres. DLCO tests were performed after the procedures. In addition, patients were specifically followed for radiation pneumonitis.

Results

The mean DLCO did not significantly change after the first (82.8 ± 19.4 vs. 83.1 ± 20.9, p = 0.921) and the second treatments (87.4 ± 19.7 vs. 88.6 ± 23.2, p = 0.256). Proportion of patients with impaired DLCO at baseline was not altered significantly after the first (37.5 vs. 45.0%, p = 0.581) and the second treatments (27.3 vs. 27.3%, p = 1.000). Also, percent change in DLCO values did not correlate with radiation dose, lung shunt fraction, or lung exposure dose (p > 0.05 for all comparisons). None of the patients developed radiation pneumonitis.

Conclusions

Our results suggest that no significant change in DLCO in association with SIRT occurs, both after the first or the second treatment sessions. Further larger studies possibly with different protocols are warranted to better delineate DLCO changes after SIRT in a larger spectrum of patients.

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The effect of selective internal radiation therapy with yttrium-90 resin microspheres on lung carbon monoxide diffusion capacity

Abstract

Background

Selective internal radiation therapy (SIRT) with embolization of branches of the hepatic artery is a valuable therapeutic tool for patients with hepatic malignancies; however, it is also associated with lung injury risk due to shunting. Diffusion capacity of the lungs for carbon monoxide (DLCO) is a clinically significant lung function test, and worsening in DLCO is suggested to reflect a limited gas exchange reserve caused by the potential toxicity of chemoradiotherapy or it may be a marker of related lung injury. This study aimed to examine the changes in DLCO during SIRT with resin microspheres in newly treated and retreated patients. Forty consecutive patients who received SIRT for a variety of malignant conditions were included. All subjects were treated with Yttrium-90 labelled resin microspheres. DLCO tests were performed after the procedures. In addition, patients were specifically followed for radiation pneumonitis.

Results

The mean DLCO did not significantly change after the first (82.8 ± 19.4 vs. 83.1 ± 20.9, p = 0.921) and the second treatments (87.4 ± 19.7 vs. 88.6 ± 23.2, p = 0.256). Proportion of patients with impaired DLCO at baseline was not altered significantly after the first (37.5 vs. 45.0%, p = 0.581) and the second treatments (27.3 vs. 27.3%, p = 1.000). Also, percent change in DLCO values did not correlate with radiation dose, lung shunt fraction, or lung exposure dose (p > 0.05 for all comparisons). None of the patients developed radiation pneumonitis.

Conclusions

Our results suggest that no significant change in DLCO in association with SIRT occurs, both after the first or the second treatment sessions. Further larger studies possibly with different protocols are warranted to better delineate DLCO changes after SIRT in a larger spectrum of patients.

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Preface

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Preface

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High CEA levels in a case of resected colorectal cancer: delayed diagnosis of metachronous medullary thyroid cancer

Abstract

Background

Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers, and its value in the surveillance of post-operative colorectal cancer is well established. Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been clinically used in colorectal cancer imaging including preoperative staging, evaluation of therapeutic response, detection of disease recurrence, and investigation of unexplained rising tumor markers.

Case presentation

We report a case of resected colorectal cancer presented with rising CEA levels in 5 years, and FDG-PET revealed no definitive evidence of recurrence except abnormal focal FDG uptake in the right thyroid lobe. However, fine needle aspiration cytology (FNAC) of the thyroid nodule showed negative for malignancy. Progressively rising CEA levels were noted over the following 5 years, but serial follow-up examinations did not find evidence of recurrence. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed subsequently and again showed focal FDG uptake in the right thyroid lobe. This time, FNAC revealed positive for malignancy, in favor of medullary thyroid carcinoma (MTC). The patient underwent total thyroidectomy and modified radical neck dissection, and MTC with cervical nodal metastasis (pT3N1) was diagnosed. He had cervical lymph nodes recurrence 2 years later, which was resected.

Conclusions

This case reminded us that FDG-PET/CT may detect occult tumors resulting in CEA elevation other than colorectal cancer. Moreover, FNA has a higher false negative rate in detecting MTC than other forms of thyroid cancer. Repeat FNAC for the initial negative cytology result and measure of serum calcitonin for the early MTC detection could be more helpful to avoid the delay in MTC diagnosis.

