Classification of C2C12 cells at differentiation by convolutional neural network of deep learning using phase contrast images

Abstract

In the field of regenerative medicine, tremendous numbers of cells are necessary for tissue/organ regeneration. Today automatic cell-culturing system has been developed. The next step is constructing a non-invasive method to monitor the conditions of cells automatically. As an image analysis method, convolutional neural network (CNN), one of the deep learning method, is approaching human recognition level. We constructed and applied the CNN algorithm for automatic cellular differentiation recognition of myogenic C2C12 cell line. Phase-contrast images of cultured C2C12 are prepared as input dataset. In differentiation process from myoblasts to myotubes, cellular morphology changes from round shape to elongated tubular shape due to fusion of the cells. CNN abstract the features of the shape of the cells and classify the cells depending on the culturing days from when differentiation is induced. Changes in cellular shape depending on the number of days of culture (Day 0, Day 3, Day 6) are classified with 91.3% accuracy. Image analysis with CNN has a potential to realize regenerative medicine industry.

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Classification of C2C12 cells at differentiation by convolutional neural network of deep learning using phase contrast images

Abstract

In the field of regenerative medicine, tremendous numbers of cells are necessary for tissue/organ regeneration. Today automatic cell-culturing system has been developed. The next step is constructing a non-invasive method to monitor the conditions of cells automatically. As an image analysis method, convolutional neural network (CNN), one of the deep learning method, is approaching human recognition level. We constructed and applied the CNN algorithm for automatic cellular differentiation recognition of myogenic C2C12 cell line. Phase-contrast images of cultured C2C12 are prepared as input dataset. In differentiation process from myoblasts to myotubes, cellular morphology changes from round shape to elongated tubular shape due to fusion of the cells. CNN abstract the features of the shape of the cells and classify the cells depending on the culturing days from when differentiation is induced. Changes in cellular shape depending on the number of days of culture (Day 0, Day 3, Day 6) are classified with 91.3% accuracy. Image analysis with CNN has a potential to realize regenerative medicine industry.

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Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration

Abstract

Background

It is uncertain whether drugs approved by the US Food and Drug Administration (FDA) have clinically meaningful benefit as determined by validated scales such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).

Methods

We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Study characteristics, outcomes, and regulatory pathways were collected from drug labels and reports of registration trials. For randomized controlled trials (RCTs), ESMO-MCBS grades were applied. Meaningful benefit was defined as a grade of A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. All statistical tests were two-sided.

Results

We identified 63 individual drugs for 118 indications. These were supported by 135 studies, among which were 105 RCTs for which ESMO-MCBS could be applied. Only 46 (43.8%) met the ESMO-MCBS meaningful benefit threshold (100% of (neo)adjuvant trials and 38.8% of palliative trials). In palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared with phase II; odds ratio [OR] = 38.45, 95% confidence interval [CI] = 3.27 to 452.00, P = .004), those with overall survival as their primary end point (compared with intermediate end points; OR = 8.28, 95% CI = 2.49 to 27.50, P = .001) and trials of targeted drugs with companion diagnostics (OR = 11.62, 95% CI = 2.95 to 45.78, P < .001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (P_trend = .04). There were insufficient (neo)adjuvant studies to perform statistical analysis.

Conclusions

The number of trials meeting the ESMO-MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit.

http://ift.tt/2AS2GHS

Hans Christian Andersen and the Value of New Cancer Treatments

In 1837, Hans Christian Andersen published the tale of The Emperor's New Clothes (1), a story about two weavers who promise the emperor a set of new clothes that they claim is invisible to those who are stupid or incompetent. The weavers receive enormous sums to craft the new wardrobe, and throughout the kingdom everyone marvels at the emperor's beautiful clothes until a child exclaims that he isn't wearing anything at all. What can we learn from this classic fable about how to assess the value of new cancer drugs?

http://ift.tt/2AQKizk

Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients

Abstract

Background

Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients.

Patients/methods

After HDC, everolimus was dosed to serum trough levels (goal 3–15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL.

Results

49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required.

Conclusions

Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.

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Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients

Abstract

Background

Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients.

Patients/methods

After HDC, everolimus was dosed to serum trough levels (goal 3–15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL.

Results

49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required.

Conclusions

Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.

http://ift.tt/2AxuVyR

Is there a role for the international prognostic index in follicular lymphoma?

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Thoracic surgeon and patient focus groups on decision-making in early-stage lung cancer surgery

Future Oncology, Ahead of Print.


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A critical review on ramucirumab in the treatment of advanced urothelial cancer

Future Oncology, Ahead of Print.


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Thoracic surgeon and patient focus groups on decision-making in early-stage lung cancer surgery

Future Oncology, Ahead of Print.


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A critical review on ramucirumab in the treatment of advanced urothelial cancer

Future Oncology, Ahead of Print.


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Issue Information

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Issue Information

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Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Junya Yan, Xiaowen Wu, Jiayi Yu, Huan Yu, Tianxiao Xu, Kevin M. Brown, Xue Bai, Jie Dai, Meng Ma, Huan Tang, Lu Si, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Yan Kong, Jun Guo
BackgroundNeuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance of NRAS gain have not been investigated on a large scale.MethodsA total of 657 melanoma samples were included in the study. NRAS copy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient-derived xenograft (PDX) models containing NRAS gain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated.ResultsThe overall incidence of NRAS gain was 14.0% (92 of 657). Incidence of NRAS gain in acral, mucosal, chronic sun-induced damage (CSD) and non-CSD melanomas was 12.2%, 15.8%, 9.5% and 19.4%, respectively. NRAS gain was mutually exclusive to NRAS mutations (P = 0.036). The median survival time for melanoma patients with NRAS gain was significantly shorter than that for patients with normal NRAS copy number (P = 0.006). For patients containing NRAS gain, the median survival time for higher copy number (>4 copies) was significantly shorter than those with lower copy number (2–4 copies; P = 0.002). The MEK inhibitor (binimetinib) inhibited the proliferation of melanoma cells and the tumour growth of PDX models with NRAS gain.ConclusionsNRAS gain is frequent in patients with melanoma and may predict a poor prognosis of melanoma. The melanoma cells and PDX models containing NRAS gain are sensitive to MEK inhibitor (binimetinib), indicating that NRAS gain might be a new therapeutic target for melanoma.



