Impact of preoperative anemia on outcomes in patients undergoing curative resection for gastric cancer: a single-institution retrospective analysis of 2163 Chinese patients

Abstract

We sought to evaluate whether preoperative anemia was an important determinant of survival in gastric cancer (GC). A single institution cohort of 2163 GC patients who underwent curative resection were retrospectively analyzed. Anemia was defined as a preoperative hemoglobin level <120 g/L in males and <110 g/L in females. Overall survival (OS) was analyzed using the Kaplan–Meier method, and a multivariate Cox proportional hazards model was performed to identify the independent prognostic factor. Anemic patients had a poorer OS compared with nonanemic patients after resection for tumor–nodes–metastasis (TNM) stage III tumors (5-year OS rate: 32.2% vs. 45.7%, P < 0.001) but not stage I (P  =  0.480) or stage II (P  =  0.917) tumors. Multivariate analysis revealed that preoperative anemia was an independent prognostic factor in TNM stage III (hazard ratio [HR], 1.771; 95% CI, 1.040–3.015; P = 0.035). In a stage-stratified analysis, preoperative anemia was still independently associated with OS in TNM stages IIIa through IIIc (P < 0.001, P = 0.075, and P = 0.012, respectively), though the association was only marginal in stage IIIb. Of note, preoperative mild anemia had a similar prognostic value in TNM stage III GC. Furthermore, preoperative anemia was significantly associated with more perioperative transfusions, postoperative complications and several nutritional-based indices, including the prognostic nutritional index (PNI), preoperative weight loss and performance status (all P < 0.05). Preoperative anemia, even mild anemia, was an important predictor of postoperative survival for TNM stage III GC.

Preoperative anemia, even mild anemia, is a useful predictor of outcomes in tumor–nodes–metastasis stage III gastric cancer.

http://ift.tt/2mM1vEm

Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation

Abstract

Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.

This work aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer patients with abnormal expression of the MLH1 protein in their tumors and without germline mutations. We provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families, most likely in patients with early onset or multiple primary tumors without significant family history.

from Cancer via ola Kala on Inoreader http://ift.tt/2reI7Ez
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Impact of preoperative anemia on outcomes in patients undergoing curative resection for gastric cancer: a single-institution retrospective analysis of 2163 Chinese patients

Abstract

We sought to evaluate whether preoperative anemia was an important determinant of survival in gastric cancer (GC). A single institution cohort of 2163 GC patients who underwent curative resection were retrospectively analyzed. Anemia was defined as a preoperative hemoglobin level <120 g/L in males and <110 g/L in females. Overall survival (OS) was analyzed using the Kaplan–Meier method, and a multivariate Cox proportional hazards model was performed to identify the independent prognostic factor. Anemic patients had a poorer OS compared with nonanemic patients after resection for tumor–nodes–metastasis (TNM) stage III tumors (5-year OS rate: 32.2% vs. 45.7%, P < 0.001) but not stage I (P  =  0.480) or stage II (P  =  0.917) tumors. Multivariate analysis revealed that preoperative anemia was an independent prognostic factor in TNM stage III (hazard ratio [HR], 1.771; 95% CI, 1.040–3.015; P = 0.035). In a stage-stratified analysis, preoperative anemia was still independently associated with OS in TNM stages IIIa through IIIc (P < 0.001, P = 0.075, and P = 0.012, respectively), though the association was only marginal in stage IIIb. Of note, preoperative mild anemia had a similar prognostic value in TNM stage III GC. Furthermore, preoperative anemia was significantly associated with more perioperative transfusions, postoperative complications and several nutritional-based indices, including the prognostic nutritional index (PNI), preoperative weight loss and performance status (all P < 0.05). Preoperative anemia, even mild anemia, was an important predictor of postoperative survival for TNM stage III GC.

Preoperative anemia, even mild anemia, is a useful predictor of outcomes in tumor–nodes–metastasis stage III gastric cancer.

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Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β-catenin signaling and sensitizes cancer cells to FH535 therapy

Abstract

The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short-hairpin RNA-mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β-catenin expression was also analyzed. CSN6 levels were determined by real-time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK-8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β-catenin and facilitated the epidermal-to-mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β-catenin expression in a β-Trcp-dependent manner and triggered expression of several EMT-related genes regulated by β-catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway.

CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration. In PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage.

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Clinical outcomes of carbon ion radiotherapy with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma in a phase 1/2 clinical trial (Protocol 1001)

Abstract

We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty-three patients were enrolled between April 2010 and March 2014. Treatment consisted of C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m². In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C-ion RT. In the phase 2 component, the efficacy and safety of C-ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow-up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose-limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3–4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2-year local control, progression-free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C-ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy.

The efficacy and safety of carbon ion radiotherapy with concurrent chemotherapy was evaluated in patients with locally advanced uterine cervical adenocarcinoma. This strategy was well tolerated in the majority of patients.

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Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation

Abstract

Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.