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Postoperative extracranial metastasis from glioblastoma: a case report and review of the literature

Abstract

Background

Glioblastoma is the most common primary malignant brain tumor. Extraneural metastases are rarely reported in the literature.

Case presentation

We report a case of a 38-year-old patient who was diagnosed with glioblastoma in 2015. Four months after surgery, local relapse was found and the patient received a second surgery. After another 4 months, we found a hard mass in the right posterior neck when she admitted to our department for fourth cycle of adjuvant chemotherapy. Immunohistochemical investigation supported the diagnosis of glioblastoma metastases to the neck after resection of the right neck mass. A few days later, spinal vertebral magnetic resonance imaging (MRI) confirmed multiple metastases in the thoracic, lumbar, sacral, and bilateral iliac bones.

Conclusions

Glioblastoma is the most common primary malignant brain tumor. Whole tumor resection and early radiotherapy and chemotherapy can delay recurrence and prolong survival. Extracranial metastases are extremely rare. We report this case with the aim of bringing attention to extracranial metastasis of brain glioma.

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High CEA levels in a case of resected colorectal cancer: delayed diagnosis of metachronous medullary thyroid cancer

Abstract

Background

Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers, and its value in the surveillance of post-operative colorectal cancer is well established. Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been clinically used in colorectal cancer imaging including preoperative staging, evaluation of therapeutic response, detection of disease recurrence, and investigation of unexplained rising tumor markers.

Case presentation

We report a case of resected colorectal cancer presented with rising CEA levels in 5 years, and FDG-PET revealed no definitive evidence of recurrence except abnormal focal FDG uptake in the right thyroid lobe. However, fine needle aspiration cytology (FNAC) of the thyroid nodule showed negative for malignancy. Progressively rising CEA levels were noted over the following 5 years, but serial follow-up examinations did not find evidence of recurrence. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed subsequently and again showed focal FDG uptake in the right thyroid lobe. This time, FNAC revealed positive for malignancy, in favor of medullary thyroid carcinoma (MTC). The patient underwent total thyroidectomy and modified radical neck dissection, and MTC with cervical nodal metastasis (pT3N1) was diagnosed. He had cervical lymph nodes recurrence 2 years later, which was resected.

Conclusions

This case reminded us that FDG-PET/CT may detect occult tumors resulting in CEA elevation other than colorectal cancer. Moreover, FNA has a higher false negative rate in detecting MTC than other forms of thyroid cancer. Repeat FNAC for the initial negative cytology result and measure of serum calcitonin for the early MTC detection could be more helpful to avoid the delay in MTC diagnosis.

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Postoperative extracranial metastasis from glioblastoma: a case report and review of the literature

Abstract

Background

Glioblastoma is the most common primary malignant brain tumor. Extraneural metastases are rarely reported in the literature.

Case presentation

We report a case of a 38-year-old patient who was diagnosed with glioblastoma in 2015. Four months after surgery, local relapse was found and the patient received a second surgery. After another 4 months, we found a hard mass in the right posterior neck when she admitted to our department for fourth cycle of adjuvant chemotherapy. Immunohistochemical investigation supported the diagnosis of glioblastoma metastases to the neck after resection of the right neck mass. A few days later, spinal vertebral magnetic resonance imaging (MRI) confirmed multiple metastases in the thoracic, lumbar, sacral, and bilateral iliac bones.

Conclusions

Glioblastoma is the most common primary malignant brain tumor. Whole tumor resection and early radiotherapy and chemotherapy can delay recurrence and prolong survival. Extracranial metastases are extremely rare. We report this case with the aim of bringing attention to extracranial metastasis of brain glioma.

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Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells

Abstract

Background

Glioma stem cells (GSCs) contribute to tumor recurrence and drug resistance. This study characterizes the tumorigenesis of CD133⁺ cells and their sensitivity to pharmacological inhibition.

Methods

GSCs from human U87 and rat C6 glioblastoma cell lines were isolated via magnetic cell sorting using CD133 as a cancer stem cell marker. Cell proliferation was determined using the WST-1 assay. An intracranial mouse model and bioluminescence imaging were used to assess the effects of drugs on tumor growth in vivo.