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No overdiagnosis in the Norwegian Breast Cancer Screening Program estimated by combining record linkage and questionnaire information in the Norwegian Women and Cancer study

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Eiliv Lund, Aurelie Nakamura, Jean-Christophe Thalabard
BackgroundThe Norwegian Breast Cancer Screening Program (NBCSP) was implemented across the country in 2005 and has been criticised for potential 'overdiagnosis', i.e. a breast cancer diagnosis that otherwise would not have been detected or treated in a woman's lifetime. We aimed to estimate overdiagnosis in the NBCSP based on the Norwegian Women and Cancer (NOWAC) study using both questionnaire information and record linkage information from NBCSP.MethodFor 124,978 women aged 49–79 years from the NOWAC study, information on screened women could be cross-validated from the NBCSP database. Based on information from the NOWAC questionnaire, unscreened women were further divided into those who had mammograms taken only outside the NBCSP and those who had never had taken a mammogram. Breast cancers diagnosed in 2005–2013 were identified through linkage to the Cancer Registry of Norway; in situ or DCIS 417; invasive 2845; combined 3262. Cumulative incidence rates (CIRs) for ages 49–79 years of breast cancer were compared using the log-rank test.ResultsAfter exclusion of women with a family history of breast cancer, screened women had a CIR of 9.7% for combined breast cancer, non-significantly lower compared with unscreened women. Screened women had a 1.1% increased CIR or 13.0% increased relative risk of breast cancer diagnosis (significant) compared with women who had never had a mammogram, but for invasive breast cancer alone the difference was reduced to −0.2% (95% CI: −9.1; 8.8). Invasive breast cancers were significantly smaller (<2.5 cm) in screened versus unscreened women. There was a borderline significant decrease in lymph node positive cancer among screened (p = 0.06).ConclusionThe findings of no significant overdiagnosis combined with smaller tumours and less lymph node metastases suggest that the prevailing view of overdiagnosis in the NBCSP should be challenged.



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Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database

Summary

Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication.

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Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database

Summary

Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication.

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Correction to: FDG uptake in cervical lymph nodes in children without head and neck cancer

Abstract

The original version of this article unfortunately contained a mistake. Author name Alaa Bakkari was incorrect. The correct spelling is given above.

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Correction to: FDG uptake in cervical lymph nodes in children without head and neck cancer

Abstract

The original version of this article unfortunately contained a mistake. Author name Alaa Bakkari was incorrect. The correct spelling is given above.

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Autologous dendritic cells pulsed with allogeneic tumor cell lysate in mesothelioma: From mouse to human

Purpose: Mesothelioma has been regarded as a non-immunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis.  Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response towards malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source.  The purpose of this study was to investigate if allogeneic lysate pulsed DC immunotherapy is effective in mice and safe in humans. Experimental Design: Firstly, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate, or injected with PBS (negative control). Survival and tumor-directed T cell responses of these mice were monitored.  Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25 or 50 million DC per vaccination. DC vaccination consisted of autologous monocyte-derived DC pulsed with tumor lysate from 5 mesothelioma cell lines. Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months (95% CI 4.1-20.3) and median OS not reached (median follow up 22.8 months). Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans.

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Clinical significance of PD-L1+ exosomes in plasma of Head and Neck Cancer patients

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCCs) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated. Methods: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFIs) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients' clinicopathological data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T-cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients' plasma was tested for soluble PD-L1 (sPD-L1) by ELISA. Results: Levels of PD-L1 carried by exosomes correlated with patients' disease activity, the UICC stage and the lymph node status (p= 0.0008-0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathological parameters. CD69 expression levels were inhibited (p<0.03) by co-incubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression. Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated correlate with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients.

http://ift.tt/2Bgre01

Neddylation blockade diminishes hepatic metastasis by dampening cancer stem-like cells and angiogenesis in uveal melanoma

Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM. Experimental Design: Expression of key proteins in neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg–(NSI) mouse model. Results: NAE1 expression was readily detectable in UM. Inhibition of neddylation pathway by MLN4924 repressed the CSCs properties in UM [capacities of tumorsphere formation and serially-replating, aldehyde dehydrogenase positive (ALDH+) cells, and frequency of CSCs] through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-B-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation which was confirmed by xenografted UM tumor in NOD-SCID mice was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2/M-phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM. Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM.

http://ift.tt/2iYf6Gk

Clinical significance of PD-L1+ exosomes in plasma of Head and Neck Cancer patients

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCCs) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated. Methods: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFIs) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients' clinicopathological data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T-cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients' plasma was tested for soluble PD-L1 (sPD-L1) by ELISA. Results: Levels of PD-L1 carried by exosomes correlated with patients' disease activity, the UICC stage and the lymph node status (p= 0.0008-0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathological parameters. CD69 expression levels were inhibited (p<0.03) by co-incubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression. Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated correlate with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients.