This work aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer patients with abnormal expression of the MLH1 protein in their tumors and without germline mutations. We provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families, most likely in patients with early onset or multiple primary tumors without significant family history.

http://ift.tt/2reI7Ez

Mechanism underlying the negative effect of prostate volume on the outcome of extensive transperineal ultrasound-guided template prostate biopsy

Abstract

Previous studies have indicated a possible relationship between increased prostate volume (PV) and decreased biopsy yield, although the mechanism involved is unclear. We evaluated 1650 patients who underwent template biopsy. The distribution of 993 cancer lesions in 302 prostatectomy specimens was compared with the biopsy data to determine whether each lesion was detected. A receiver operating characteristic (ROC) model was used to determine the diagnostic accuracy of prostate-specific antigen (PSA) and related markers. A medical record number (MRN) was used as a negative control. The cancer positive rate did not change as PSA increased in patients with PV ≥50 mL (P = 0.466), although it increased as PSA increased in patients with PV<50 mL (P = 0.001). The detection rate of cancer lesions decreased as the diameter of the lesions decreased (P = 0.018), but remained unchanged with respect to PV. The diameters of the maximum lesions in patients with PV ≥ 50 mL were significantly smaller than those in patients with PV<50 mL (P = 0.003). In patients with PV ≥ 50 mL, the areas under the ROC curves for PSA-related markers did not differ significantly from that for MRN, although they were significantly greater than that for MRN in patients with PV<50 mL (P < 0.001). These results suggest that an increase in PV is associated with a decrease in size and detectability of cancer lesions resulting in a decrease in biopsy yield. Loss of diagnostic accuracy of markers in patients with PV ≥ 50 mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

The currents study indicates that the diameters of maximum cancer lesions in patients with prostate volume ≥ 50 mL were significantly smaller than those in patients with prostate volume <50 mL. Loss of diagnostic accuracy of markers in patients with prostate volume ≥ 50mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

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via IFTTT

Nuclear division cycle 80 promotes malignant progression and predicts clinical outcome in colorectal cancer

Abstract

Colorectal cancer (CRC) is a common human malignancy worldwide and increasing studies have attributed its malignant progression to abnormal molecular changes in cancer cells. Nuclear division cycle 80 (NDC80) is a newly discovered oncoprotein that regulates cell proliferation and cycle in numerous malignancies. However, its clinical significance and biological role in CRC remain unclear. Therefore, in this study, we firstly analyze its expression in a retrospective cohort enrolling 224 CRC patients and find its overexpression is significantly correlated with advanced tumor stage and poor prognosis in CRC patients. In addition, our result reveals it is an independent adverse prognostic factor affecting CRC-specific and disease-free survival. The subgroup analysis indicates NDC80 expression can stratify the clinical outcome in stage II and III patients, but fails in stage I and IV patients. In cellular assays, we find knockdown of NDC80 dramatically inhibits the proliferative ability, apoptosis resistance, cell cycle progression, and clone formation of CRC cells in vitro. Using xenograft model, we further prove knockdown of NDC80 also inhibits the tumorigenic ability of CRC cells in vivo. Finally, the microarray analysis is utilized to preliminarily clarify the oncogenic molecular mechanisms regulated by NDC80 and the results suggest it may promote CRC progression partly by downregulating tumor suppressors such as dual specificity phosphatase 5 and Forkhead box O1. Taken together, our study provides novel evidences to support that NDC80 is not only a promising clinical biomarker but also a potential therapeutical target for CRC precise medicine.

In summary, our results indicate that high NDC80 expression is correlated with advanced tumor stage and unfavorable prognosis in CRC patients. In addition, we also find NDC80 drives malignant progression of CRC cells partly by inactivating DUSP5 and FOXO1. Taken together, these evidences suggest NDC80 is not only a promising clinical biomarker for patient management, but also a potential therapeutical target for CRC diagnosis and treatment.

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

Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β-catenin signaling and sensitizes cancer cells to FH535 therapy

Abstract

The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short-hairpin RNA-mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β-catenin expression was also analyzed. CSN6 levels were determined by real-time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK-8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β-catenin and facilitated the epidermal-to-mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β-catenin expression in a β-Trcp-dependent manner and triggered expression of several EMT-related genes regulated by β-catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway.

CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration. In PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage.

http://ift.tt/2rhOVRE

Clinical outcomes of carbon ion radiotherapy with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma in a phase 1/2 clinical trial (Protocol 1001)

Abstract

We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty-three patients were enrolled between April 2010 and March 2014. Treatment consisted of C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m². In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C-ion RT. In the phase 2 component, the efficacy and safety of C-ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow-up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose-limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3–4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2-year local control, progression-free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C-ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy.

The efficacy and safety of carbon ion radiotherapy with concurrent chemotherapy was evaluated in patients with locally advanced uterine cervical adenocarcinoma. This strategy was well tolerated in the majority of patients.

http://ift.tt/2mQJaGj

Mechanism underlying the negative effect of prostate volume on the outcome of extensive transperineal ultrasound-guided template prostate biopsy