Results

CD133⁺ cells expressed stem cell markers and exhibited self-renewal and enhanced tumor formation. Minocycline (Mino) was more effective in reducing the survival rate of CD133⁺ cells, whereas CD133⁻ cells were more sensitive to inhibition by the signal transducer and activator of transcription 3 (STAT3) inhibitor. Inhibition of STAT3 decreased the expression of CD133⁺ stem cell markers. The combination of Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells. Furthermore, this combination synergistically suppressed tumor growth in nude mice.

Conclusion

The results suggest that concurrent targeting of different subpopulations of glioblastoma cells may be an effective therapeutic strategy for patients with malignant glioma.

http://ift.tt/2zJMgiI

Galectin 3 expression in primary oral squamous cell carcinomas

Abstract

Background

Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens.

Methods

Preoperative diagnostic biopsies (n = 26) and tumor resection specimens (n = 34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed.

Results

In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p < 0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p < 0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p < 0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p < 0.05) with higher grading (G3) in tumor resection specimens.

Conclusion

High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target.

http://ift.tt/2C7ehab

Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer

Abstract

Background

The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer.

Methods

The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy.

Results

Five-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p < 0.001) and extracapsular spread (p = 0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p = 0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p = 0.028) were significant factors associated with 5-year DFS. In univariate analysis, cervical lymph node metastasis (p = 0.048), lymphovascular invasion (p = 0.041), extracapsular spread (p = 0.015), and esophageal invasion (p = 0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p = 0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p = 0.005) remained significant factors associated with 5-year DSS.

Conclusion

Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery.

http://ift.tt/2zJBTvm

Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells

Abstract

Background

Glioma stem cells (GSCs) contribute to tumor recurrence and drug resistance. This study characterizes the tumorigenesis of CD133⁺ cells and their sensitivity to pharmacological inhibition.

Methods

GSCs from human U87 and rat C6 glioblastoma cell lines were isolated via magnetic cell sorting using CD133 as a cancer stem cell marker. Cell proliferation was determined using the WST-1 assay. An intracranial mouse model and bioluminescence imaging were used to assess the effects of drugs on tumor growth in vivo.

Results

CD133⁺ cells expressed stem cell markers and exhibited self-renewal and enhanced tumor formation. Minocycline (Mino) was more effective in reducing the survival rate of CD133⁺ cells, whereas CD133⁻ cells were more sensitive to inhibition by the signal transducer and activator of transcription 3 (STAT3) inhibitor. Inhibition of STAT3 decreased the expression of CD133⁺ stem cell markers. The combination of Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells. Furthermore, this combination synergistically suppressed tumor growth in nude mice.

Conclusion

The results suggest that concurrent targeting of different subpopulations of glioblastoma cells may be an effective therapeutic strategy for patients with malignant glioma.

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Galectin 3 expression in primary oral squamous cell carcinomas

Abstract

Background

Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens.

Methods

Preoperative diagnostic biopsies (n = 26) and tumor resection specimens (n = 34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed.

Results

In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p < 0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p < 0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p < 0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p < 0.05) with higher grading (G3) in tumor resection specimens.

Conclusion

High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target.

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Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer

Abstract

Background

The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer.

Methods

The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy.

Results

Five-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p < 0.001) and extracapsular spread (p = 0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p = 0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p = 0.028) were significant factors associated with 5-year DFS. In univariate analysis, cervical lymph node metastasis (p = 0.048), lymphovascular invasion (p = 0.041), extracapsular spread (p = 0.015), and esophageal invasion (p = 0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p = 0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p = 0.005) remained significant factors associated with 5-year DSS.

Conclusion

Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery.

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c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [Research Articles]

The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that the family member c-MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.

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Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains

Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry. We found that the BAP1-ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable.

http://ift.tt/2pMTouU

Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains

Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry. We found that the BAP1-ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable.

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Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Abstract

Background

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.

Methods

The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).

Results

TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the "skin sparing effect". Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.

Conclusions

Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.

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Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Abstract

Background

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.

Methods

The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).

Results

TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the "skin sparing effect". Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.