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Neddylation blockade diminishes hepatic metastasis by dampening cancer stem-like cells and angiogenesis in uveal melanoma

Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM. Experimental Design: Expression of key proteins in neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg–(NSI) mouse model. Results: NAE1 expression was readily detectable in UM. Inhibition of neddylation pathway by MLN4924 repressed the CSCs properties in UM [capacities of tumorsphere formation and serially-replating, aldehyde dehydrogenase positive (ALDH+) cells, and frequency of CSCs] through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-B-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation which was confirmed by xenografted UM tumor in NOD-SCID mice was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2/M-phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM. Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM.

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Single-cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell cycle-related transcription and attenuated androgen response

Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen-deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2/M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell cycle-related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver-operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen-deprivation therapies and reveals characteristics of subpopulations resistant to this treatment.

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Targeting CDK6 and BCL2 exploits the "MYB addiction" of Ph+ acute lymphoblastic leukemia

Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is currently treated with BCR-ABL1 tyrosine kinase inhibitors (TKI) in combination with chemotherapy. However, most patients develop resistance to TKI through BCR-ABL1-dependent and -independent mechanisms. Newly developed TKI can target Ph+ ALL cells with BCR-ABL1-dependent resistance; however, overcoming BCR-ABL1-independent mechanisms of resistance remains challenging because transcription factors (TF), which are difficult to inhibit, are often involved. We show here that: i) the growth of Ph+ ALL cell lines and primary cells is highly dependent on MYB-mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2 and ii) restoring their expression in MYB-silenced Ph+ ALL cells rescues their impaired proliferation and survival. Levels of MYB and CDK6 were highly correlated in adult Ph+ ALL (p=0.00008). Moreover, Ph+ ALL cells exhibited a specific requirement for CDK6 but not CDK4 expression, most likely because, in these cells, CDK6 was predominantly localized in the nucleus while CDK4 was almost exclusively cytoplasmic. Consistent with their essential role in Ph+ ALL, pharmacological inhibition of CDK6 and BCL2 markedly suppressed proliferation, colony formation, and survival of Ph+ ALL cells ex vivo and in mice. In summary, these findings provide a proof-of-principle, rational strategy to target the MYB "addiction" of Ph+ ALL.

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Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma

Pancreatoblastoma (PBL) is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multi-omics study of whole exome and RNA sequencing as well as genome-wide copy number and methylation analyses of 10 PBL cases. The PBL genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) were universally detected. At the transcriptome level, PBL exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for PBL and highlight rational therapeutic targets for its treatment.

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Comprehensive mutation and copy number profiling in archived circulating breast cancer tumor cells documents heterogeneous resistance mechanisms

Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer, to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTC and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTC isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTC and metastatic tissues. In 76 individual and pooled informative CTC from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTC and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTC, and vice versa. CTC profiling identified diverse intra- and inter-patient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity (LOH) in individual CTC. For example, in one patient, we observed CTC that were either wildtype for ESR1 (n=5/32), harbored the known activating ESR1 p.Y537S mutation (n=26/32), or harbored a novel ESR1 p.A569S (n=1/32). ESR1 p.A569S was modestly activating in vitro, consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTC. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.

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A20 regulates the DNA damage response and mediates tumor cell resistance to DNA damaging therapy

A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen DDR can blunt the efficacy of chemotherapy and radiotherapy which cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168-H2A interaction in a manner independent of its enzymatic activity. Further, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone non-homologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed consistent with its candidacy as a therapeutic target. Taken together, our findings suggest A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NF-κB regulated ubiquitin-editing enzyme and the DDR pathway.

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Single-cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell cycle-related transcription and attenuated androgen response

Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen-deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2/M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell cycle-related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver-operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen-deprivation therapies and reveals characteristics of subpopulations resistant to this treatment.

http://ift.tt/2yjQooU

Targeting CDK6 and BCL2 exploits the "MYB addiction" of Ph+ acute lymphoblastic leukemia

Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is currently treated with BCR-ABL1 tyrosine kinase inhibitors (TKI) in combination with chemotherapy. However, most patients develop resistance to TKI through BCR-ABL1-dependent and -independent mechanisms. Newly developed TKI can target Ph+ ALL cells with BCR-ABL1-dependent resistance; however, overcoming BCR-ABL1-independent mechanisms of resistance remains challenging because transcription factors (TF), which are difficult to inhibit, are often involved. We show here that: i) the growth of Ph+ ALL cell lines and primary cells is highly dependent on MYB-mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2 and ii) restoring their expression in MYB-silenced Ph+ ALL cells rescues their impaired proliferation and survival. Levels of MYB and CDK6 were highly correlated in adult Ph+ ALL (p=0.00008). Moreover, Ph+ ALL cells exhibited a specific requirement for CDK6 but not CDK4 expression, most likely because, in these cells, CDK6 was predominantly localized in the nucleus while CDK4 was almost exclusively cytoplasmic. Consistent with their essential role in Ph+ ALL, pharmacological inhibition of CDK6 and BCL2 markedly suppressed proliferation, colony formation, and survival of Ph+ ALL cells ex vivo and in mice. In summary, these findings provide a proof-of-principle, rational strategy to target the MYB "addiction" of Ph+ ALL.

http://ift.tt/2AA1YlO

Comprehensive mutation and copy number profiling in archived circulating breast cancer tumor cells documents heterogeneous resistance mechanisms

Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer, to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTC and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTC isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTC and metastatic tissues. In 76 individual and pooled informative CTC from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTC and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTC, and vice versa. CTC profiling identified diverse intra- and inter-patient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity (LOH) in individual CTC. For example, in one patient, we observed CTC that were either wildtype for ESR1 (n=5/32), harbored the known activating ESR1 p.Y537S mutation (n=26/32), or harbored a novel ESR1 p.A569S (n=1/32). ESR1 p.A569S was modestly activating in vitro, consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTC. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.