Abstract

Previous studies have indicated a possible relationship between increased prostate volume (PV) and decreased biopsy yield, although the mechanism involved is unclear. We evaluated 1650 patients who underwent template biopsy. The distribution of 993 cancer lesions in 302 prostatectomy specimens was compared with the biopsy data to determine whether each lesion was detected. A receiver operating characteristic (ROC) model was used to determine the diagnostic accuracy of prostate-specific antigen (PSA) and related markers. A medical record number (MRN) was used as a negative control. The cancer positive rate did not change as PSA increased in patients with PV ≥50 mL (P = 0.466), although it increased as PSA increased in patients with PV<50 mL (P = 0.001). The detection rate of cancer lesions decreased as the diameter of the lesions decreased (P = 0.018), but remained unchanged with respect to PV. The diameters of the maximum lesions in patients with PV ≥ 50 mL were significantly smaller than those in patients with PV<50 mL (P = 0.003). In patients with PV ≥ 50 mL, the areas under the ROC curves for PSA-related markers did not differ significantly from that for MRN, although they were significantly greater than that for MRN in patients with PV<50 mL (P < 0.001). These results suggest that an increase in PV is associated with a decrease in size and detectability of cancer lesions resulting in a decrease in biopsy yield. Loss of diagnostic accuracy of markers in patients with PV ≥ 50 mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

The currents study indicates that the diameters of maximum cancer lesions in patients with prostate volume ≥ 50 mL were significantly smaller than those in patients with prostate volume <50 mL. Loss of diagnostic accuracy of markers in patients with prostate volume ≥ 50mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

http://ift.tt/2rhDN7w

Nuclear division cycle 80 promotes malignant progression and predicts clinical outcome in colorectal cancer

Abstract

Colorectal cancer (CRC) is a common human malignancy worldwide and increasing studies have attributed its malignant progression to abnormal molecular changes in cancer cells. Nuclear division cycle 80 (NDC80) is a newly discovered oncoprotein that regulates cell proliferation and cycle in numerous malignancies. However, its clinical significance and biological role in CRC remain unclear. Therefore, in this study, we firstly analyze its expression in a retrospective cohort enrolling 224 CRC patients and find its overexpression is significantly correlated with advanced tumor stage and poor prognosis in CRC patients. In addition, our result reveals it is an independent adverse prognostic factor affecting CRC-specific and disease-free survival. The subgroup analysis indicates NDC80 expression can stratify the clinical outcome in stage II and III patients, but fails in stage I and IV patients. In cellular assays, we find knockdown of NDC80 dramatically inhibits the proliferative ability, apoptosis resistance, cell cycle progression, and clone formation of CRC cells in vitro. Using xenograft model, we further prove knockdown of NDC80 also inhibits the tumorigenic ability of CRC cells in vivo. Finally, the microarray analysis is utilized to preliminarily clarify the oncogenic molecular mechanisms regulated by NDC80 and the results suggest it may promote CRC progression partly by downregulating tumor suppressors such as dual specificity phosphatase 5 and Forkhead box O1. Taken together, our study provides novel evidences to support that NDC80 is not only a promising clinical biomarker but also a potential therapeutical target for CRC precise medicine.

In summary, our results indicate that high NDC80 expression is correlated with advanced tumor stage and unfavorable prognosis in CRC patients. In addition, we also find NDC80 drives malignant progression of CRC cells partly by inactivating DUSP5 and FOXO1. Taken together, these evidences suggest NDC80 is not only a promising clinical biomarker for patient management, but also a potential therapeutical target for CRC diagnosis and treatment.

http://ift.tt/2mMIkdp

Abnormal distance of the extralaryngeal bifurcation point of the recurrent laryngeal nerve from the cricothyroid joint

Abstract

The extralaryngeal bifurcation point of the recurrent laryngeal nerve (RLN) is typically located in a mean distance of 0–2 cm from the cricothyroid joint (CTJ). In the presented case though, the left RLN was unexpectedly identified bifurcating in a mean distance of 7 cm from the left CTJ in a young woman with multinodular goiter during total thyroidectomy. The RLN was carefully exposed throughout its course for the avoidance of iatrogenic injury of the nerval structure. The operation was uneventful. The present manuscript aims to highlight a scarce anatomic variation and its implications for thyroidectomy. Rare anatomic variations of the RLN such as the presented one encumber thyroid surgery and represent a severe risk factor of RLN injury. Meticulous operative technique combined with surgeons' perpetual awareness concerning this peculiar anatomical aberration leads to an injury-free thyroid surgery.

http://ift.tt/2DhrKN3

Intrabilary obstruction by colorectal metastases

Abstract

Intrabiliary colorectal metastases are rare. We present a case of an 84-year-old man who developed obstructive jaundice secondary to intrabiliary growth of colorectal metastases. The patient presented with three weeks of jaundice and significant weight loss in the preceding months. The patient's background included metastatic colorectal carcinoma, with a previous right hemicolectomy and left hepatectomy for liver metastases. A MRCP showed an obstruction of the biliary tract transitioning at the ampulla. Histology confirmed a malignant adenocarcinoma. When compared to the patient's previous resected colorectal liver metastases, morphology and immunohistochemistry was consistent with colorectal metastases. This case highlights the importance of differentiating a new intraductal papillary neoplasm from a colorectal metastasis. Correctly identifying these lesions requires the use of MRCP and ERCP, as well as immunohistochemistry. This is a priority for clinicians to ensure appropriate therapy.

http://ift.tt/2DhgxMu

Metastatic squamous cell cancer of the lung presenting as a perforated cecal cancer

Abstract

Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of diagnoses. Metastasis occurs in ~50% of cases but clinically evident isolated gastrointestinal (GI) metastasis is rare. We present a 78-year-old female who underwent an urgent right hemi-colectomy after cross-sectional imaging revealed a perforated cecal mass. Final pathology demonstrated squamous cell cancer of lung origin. We review the literature on NSCLC with clinically evident metastases to the GI tract, as well as important diagnostic considerations.

http://ift.tt/2Dho129

Assessment of potential risk factors for breast cancer in a population in Southern Brazil

Abstract

Purpose

The aim of this study is to assess potential risk factors for breast cancer in a population in Southern Brazil and build a multivariate logistic model using these factors for breast cancer risk prediction.