Conclusions

Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.

http://ift.tt/2EawIIg

Pembrolizumab in Asia-Pacific patients with advanced head and neck squamous cell carcinoma: analyses from KEYNOTE-012

Abstract

KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST v1.1]), and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1, central review). Secondary endpoints included overall survival (OS) and response duration (DOR). Patients enrolled at any of the five centers throughout the Asia-Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. Median age was 62 years; 65% had ECOG PS 1; 62% received ≥2 prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment-related adverse event (AE) of any grade, including 2 (8%) patients who experienced ≥1 events of grade 3 severity. No treatment-related deaths occurred. ORR was 19% (95% confidence interval [CI], 7–39). After a median follow-up of 12 months (range, 2–21), median DOR was not reached (range, 6–17+ months); four of five responses lasted ≥6 months. Median OS was 12 months (95% CI, 5–17). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region

This article is protected by copyright. All rights reserved.

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Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin mediated PI3K/AKT/mTOR

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) have been shown to be recruited to tumor microenvironment and exert a tumor-promoting effect in a variety of cancers. However, the molecular mechanisms related to the tumor-promoting effect of BMMSCs on head and neck cancer (HNC) were not clear. In this study, we investigated Periostin (POSTN) and its roles in tumor-promoting effect of BMMSCs on HNC. In vitro analysis of HNC cells cultured in BMMSCs conditioned media (MSC-CM) showed that MSC-CM significantly promoted the cancer progression by enhancing cell proliferation, migration, epithelial-mesenchymal transformation (EMT), altering expression of cell cycle regulatory proteins and inhibition of apoptosis. Moreover, MSC-CM promoted the expression of POSTN and POSTN promoted HNC progression through the activation of PI3K/AKT/mTOR signaling pathway. In a murine model of HNC, we found that BMMSCs promoted the tumor growth, invasion, metastasis and enhanced the expression of POSTN and EMT in tumor tissues. Clinical samples analysis further confirmed that the expression of POSTN and N-cadherin were correlated with pathological grade and lymph node metastasis of HNC. In conclusion, this study indicated that BMMSCs promoted proliferation, invasion, survival, tumorigenicity and migration of head and neck cancer through POSTN mediated PI3K/AKT/mTOR activation.

This article is protected by copyright. All rights reserved.

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Pembrolizumab in Asia-Pacific patients with advanced head and neck squamous cell carcinoma: analyses from KEYNOTE-012

Abstract

KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST v1.1]), and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1, central review). Secondary endpoints included overall survival (OS) and response duration (DOR). Patients enrolled at any of the five centers throughout the Asia-Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. Median age was 62 years; 65% had ECOG PS 1; 62% received ≥2 prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment-related adverse event (AE) of any grade, including 2 (8%) patients who experienced ≥1 events of grade 3 severity. No treatment-related deaths occurred. ORR was 19% (95% confidence interval [CI], 7–39). After a median follow-up of 12 months (range, 2–21), median DOR was not reached (range, 6–17+ months); four of five responses lasted ≥6 months. Median OS was 12 months (95% CI, 5–17). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region

This article is protected by copyright. All rights reserved.

http://ift.tt/2BTBrfK

Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin mediated PI3K/AKT/mTOR

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) have been shown to be recruited to tumor microenvironment and exert a tumor-promoting effect in a variety of cancers. However, the molecular mechanisms related to the tumor-promoting effect of BMMSCs on head and neck cancer (HNC) were not clear. In this study, we investigated Periostin (POSTN) and its roles in tumor-promoting effect of BMMSCs on HNC. In vitro analysis of HNC cells cultured in BMMSCs conditioned media (MSC-CM) showed that MSC-CM significantly promoted the cancer progression by enhancing cell proliferation, migration, epithelial-mesenchymal transformation (EMT), altering expression of cell cycle regulatory proteins and inhibition of apoptosis. Moreover, MSC-CM promoted the expression of POSTN and POSTN promoted HNC progression through the activation of PI3K/AKT/mTOR signaling pathway. In a murine model of HNC, we found that BMMSCs promoted the tumor growth, invasion, metastasis and enhanced the expression of POSTN and EMT in tumor tissues. Clinical samples analysis further confirmed that the expression of POSTN and N-cadherin were correlated with pathological grade and lymph node metastasis of HNC. In conclusion, this study indicated that BMMSCs promoted proliferation, invasion, survival, tumorigenicity and migration of head and neck cancer through POSTN mediated PI3K/AKT/mTOR activation.

This article is protected by copyright. All rights reserved.

http://ift.tt/2CeUox7