http://ift.tt/2ykwoCB

A20 regulates the DNA damage response and mediates tumor cell resistance to DNA damaging therapy

A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen DDR can blunt the efficacy of chemotherapy and radiotherapy which cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168-H2A interaction in a manner independent of its enzymatic activity. Further, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone non-homologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed consistent with its candidacy as a therapeutic target. Taken together, our findings suggest A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NF-κB regulated ubiquitin-editing enzyme and the DDR pathway.

http://ift.tt/2AB3fsP

Role for Immune Therapy in Advanced Breast Cancer [News in Brief]

Data suggest that pembrolizumab can control growth of trastuzumab-resistant HER2-positive tumors.

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Rapid Responses to Avapritinib (BLU-285) in Mastocytosis [News in Brief]

Targeted therapy produces lasting reductions in mast cells and molecular levels of KIT D816V.

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Association between PDE4D rs966221 polymorphism and risk of ischemic stroke: a systematic review and meta-analysis

Abstract

PDE4D polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to ischemic stroke (IS), however, the results were inconclusive. An electronic search of Embase, PubMed, CNKI and Wan Fang Date was performed to identify relevant studies published throughout April 2017. A total of 26 studies were enrolled in the analysis. No significant association between the rs9662221 polymorphism and IS was observed in the overall analysis. Nevertheless, in the subgroup analysis, our results showed a significant association between the SNP83 polymorphism and IS in CC+ CT vs. TT (OR = 1.19, 95% CI: 1.02–1.38), CT vs.TT (OR = 1.14, 95% CI: 1.01–1.29) and C vs. T (OR = 1.25, 95% CI: 1.06–1.48) in Asian population. But we did not found any association in CC vs. CT + TT (OR = 1.2, 95% CI: 0.9–1.61) and CC vs. TT (OR = 1.26, 95% CI: 0.91–1.75) in the Asian populations. Meantime, no significant correlations were observed under the five genetic model in Caucasian population (p > 0.05). In conclusion, our meta-analysis demonstrated that the SNP83 polymorphism in the PDE4D gene might contribute to IS susceptibility especially in Asian populations. Whereas the relationship of the polymorphism to the disease in Caucasian population was still in controversial. In future, additional well designed studies with larger sample sizes are still required to further elucidate this association.

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Statistical models to predict adverse perioperative outcomes: A case for longer follow up time frames

Large datasets have become available and widely adopted by perioperative medicine researchers in the last decade [1–3]. The use of electronic medical records has facilitated massive data collection not only by single institutions, but also by multicenter initiatives [4–6]. Large datasets enabled the evaluation of infrequent (but important) perioperative outcome with the expectation that interventions could have been implemented to improve the care of patients undergoing surgical procedures.

http://ift.tt/2nSUxAh

Alcohol and oestrogen metabolites in postmenopausal women in the Women’s Health Initiative Observational Study

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study, Published online: 12 December 2017; doi:10.1038/bjc.2017.419

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study

http://ift.tt/2BXy8Ef

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Targeting the Raf kinases in human cancer: the Raf dimer dilemma, Published online: 12 December 2017; doi:10.1038/bjc.2017.399

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

http://ift.tt/2BX6Duh

Anthropometric measurements and survival after a prostate cancer diagnosis

Anthropometric measurements and survival after a prostate cancer diagnosis

Anthropometric measurements and survival after a prostate cancer diagnosis, Published online: 12 December 2017; doi:10.1038/bjc.2017.440

Anthropometric measurements and survival after a prostate cancer diagnosis

http://ift.tt/2BXykmX

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

ALDH1A3 affects colon cancer <i>in vitro</i> proliferation and invasion depending on CXCR4 status, Published online: 12 December 2017; doi:10.1038/bjc.2017.363

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

http://ift.tt/2BXyoTJ

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma, Published online: 12 December 2017; doi:10.1038/bjc.2017.430

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

http://ift.tt/2BX6JlD

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma, Published online: 12 December 2017; doi:10.1038/bjc.2017.433

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

http://ift.tt/2BX6AyB

Cell and molecular biology: a new section joins the fight against cancer

Cell and molecular biology: a new section joins the fight against cancer

Cell and molecular biology: a new section joins the fight against cancer, Published online: 12 December 2017; doi:10.1038/bjc.2017.443

Cell and molecular biology: a new section joins the fight against cancer

http://ift.tt/2BXyg6H

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial, Published online: 12 December 2017; doi:10.1038/bjc.2017.423

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

http://ift.tt/2BWM5lQ

Retreatment with Vismodegib after Progression in Advanced Basal Cell Carcinoma: First-Time Report of a Single-Institution Experience

Abstract

Retreatment with vismodegib in advanced basal cell carcinoma (BCC) patients who previously discontinued the drug due to disease progression (PD) has not been reported yet. The objective of our report is to determine whether vismodegib is still active when used in BCC patients who progressed during a first vismodegib course (FVC). We conducted a retrospective study on six advanced BCC patients enrolled in a clinical trial (STEVIE, NCT01367665) who discontinued vismodegib due to PD and were then retreated with the same drug. All patients underwent intercurrent therapies between the FVC and the second vismodegib course (SVC). Disease control (complete response, CR; partial response, PR; and stable disease) was achieved in 100% and 80% of cases in FVC and SVC, respectively. The overall response rate was 80% for FVC (50% of CR) and 50% for SVC (only PR). Median treatment duration of FVC and SVC was 19.5 months (range: 13–35) and 8 months (range: 3–14+), respectively. G3-G4 AEs were reported only during SVC (two cases), leading to permanent discontinuation in one case. The median interval between FVC and SVC was 21.5 months (range: 13–30). After a median follow-up of 54 months (range: 46–63) only one patient with metastatic disease had rapid progression, discontinued vismodegib, and died. All other patients are still alive and two are currently on therapy. We concluded that vismodegib rechallenge is feasible and potentially active in advanced BCC patients who previously discontinued the drug due to disease progression.