Methods

A total of 4242 women between 40 and 69 years of age without a history of breast cancer were selected at primary healthcare facilities in Porto Alegre and submitted to mammographic screening. They were evaluated for potential risk factors.

Results

In all, 73 participants among the 4242 women had a breast cancer diagnosis during the follow-up of the project (10 years). The multivariate analysis considering all the patients aged 40–69 years showed that older age (OR 1.08, 95% CI 1.04–1.12), higher height (OR 1.04, 95% CI 1.01–1.09), and history of previous breast biopsy (OR 2.66, 95% CI 1.38–5.13) were associated with the development of breast cancer. Conversely, the number of pregnancies (OR 0.87, 95% CI 0.78–0.98) and use of hormone replacement therapy (OR 0.39, 95% CI 0.20–0.75) were considered a protective factor. Additionally, we performed an analysis separating the participants into groups of 40–49 and 50–69 years old, since a risk factor could have a specific behavior in these age groups. No additional risk factors were identified within these age brackets, and some factors lost statistical significance.

Conclusion

The risk prediction model indicates that the following variables should be assessed in this specific population: age, height, having had previous breast biopsies, number of pregnancies, and use of hormone replacement therapy. These findings may help to better understand the causal model of breast cancer in Southern Brazil.

http://ift.tt/2mBkkZU

Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia

Abstract

Purpose

The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility.

Methods

DNA testing of family members was conducted for assessment of pathogenicity of the genetic variant. For functional analysis, Ca²⁺ measurement using patient-derived myotubes and p.Thr84Met RYR1-transfected human embryonic kidney (HEK)-293 cells was performed to evaluate reactivity to RYR1 activators. The half-maximal effective concentration (EC₅₀) values of two RYR1 activators, caffeine and 4-chloro-m-cresol (4CmC), were calculated from the acquired dose–response curves. The EC₅₀ was compared between two groups: for myotubes, the control group and the patient, and for HEK-293 cells, WT and p.Thr84Met.

Results

Dose–response curves for caffeine and 4CmC were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4CmC were significantly lower in both myotubes and HEK-293 cells compared to controls (P < 0.001 for all comparisons).

Conclusions

Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4CmC. We conclude that the genetic variant was associated with MH susceptibility.

http://ift.tt/2DhkrVI

Cancer-Related Genetic Testing and Personalized Medicine for Adolescents: A Narrative Review of Impact and Understanding

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2DIMtGN

Educational Needs of Health Professionals Caring for Adolescents and Young Adults with Cancer

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2DeBwf2

Current Practice Patterns Surrounding Fertility Concerns in Stage I Seminoma Patients: Survey of United States Radiation Oncologists

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2DGUBrg

Cancer-Related Genetic Testing and Personalized Medicine for Adolescents: A Narrative Review of Impact and Understanding

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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

Educational Needs of Health Professionals Caring for Adolescents and Young Adults with Cancer

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


from Cancer via ola Kala on Inoreader http://ift.tt/2DeBwf2
via IFTTT

Current Practice Patterns Surrounding Fertility Concerns in Stage I Seminoma Patients: Survey of United States Radiation Oncologists

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Future Oncology, Ahead of Print.


http://ift.tt/2DpfuJA

Endovascular implantation of 125I seed combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Future Oncology, Ahead of Print.


http://ift.tt/2mE6zti

NrF2/ARE and NF-κB pathway regulation may be the mechanism for lutein inhibition of human breast cancer cell

Future Oncology, Ahead of Print.


http://ift.tt/2Dk9oKH

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Future Oncology, Ahead of Print.


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

Endovascular implantation of 125I seed combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2mE6zti
via IFTTT

NrF2/ARE and NF-κB pathway regulation may be the mechanism for lutein inhibition of human breast cancer cell

Future Oncology, Ahead of Print.


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via IFTTT

Associations of coffee consumption and caffeine intake with mammographic breast density

Abstract

Purpose

Previous studies suggest that coffee and caffeine intake may be associated with reduced breast cancer risk. We investigated the association of coffee and caffeine intake with mammographic breast density by woman's menopausal status and, in postmenopausal women, by hormone therapy (HT).

Methods

This study included 4130 cancer-free women within the Nurses' Health Study and Nurses' Health Study II cohorts. Percent breast density (PD) was measured from digitized film mammograms using a computer-assisted thresholding technique and square root-transformed for the analysis. Average cumulative coffee/caffeine consumption was calculated using data from all food frequency questionnaires preceding the mammogram date. Information regarding breast cancer risk factors was obtained from questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations of regular, decaffeinated, and total coffee, and energy-adjusted caffeine intake with percent density.

Results

In multivariable analyses, decaffeinated coffee was positively associated with PD in premenopausal women (2+ cups/day: β = 0.23, p trend = 0.03). In postmenopausal women, decaffeinated and total coffee were inversely associated with PD (decaffeinated 2+ cups/day: β = − 0.24, p trend = 0.04; total 4+ cups/day: β = − 0.16, p trend = 0.02). Interaction of decaffeinated coffee with menopausal status was significant (p-interaction < 0.001). Among current HT users, regular coffee and caffeine were inversely associated with PD (regular coffee 4+ cups/day: β = − 0.29, p trend = 0.01; caffeine 4th vs. 1st quartile: β = − 0.32, p trend = 0.01). Among past users, decaffeinated coffee was inversely associated with PD (2+ cups/day β = − 0.70, p trend = 0.02).

Conclusions

Associations of decaffeinated coffee with percent density differ by woman's menopausal status. Associations of regular coffee and caffeine with percent density may differ by HT status.

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Repurposing tin mesoporphyrin as an immune checkpoint inhibitor shows therapeutic efficacy in preclinical models of cancer

Purpose: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer. Experimental design: SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (MMTV-PyMT). Single-cell RNA sequencing analysis, tumor microarray and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations. Results: We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8+ T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. In vivo, we therapeutically compared the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably to PD-1 blockade in preclinical models. Conclusions: SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy.

http://ift.tt/2rfhJdK

IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors

Purpose: Somatic mutations in IDH1/2 occur in ~20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increases in DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation and PARP inhibitors. Results: IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells. Conclusions: IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML.

http://ift.tt/2mMbZ6H

Repurposing tin mesoporphyrin as an immune checkpoint inhibitor shows therapeutic efficacy in preclinical models of cancer

Purpose: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer. Experimental design: SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (MMTV-PyMT). Single-cell RNA sequencing analysis, tumor microarray and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations. Results: We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8+ T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. In vivo, we therapeutically compared the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably to PD-1 blockade in preclinical models. Conclusions: SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy.

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IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors

Purpose: Somatic mutations in IDH1/2 occur in ~20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increases in DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation and PARP inhibitors. Results: IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells. Conclusions: IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML.

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New insights in the relative radiobiological effectiveness of proton irradiation

Proton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inv...

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New insights in the relative radiobiological effectiveness of proton irradiation

Proton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inv...

http://ift.tt/2DiT910

Relative Target Affinities of T Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution and non-invasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3 expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short term pharmacokinetics, tissue distribution and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy.

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INHIBITION OF FLT3 AND PIM KINASES BY EC-70124 EXERTS POTENT ACTIVITY IN PRECLINICAL MODELS OF ACUTE MYELOID LEUKEMIA

Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as Pim kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared to midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and Pim-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants which carry other molecular pathways alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment, based on its ability to interfere the complex oncogenic events activated in AML at several levels.

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Relative Target Affinities of T Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution and non-invasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3 expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short term pharmacokinetics, tissue distribution and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy.

http://ift.tt/2mNmuX6

INHIBITION OF FLT3 AND PIM KINASES BY EC-70124 EXERTS POTENT ACTIVITY IN PRECLINICAL MODELS OF ACUTE MYELOID LEUKEMIA

Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as Pim kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared to midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and Pim-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants which carry other molecular pathways alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment, based on its ability to interfere the complex oncogenic events activated in AML at several levels.

http://ift.tt/2rffGq4

First Comprehensive Companion Diagnostic OK'd [News in Brief]

Test uses next-generation sequencing to determine mutation status for 324 genes.

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Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells aberrantly poised genes may facilitate changes in transcriptional states after exposure to anti-cancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3 and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that pre-existing histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.

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Role of chromatin damage and chromatin trapping of FACT in mediating the anticancer cytotoxicity of DNA-binding small molecule drugs

Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from chromatin damage in cells. Recent work on curaxins, a class of small molecule drugs with broad anticancer activity, show that they interfere with histone-DNA interactions and destabilize nucleosomes without binding DNA or causing detectable DNA damage. Chromatin unfolding caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes and causes chromatin trapping (c-trapping). In this study, we investigated whether classical DNA-targeting chemotherapeutic drugs also similarly disturbed chromatin to cause c-trapping. Drugs that directly bound DNA induced both chromatin damage and c-trapping. However, chromatin damage occurred in the absence of direct DNA damage and was dependent on how a drug bound DNA, specifically, in the way it bound chromatinized DNA in cells. FACT was sensitive to a plethora of nucleosome perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Strikingly, we found that the cytotoxicity of DNA-binding small molecules correlated with their ability to cause chromatin damage, not DNA damage. Our results suggest implications for the development of chromatin-damaging agents as selective anticancer drugs.

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AMPK-AKT double negative feedback loop in breast cancer cells regulates their adaptation to matrix deprivation

Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and re-initiate cell division. In this study, we illuminate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the AKT phosphatase PHLPP2. The resultant pAMPKhigh/pAKTlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix re-attachment led to AKT-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAKThigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an AKT-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between AKT and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.

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PHD3 controls lung cancer metastasis and resistance to EGFR inhibitors through TGF{alpha}

Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and develop therapy resistance. Adaptive responses to hypoxia and epithelial-mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Re-expression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.

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E6 protein expressed by high-risk HPV activates super-enhancers of the EGFR and c-MET oncogenes by destabilizing the histone demethylase KDM5C

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events are poorly understood. Here we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bi-directional eRNA transcription. Depletion of KDM5C or HPV-16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by high-risk HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.