http://ift.tt/2AdN94b

Alcohol and oestrogen metabolites in postmenopausal women in the Women’s Health Initiative Observational Study

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study, Published online: 12 December 2017; doi:10.1038/bjc.2017.419

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study

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Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Targeting the Raf kinases in human cancer: the Raf dimer dilemma, Published online: 12 December 2017; doi:10.1038/bjc.2017.399

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

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Anthropometric measurements and survival after a prostate cancer diagnosis

Anthropometric measurements and survival after a prostate cancer diagnosis

Anthropometric measurements and survival after a prostate cancer diagnosis, Published online: 12 December 2017; doi:10.1038/bjc.2017.440

Anthropometric measurements and survival after a prostate cancer diagnosis

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ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

ALDH1A3 affects colon cancer <i>in vitro</i> proliferation and invasion depending on CXCR4 status, Published online: 12 December 2017; doi:10.1038/bjc.2017.363

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

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The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma, Published online: 12 December 2017; doi:10.1038/bjc.2017.430

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

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Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma, Published online: 12 December 2017; doi:10.1038/bjc.2017.433

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

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Cell and molecular biology: a new section joins the fight against cancer

Cell and molecular biology: a new section joins the fight against cancer

Cell and molecular biology: a new section joins the fight against cancer, Published online: 12 December 2017; doi:10.1038/bjc.2017.443

Cell and molecular biology: a new section joins the fight against cancer

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Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial, Published online: 12 December 2017; doi:10.1038/bjc.2017.423

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

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Serial 4DCT/4DPET imaging to predict and monitor response for locally-advanced non-small cell lung cancer chemo-radiotherapy

A FDG-PET/CT image feature with optimal prognostic potential for locally-advanced non-small cell lung cancer (LA-NSCLC) patients has yet to be identified, and neither has the optimal time for FDG-PET/CT response assessment; furthermore, nodal features have been largely ignored in the literature. We propose to identify image features or imaging time point with maximal prognostic power.

http://ift.tt/2iVZYcr

Exposure of the lungs in breast cancer radiotherapy: A systematic review of lung doses published 2010–2015

We report a systematic review of lung radiation doses from breast cancer radiotherapy.

http://ift.tt/2BiRZAQ

Staging, Treatment, and Future Approaches of Gallbladder Carcinoma

Abstract

Background

Gallbladder cancer is the most common malignant cancer of the bile ducts and third most common gastrointestinal malignant in the world for public health. Its relatively low incidence and confused symptoms result in advanced disease at the time of presentation, contributing to poor prognosis and reduced survival associated with this disease. The main function of the gallbladder is to store excreted bile acids from the liver in preparation for a meal. Its main risk factor is prolonged exposure to biliary calculations, although bacterial infections and other inflammatory conditions are associated. Chronic inflammatory bowel conditions are associated with gallbladder cancer. T stage translates to identifying residual disease at reoperation for incidental gallbladder cancer and residual disease negatively affects survival.

Conclusion

It is the most common cancer of gallbladder, gallbladder cancer remains a rare disease. Gallbladder cancer is a rare disease that can be accidentally diagnosed after cholecystectomy or accidentally, often with more advanced disease. The prognosis is generally extremely poor and improvements in surgical resection of this approach have to be re-evaluated, while the role of chemotherapy and radiotherapy remains controversial.

http://ift.tt/2C6I2Eh

Staging, Treatment, and Future Approaches of Gallbladder Carcinoma

Abstract

Background

Gallbladder cancer is the most common malignant cancer of the bile ducts and third most common gastrointestinal malignant in the world for public health. Its relatively low incidence and confused symptoms result in advanced disease at the time of presentation, contributing to poor prognosis and reduced survival associated with this disease. The main function of the gallbladder is to store excreted bile acids from the liver in preparation for a meal. Its main risk factor is prolonged exposure to biliary calculations, although bacterial infections and other inflammatory conditions are associated. Chronic inflammatory bowel conditions are associated with gallbladder cancer. T stage translates to identifying residual disease at reoperation for incidental gallbladder cancer and residual disease negatively affects survival.

Conclusion

It is the most common cancer of gallbladder, gallbladder cancer remains a rare disease. Gallbladder cancer is a rare disease that can be accidentally diagnosed after cholecystectomy or accidentally, often with more advanced disease. The prognosis is generally extremely poor and improvements in surgical resection of this approach have to be re-evaluated, while the role of chemotherapy and radiotherapy remains controversial.

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Alcohol and oestrogen metabolites in postmenopausal women in the Women’s Health Initiative Observational Study

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Targeting the Raf kinases in human cancer: the Raf dimer dilemma

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Anthropometric measurements and survival after a prostate cancer diagnosis

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ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

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The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

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Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

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Cell and molecular biology: a new section joins the fight against cancer

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via IFTTT

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

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Alcohol and oestrogen metabolites in postmenopausal women in the Women’s Health Initiative Observational Study

http://ift.tt/2yj1N8z

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

http://ift.tt/2AwoITD

Anthropometric measurements and survival after a prostate cancer diagnosis

http://ift.tt/2yj5LxV

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

http://ift.tt/2Axpn7D

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

http://ift.tt/2yiC5Rq

Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma

http://ift.tt/2AxpfoF

Cell and molecular biology: a new section joins the fight against cancer

http://ift.tt/2yiGtQI

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

http://ift.tt/2AvoT1D

Oncological Assessment of Stent Placement for Obstructive Colorectal Cancer from Circulating Cell-Free DNA and Circulating Tumor DNA Dynamics

Abstract

Background

The self-expanding metallic stent (SEMS) provides effective decompression for patients with malignant large bowel obstruction (MLBO); however, mechanical damage to malignant cells from insertion may negatively affect prognosis, similar to surgical manipulation, and its oncological safety is unclear. We examined mechanical damage from SEMS placement using circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA).

Methods

Between 1 November 2014 and 30 June 2017, 35 MLBO patients were analyzed, comprising 25 SEMS patients and 10 transanal decompression tube (TDT) patients (control). Blood samples were collected before and after decompression on days 0, 1, 3, and 7. cfDNA, ctDNA, white blood cells, C-reactive protein, and lactate dehydrogenase were analyzed.

Results

The clinical success rates of SEMS and TDT were 88 and 90%, respectively (p = 1.0). The cfDNA concentration on day 7 was significantly higher in the SEMS group than in the TDT group (992 vs. 308 ng/mL; p = 0.005). A significant increase in ctDNA was observed in the SEMS group compared with the TDT group (83% vs. 22%; p = 0.002). The cfDNA concentration showed strong positive correlations with ctDNA and lactate dehydrogenase (R ² = 0.838 and 0.593, respectively), and a weak positive correlation with C-reactive protein (R ² = 0.263).

Conclusions

Despite equivalent clinical success rates, SEMS placement increased plasma levels of cfDNA and ctDNA by tumor manipulation, but TDT did not. Colonic stenting showed oncological risk in terms of molecular analysis.

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Oncological Assessment of Stent Placement for Obstructive Colorectal Cancer from Circulating Cell-Free DNA and Circulating Tumor DNA Dynamics

Abstract

Background

The self-expanding metallic stent (SEMS) provides effective decompression for patients with malignant large bowel obstruction (MLBO); however, mechanical damage to malignant cells from insertion may negatively affect prognosis, similar to surgical manipulation, and its oncological safety is unclear. We examined mechanical damage from SEMS placement using circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA).

Methods

Between 1 November 2014 and 30 June 2017, 35 MLBO patients were analyzed, comprising 25 SEMS patients and 10 transanal decompression tube (TDT) patients (control). Blood samples were collected before and after decompression on days 0, 1, 3, and 7. cfDNA, ctDNA, white blood cells, C-reactive protein, and lactate dehydrogenase were analyzed.

Results

The clinical success rates of SEMS and TDT were 88 and 90%, respectively (p = 1.0). The cfDNA concentration on day 7 was significantly higher in the SEMS group than in the TDT group (992 vs. 308 ng/mL; p = 0.005). A significant increase in ctDNA was observed in the SEMS group compared with the TDT group (83% vs. 22%; p = 0.002). The cfDNA concentration showed strong positive correlations with ctDNA and lactate dehydrogenase (R ² = 0.838 and 0.593, respectively), and a weak positive correlation with C-reactive protein (R ² = 0.263).

Conclusions

Despite equivalent clinical success rates, SEMS placement increased plasma levels of cfDNA and ctDNA by tumor manipulation, but TDT did not. Colonic stenting showed oncological risk in terms of molecular analysis.

http://ift.tt/2C6JXJ6

Intrinsic Contact Between T and N Classifications in Resected Well–Moderately Differentiated Locoregional Pancreatic Neuroendocrine Neoplasms

Abstract

Background

The role of N classification is controversial in several prognostication systems proposed for pancreatic neuroendocrine neoplasms (pNENs). The widely accepted modified European Neuroendocrine Tumor Society (mENETS) system suggests this contradiction may be related to T classification.

Methods

Data were collected retrospectively from 981 patients in the Surveillance, Epidemiology, and End Results (SEER) database (1973–2012; cohort 1) and 140 patients from the Pancreatic Cancer Institute of Fudan University (2006–2016; cohort 2). All patients had resected well- to moderately differentiated locoregional pNENs, whereby the mENETS system was adopted. Factors related to N1 classification and the association between N and T classifications were analyzed, and N classification prognosis based on T classification was assessed.

Results

In cohorts 1 and 2, tumor size (2–4 cm: p < 0.001 and p = 0.037, respectively; > 4 cm: p < 0.001 and p = 0.012, respectively) and tumors extending beyond the pancreas (p < 0.001 and p = 0.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (p < 0.001 and p = 0.046, respectively) and predicted poor disease-specific survival (DSS), while for tumors extending beyond the pancreas, the N1 classification did not affect patient outcomes. Findings obtained with data from the SEER database were reproducible with our institutional data.

Conclusions

N classification is associated with T classification, limiting the value of N1 classification for the pNENs tumor-node-metastasis system. A new risk model is necessary to predict patient outcomes and guide clinical practice for the prognosis of pNENs.

http://ift.tt/2AxtwIA

Snapshot Study on the Value of Omentoplasty in Abdominoperineal Resection with Primary Perineal Closure for Rectal Cancer

Abstract

Background

Perineal wound complications are often encountered following abdominoperineal resection (APR). Filling of the pelvic space by omentoplasty (OP) might prevent these complications, but there is scant evidence to support its routine application.