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Radio-resistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism

Highly glycolytic cervical cancers largely resist treatment by cisplatin and co-administered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species (ROS) were compared before and after treatment. Highly radio-resistant cells were the most sensitive to 2-DG, whereas intermediate radio-resistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutatione, redox-sensitive dye oxidation and decreased glucose utilization via multiple metabolic pathways including the TCA cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radio-resistant cells and effectively radio-sensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radio-resistant cervical cancers.

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The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1

The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional co-activator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumour microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2) and large tumour suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase PD-L1 promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse PD-L1 promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we perform a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiological/pathological immune responses and provide evidence implicating TAZ in human cancer immune evasion.

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STAT3/PIAS3 levels serve as "early signature" genes in the development of high-grade serous carcinoma from the fallopian tube

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal peritoneal junction (TPJ), p53 signature fallopian tube tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared to high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in fallopian tube secretory epithelial cells (FTSEC) promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest pre-malignant states.

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Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells aberrantly poised genes may facilitate changes in transcriptional states after exposure to anti-cancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3 and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that pre-existing histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.

http://ift.tt/2Dhd2pb

Role of chromatin damage and chromatin trapping of FACT in mediating the anticancer cytotoxicity of DNA-binding small molecule drugs

Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from chromatin damage in cells. Recent work on curaxins, a class of small molecule drugs with broad anticancer activity, show that they interfere with histone-DNA interactions and destabilize nucleosomes without binding DNA or causing detectable DNA damage. Chromatin unfolding caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes and causes chromatin trapping (c-trapping). In this study, we investigated whether classical DNA-targeting chemotherapeutic drugs also similarly disturbed chromatin to cause c-trapping. Drugs that directly bound DNA induced both chromatin damage and c-trapping. However, chromatin damage occurred in the absence of direct DNA damage and was dependent on how a drug bound DNA, specifically, in the way it bound chromatinized DNA in cells. FACT was sensitive to a plethora of nucleosome perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Strikingly, we found that the cytotoxicity of DNA-binding small molecules correlated with their ability to cause chromatin damage, not DNA damage. Our results suggest implications for the development of chromatin-damaging agents as selective anticancer drugs.

http://ift.tt/2B75BuY

AMPK-AKT double negative feedback loop in breast cancer cells regulates their adaptation to matrix deprivation

Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and re-initiate cell division. In this study, we illuminate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the AKT phosphatase PHLPP2. The resultant pAMPKhigh/pAKTlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix re-attachment led to AKT-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAKThigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an AKT-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between AKT and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.

http://ift.tt/2DhFirP

PHD3 controls lung cancer metastasis and resistance to EGFR inhibitors through TGF{alpha}

Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and develop therapy resistance. Adaptive responses to hypoxia and epithelial-mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Re-expression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.

http://ift.tt/2B5PkXk

E6 protein expressed by high-risk HPV activates super-enhancers of the EGFR and c-MET oncogenes by destabilizing the histone demethylase KDM5C

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events are poorly understood. Here we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bi-directional eRNA transcription. Depletion of KDM5C or HPV-16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by high-risk HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.

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Radio-resistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism

Highly glycolytic cervical cancers largely resist treatment by cisplatin and co-administered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species (ROS) were compared before and after treatment. Highly radio-resistant cells were the most sensitive to 2-DG, whereas intermediate radio-resistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutatione, redox-sensitive dye oxidation and decreased glucose utilization via multiple metabolic pathways including the TCA cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radio-resistant cells and effectively radio-sensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radio-resistant cervical cancers.

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The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1

The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional co-activator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumour microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2) and large tumour suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase PD-L1 promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse PD-L1 promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we perform a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiological/pathological immune responses and provide evidence implicating TAZ in human cancer immune evasion.

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STAT3/PIAS3 levels serve as "early signature" genes in the development of high-grade serous carcinoma from the fallopian tube

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal peritoneal junction (TPJ), p53 signature fallopian tube tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared to high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in fallopian tube secretory epithelial cells (FTSEC) promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest pre-malignant states.

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Acute intestinal obstruction due to extrinsic compression by previa myoma and ectopic pregnancy: a case report

Acute intestinal obstruction during pregnancy is a rare digestive surgical emergency with significant maternal and fetal mortality. Diagnosis is difficult, often delaying the management. Here, we report an exc...

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The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer, Published online: 16 January 2018; doi:10.1038/bjc.2017.441

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

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How the evolution of multicellularity set the stage for cancer

How the evolution of multicellularity set the stage for cancer

How the evolution of multicellularity set the stage for cancer, Published online: 16 January 2018; doi:10.1038/bjc.2017.398

How the evolution of multicellularity set the stage for cancer

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Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2, Published online: 16 January 2018; doi:10.1038/bjc.2017.436

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

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The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer, Published online: 16 January 2018; doi:10.1038/bjc.2017.441

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

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How the evolution of multicellularity set the stage for cancer

How the evolution of multicellularity set the stage for cancer

How the evolution of multicellularity set the stage for cancer, Published online: 16 January 2018; doi:10.1038/bjc.2017.398

How the evolution of multicellularity set the stage for cancer

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Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2, Published online: 16 January 2018; doi:10.1038/bjc.2017.436

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

http://ift.tt/2mCOegu

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

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How the evolution of multicellularity set the stage for cancer

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Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

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The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

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How the evolution of multicellularity set the stage for cancer

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Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

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Innovative case-writing software can engage millennials in learning pathology topics

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Innovative case-writing software can engage millennials in learning pathology topics

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Fasting Blood Glucose Level in Locally Advanced Non-Small Cell Lung Cancer: a New Prognostic Factor?