Objective

The aim of this study was to evaluate the impact of OP on perineal wound complications.

Methods

All patients undergoing APR with primary perineal closure (PPC) for non-locally advanced rectal cancer in 71 Dutch centers in 2011 were selected from a cross-sectional snapshot study. Outcomes were compared between PPC with or without OP, which was based on variability in practice among surgeons.

Results

Of 639 patients who underwent APR for rectal cancer, 477 had a non-locally advanced tumor and PPC was performed. Of those, 172 (36%) underwent OP. Patients with OP statistically more often underwent an extralevator approach (32% vs. 14%). Median follow-up was 41 months (interquartile range 22–47). There were no significant differences with or without OP in terms of non-healing of the perineal wound at 30 days (47% vs. 48%), non-healing at the end of follow-up (9% vs. 5%), pelvic abscess (12% vs. 13%) or re-intervention for ileus (5% vs. 3%). Perineal hernia developed significantly more often after OP (13% vs. 7%), also by multivariable analysis (odds ratio 2.61, 95% confidence interval 1.271–5.364; p = 0.009).

Conclusions

In contrast to previous assumptions, OP after APR with PPC appeared not to improve perineal wound healing and seemed to increase the occurrence of perineal hernia. These findings question the routine use of OP for primary filling of the pelvic space.

http://ift.tt/2yi8Zlq

Intrinsic Contact Between T and N Classifications in Resected Well–Moderately Differentiated Locoregional Pancreatic Neuroendocrine Neoplasms

Abstract

Background

The role of N classification is controversial in several prognostication systems proposed for pancreatic neuroendocrine neoplasms (pNENs). The widely accepted modified European Neuroendocrine Tumor Society (mENETS) system suggests this contradiction may be related to T classification.

Methods

Data were collected retrospectively from 981 patients in the Surveillance, Epidemiology, and End Results (SEER) database (1973–2012; cohort 1) and 140 patients from the Pancreatic Cancer Institute of Fudan University (2006–2016; cohort 2). All patients had resected well- to moderately differentiated locoregional pNENs, whereby the mENETS system was adopted. Factors related to N1 classification and the association between N and T classifications were analyzed, and N classification prognosis based on T classification was assessed.

Results

In cohorts 1 and 2, tumor size (2–4 cm: p < 0.001 and p = 0.037, respectively; > 4 cm: p < 0.001 and p = 0.012, respectively) and tumors extending beyond the pancreas (p < 0.001 and p = 0.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (p < 0.001 and p = 0.046, respectively) and predicted poor disease-specific survival (DSS), while for tumors extending beyond the pancreas, the N1 classification did not affect patient outcomes. Findings obtained with data from the SEER database were reproducible with our institutional data.

Conclusions

N classification is associated with T classification, limiting the value of N1 classification for the pNENs tumor-node-metastasis system. A new risk model is necessary to predict patient outcomes and guide clinical practice for the prognosis of pNENs.

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Snapshot Study on the Value of Omentoplasty in Abdominoperineal Resection with Primary Perineal Closure for Rectal Cancer

Abstract

Background

Perineal wound complications are often encountered following abdominoperineal resection (APR). Filling of the pelvic space by omentoplasty (OP) might prevent these complications, but there is scant evidence to support its routine application.

Objective

The aim of this study was to evaluate the impact of OP on perineal wound complications.

Methods

All patients undergoing APR with primary perineal closure (PPC) for non-locally advanced rectal cancer in 71 Dutch centers in 2011 were selected from a cross-sectional snapshot study. Outcomes were compared between PPC with or without OP, which was based on variability in practice among surgeons.

Results

Of 639 patients who underwent APR for rectal cancer, 477 had a non-locally advanced tumor and PPC was performed. Of those, 172 (36%) underwent OP. Patients with OP statistically more often underwent an extralevator approach (32% vs. 14%). Median follow-up was 41 months (interquartile range 22–47). There were no significant differences with or without OP in terms of non-healing of the perineal wound at 30 days (47% vs. 48%), non-healing at the end of follow-up (9% vs. 5%), pelvic abscess (12% vs. 13%) or re-intervention for ileus (5% vs. 3%). Perineal hernia developed significantly more often after OP (13% vs. 7%), also by multivariable analysis (odds ratio 2.61, 95% confidence interval 1.271–5.364; p = 0.009).

Conclusions

In contrast to previous assumptions, OP after APR with PPC appeared not to improve perineal wound healing and seemed to increase the occurrence of perineal hernia. These findings question the routine use of OP for primary filling of the pelvic space.

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Acalabrutinib Receives FDA Approval for Mantle Cell Lymphoma

The FDA has granted accelerated approval to acalabrutinib (Calquence®) for the treatment of adults with mantle cell lymphoma whose cancer has progressed after receiving at least one prior therapy.

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Acalabrutinib Receives FDA Approval for Mantle Cell Lymphoma

The FDA has granted accelerated approval to acalabrutinib (Calquence®) for the treatment of adults with mantle cell lymphoma whose cancer has progressed after receiving at least one prior therapy.

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Normal magnetic resonance appearances of the temporomandibular joints in children and young adults aged 2–18 years

Abstract

Background

Knowledge of normal appearances of the temporomandibular joint (TMJ) is paramount when assessing the joint for disease in juvenile idiopathic arthritis. Reliable features defining normal TMJs in children are limited.

Objective

To establish reliable normal standards for the TMJ at magnetic resonance imaging (MRI).

Materials and methods

We included children and young adults aged 2–18 years undergoing a head MRI for reasons not believed to affect the TMJs. We assessed TMJ anatomy and contrast enhancement using a high-resolution 3-D T1-weighted sequence. We noted joint fluid and bone marrow oedema based on a T2-weighted sequence. Three experienced radiologists read all examinations twice in consensus and defined intraobserver consensus agreement.