Abstract

Hyperglycemia may lead to proliferation, invasion, apoptosis inhibition, migration, and eventually metastasis of cancer cells by several mechanisms. In this study, the effect of hyperglycemia on overall survival (OS), disease-free survival (DFS), and locoregional recurrence (LRR) was investigated in NSCLC. One stage IIIA-IIIB NSCLC patient treated with chemoradiotherapy between 2010 and 2015 was enrolled. Fasting blood glucose (FBG) levels were recorded in pre-treatment, treatment, and post-treatment periods. Median age was 54 years (51–62). Fifty-two patients had squamous cell carcinoma (SCC); 19 had adenocarcinoma. Median follow-up was 19 (11–30), median survival was 19 (13–24), and DFS was 9 (7–11) months. Diabetic patients had shorter survival than non-diabetics 12 (95%CI, 10–14) vs. 25 months (95%CI,18–32), p = 0.005. Number of patients with LRR was also higher in diabetics compared to non-diabetics (8/12 vs. 11/37, p = 0.039). OS was shorter in patients with hyperglycemic-FBG and diabetic-FBG levels in pre-treatment period (log-rank p = 0.03 and 0.023, respectively). Diabetic-FBG level in pre-treatment period was found to be the only independent risk factor for survival. In subgroup analysis, these differences were apparent in SCC (log-rank p = 0.009 for hyperglicemic, log-rank p = 0.017 for diabetic-FBG). LRR was 68% in patients with diabetic-FBG, 36.5% in patients with non-diabetic-FBG in post-treatment period (p = 0.015). Patients with LRR had significantly higher median FBG value in post-treatment period compared to non-relapsing patients, 138 mg/dL (119–228) and 111 mg/dL (99–164), respectively (p = 0.022). The patients with hyperglycemic and diabetic-FBG levels in pre-treatment period had shorter survival compared to normoglycemic ones. The patients with diabetic-FBG level in post-treatment period had higher LRR, and relapsing patients had higher FBG levels in post-treatment period.

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Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer

Abstract

The androgen receptor (AR) is a promising therapeutic target for a subset of triple-negative breast cancers (TNBCs) in which AR is expressed. However, the mechanistic action of AR and the degree to which primary and metastatic tumors depend on AR, both before and after conventional treatment, remain to be defined. We discuss preclinical and clinical data for AR+ TNBC, the difficulties in monitoring AR protein levels, new methods for determining AR status, the influence of AR on "stemness" in the context of TNBC, the role of combined inhibition of sex steroid production and AR, and the role of AR in regulation of the immune system. Although the exact role of AR in subsets of TNBC is still being characterized, new therapies that target AR and the production of androgens may provide additional options for patients with TNBC for whom chemotherapy is currently the sole treatment option.

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Bladder cancer and the National Cancer Data Base: New insight or misinformation?

In the absence of randomised clinical trials big data base sets can provide insights into patient management, however it is import to be aware of the weaknesses of each data base so appropriate conclusion can be drawn. Overinterpretation must be avoided.

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Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

BACKGROUND

In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies.

METHODS

In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas.

RESULTS

A total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB-mutated samples, and ERBB3-mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2-amplified samples compared with wild-type CRC samples (51.8%), and ERBB2- or ERBB3-mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways.

CONCLUSIONS

Although observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti-HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2-positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti-HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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Racial/ethnic differences in thyroid cancer incidence in the United States, 2007-2014

BACKGROUND

Small tumor diagnostic tools including ultrasound-guided fine needle aspiration (FNA) and computed tomography (CT) could be causing rising and racially/ethnically different thyroid cancer incidence rates due to variable overdiagnosis of indolent tumors. Papillary tumors and <40 mm tumors are most likely to be overdiagnosed as indolent tumors by FNA and CT.

METHODS

Age-adjusted incidence rates (AAIRs) for the years 2007-2014 were calculated for race/ethnicity (white, Hispanic, Asian, African American, Native American) by patient/tumor characteristics for microscopically confirmed malignant thyroid cancer cases in the Surveillance, Epidemiology, and End Results Program 18 database (SEER 18; N = 93,607). Multivariate analysis determined cancer patients' odds ratios of diagnosis with papillary thyroid carcinoma (vs other histologies) and tumors <40 mm (vs ≥40 mm).

RESULTS

For both males and females, there were statistically significant differences in incidence rates between race/ethnicity, with whites having the highest AAIRs and African Americans the lowest AAIRs. Among thyroid cancer patients, tumor size and histology differed significantly by race and insurance coverage after controlling for age, sex, stage, and tumor sequence. Non-whites with thyroid cancer (vs whites) were less associated with small tumors (odds ratio [OR], 0.51-0.79; P < .0001). Medicaid and uninsured patients with thyroid cancer were less associated with tumors <40 mm (OR, 0.55-0.71; 95% confidence interval [CI], 0.49-0.76) and papillary carcinoma (OR, 0.86; 95% CI, 0.80-0.93).

CONCLUSION

The diagnosis of small tumors is occurring at greater rates in whites (vs non-whites) and insured (vs Medicaid and uninsured) patients; consequently, these groups may be vulnerable to unnecessary tests and treatments or potentially aided by early detection. Guidelines that define postdetection interventions may be needed to limit the overtreatment of indolent and small papillary carcinomas. Cancer 2018. © 2018 American Cancer Society.

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Margins in breast cancer: How much is enough?

The appropriate negative margin width for women undergoing breast-conserving surgery for both ductal carcinoma in situ (DCIS) and invasive carcinoma is controversial. This review examines the available data on the margin status for invasive breast cancer and DCIS, and highlights the similarities and differences in tumor biology and standard treatments that affect the local recurrence (LR) risk and, therefore, the optimal surgical margin. Consensus guidelines support a negative margin, defined as no ink on tumor, for invasive carcinoma treated with breast-conserving therapy. Because of differences in the growth pattern and utilization of systemic therapy, a margin of 2 mm has been found to minimize the LR risk for women with DCIS undergoing lumpectomy and radiation therapy (RT). Wider negative margins do not improve local control for DCIS or invasive carcinoma when they are treated with lumpectomy and RT. Re-excision for negative margins should be individualized, and the routine practice of performing additional surgery to obtain a wider negative margin is not supported by the literature. Cancer 2018. © 2018 American Cancer Society.

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Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma

BACKGROUND

A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA–) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival.

METHODS

Gemcitabine and cisplatin were dosed at 600 and 25 mg/m², respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]).

RESULTS

Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA– patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA– patients was 11 months (95% CI, 1.5-12.1 months).

CONCLUSIONS

The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018. © 2018 American Cancer Society.

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Impact of time to testosterone rebound and comorbidity on the risk of cause-specific mortality in men with unfavorable-risk prostate cancer

BACKGROUND

Herein, the authors evaluated how the time to testosterone rebound (TTR) after radiotherapy (RT) and 6 months of androgen deprivation therapy (ADT) impacted the risk of prostate cancer-specific mortality (PCSM) and cardiovascular-specific mortality (CVM) among men with varying comorbidity extent.

METHODS

Between 1995 and 2001, a total of 206 men who were randomized to receive RT either alone or with 6 months of ADT for unfavorable-risk PC and who had a comorbidity score assigned using the Adult Comorbidity Evaluation 27 metric comprised the study cohort. Multivariable competing risk regression was used to evaluate the impact of and possible interaction between comorbidity and TTR on PCSM and CVM.

RESULTS

After a median follow-up of 18.19 years, 30 men (18.6%), 39 men (24.2%), and 92 men (57.1%), respectively, had died of PC, CV disease, or other causes. As TTR increased, PCSM significantly decreased in men with no or minimal (adjusted hazard ratio [AHR], 0.53, 95% confidence interval [95% CI], 0.34-0.84 [P =.007]) and moderate to severe (AHR, 0.37; 95% CI, 0.14-0.99 [P = .048]) comorbidity. However, increasing TTR significantly increased the risk of CVM among men with moderate to severe comorbidity (AHR, 1.87; 95% CI, 1.40-2.49 [P <.001]), but not those with no or minimal comorbidity (AHR, 0.86; 95% CI, 0.57-1.29 [P =.46]), leading to a significant interaction between TTR and comorbidity (P = .001).

CONCLUSIONS

The results of the current study indicate that considering an intermittent course of ADT such that the TTR approaches 18 months, instead of continuous long-term administration of ADT, in men with moderate to severe comorbidity and high-risk PC may reduce the increased risk of CVM without increasing the risk of PCSM. Cancer 2018. © 2018 American Cancer Society.

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Influence of provider factors and race on uptake of breast cancer gene expression profiling

BACKGROUND

Gene expression profiling (GEP) has been rapidly adopted for early breast cancer and can aid in chemotherapy decision making. Study results regarding racial disparities in testing are conflicting, and may reflect different care settings. To the authors' knowledge, data regarding the influence of provider factors on testing are scarce.

METHODS

The authors used a statewide, multipayer, insurance claims database linked to cancer registry records to examine the impact of race and provider characteristics on GEP uptake in a cohort of patients newly diagnosed with breast cancer between 2005 and 2012. Incidence proportion models were used to examine the adjusted likelihood of testing. Models were stratified by lymph node status (N0 vs N1).

RESULTS

Among 11,958 eligible patients, 23% of black and 26% of non-Hispanic white patients received GEP. Among patients with N0 disease, black individuals were 16% less likely to receive testing after adjustment for clinical factors and the provider's specialty and volume of patients with breast cancer (95% confidence interval, 0.77-0.93). Adjustment for provider characteristics did not attenuate the effect of race on testing. Patients of middle-volume providers were more likely to be tested compared with those with either high-volume or low-volume providers, whereas patients seeing a medical oncologist were more likely to be tested compared with those whose only providers were from surgical specialties.

CONCLUSIONS

Provider volume and specialty were found to be significant predictors of GEP use, but did not explain racial disparities in testing. Further research concerning the key contributors to lagging test use among black women is needed to optimize the equitable use of GEPs and support personalized treatment decision making for all patients. Cancer 2018. © 2018 American Cancer Society.

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