Results

We evaluated the TMJs in 101 children and young adults (45 female), mean age 10.7 years (range 2–18 years). The intraobserver consensus agreement for the assessment of anterior condylar inclination in the sagittal/oblique plane was moderate to good (Cohen κ=0.7 for the right side). Cohen κ for intraobserver consensus agreement for condylar shape in the coronal plane on a 0–2 scale was 0.4 for the right and 0.6 for the left. Intraobserver agreement for measurement of joint space height and assessment of bone marrow oedema was poor. There was a statistically significant increase in anterior inclination by age in the sagittal plane on a 0–2 scale (P<0.0001). Eighty percent of the condyles showed a rounded shape in the coronal plane while 20% showed mild flattening. Thirty-five of 36 right TMJs showed contrast enhancement (mild enhancement in 32 joints, moderate in 3 joints).

Conclusion

Subjective assessment of the anterior condylar inclination in the sagittal/oblique plane and condylar flattening in the coronal plane can be considered precise features for describing TMJ anatomy in healthy children. There is an increasing anterior inclination by age. Mild contrast enhancement of the TMJs should be considered a normal finding.

http://ift.tt/2jTM7En

Normal magnetic resonance appearances of the temporomandibular joints in children and young adults aged 2–18 years

Abstract

Background

Knowledge of normal appearances of the temporomandibular joint (TMJ) is paramount when assessing the joint for disease in juvenile idiopathic arthritis. Reliable features defining normal TMJs in children are limited.

Objective

To establish reliable normal standards for the TMJ at magnetic resonance imaging (MRI).

Materials and methods

We included children and young adults aged 2–18 years undergoing a head MRI for reasons not believed to affect the TMJs. We assessed TMJ anatomy and contrast enhancement using a high-resolution 3-D T1-weighted sequence. We noted joint fluid and bone marrow oedema based on a T2-weighted sequence. Three experienced radiologists read all examinations twice in consensus and defined intraobserver consensus agreement.

Results

We evaluated the TMJs in 101 children and young adults (45 female), mean age 10.7 years (range 2–18 years). The intraobserver consensus agreement for the assessment of anterior condylar inclination in the sagittal/oblique plane was moderate to good (Cohen κ=0.7 for the right side). Cohen κ for intraobserver consensus agreement for condylar shape in the coronal plane on a 0–2 scale was 0.4 for the right and 0.6 for the left. Intraobserver agreement for measurement of joint space height and assessment of bone marrow oedema was poor. There was a statistically significant increase in anterior inclination by age in the sagittal plane on a 0–2 scale (P<0.0001). Eighty percent of the condyles showed a rounded shape in the coronal plane while 20% showed mild flattening. Thirty-five of 36 right TMJs showed contrast enhancement (mild enhancement in 32 joints, moderate in 3 joints).

Conclusion

Subjective assessment of the anterior condylar inclination in the sagittal/oblique plane and condylar flattening in the coronal plane can be considered precise features for describing TMJ anatomy in healthy children. There is an increasing anterior inclination by age. Mild contrast enhancement of the TMJs should be considered a normal finding.

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Correction to: Metastasectomy for Tumor-Infiltrating Lymphocytes: An Emerging Operative Indication in Surgical Oncology

Abstract

In the original article the middle initial of Nicholas D. Klemen was inadvertently omitted. On the first page of the original article, under the heading A Novel Way to Fight Cancer, there was an error in the third sentence. The corrected text is as follows: For example, the presence of T cells within tumors of colorectal origin can be a superior predictor of patient survival compared with the standard histopathologic methods currently used to stage colorectal cancer.^6,7

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Predictors for incidence of increased time spent in hospital after ambulatory surgery in children: a retrospective cohort study

Abstract

Purpose

Recently, pediatric ambulatory surgery has become common. However, for some of these patients, unplanned admission or prolonged hospital stay is also necessary, which can increase the mental burden on these patients. The aim of this study was to identify the predictors of the incidence of increased time spent in hospitals associated with pediatric ambulatory surgery.

Methods

Data were obtained from the medical and anesthetic records of 1087 consecutive patients aged < 18 years who underwent ambulatory surgery under general anesthesia. We defined the incidence of increased time spent in a hospital as a composite outcome of unplanned admission and prolonged hospital stay. Multivariate logistic regression analysis was used to examine the associations between the incidence of increased time spent in a hospital and 14 parameters including patient characteristics, anesthesia, and operative factors.

Results

Multivariate analysis identified American Society of Anesthesiologist Physical Status (ASA-PS), type of regional block, intraoperative fluid volume, and type of surgery as predictors for the incidence of increased time spent in a hospital. Specifically, caudal block compared to no regional block [odds ratio (OR) (95% confidence interval (CI)) = 0.44 (0.22–0.90)]; increasing intraoperative fluid volume [OR (95% CI) = 0.71 (0.55–0.92) in every increment of 5 ml/kg/h); and ear, nose, and throat (ENT) and urology surgery compared to other types of surgery [OR (95% CI) = 0.13 (0.03–0.64), and 3.93 (1.99–7.77), respectively] were identified as strong predictors.

Conclusions

This study found that the incidence of increased time spent in a hospital in pediatric ambulatory surgery was affected by the type of regional block, intraoperative fluid volume, type of surgery. Potentially modifiable factors, such as intraoperative fluid volume or type of regional block, should be further investigated in future prospective studies.

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Correction to: Metastasectomy for Tumor-Infiltrating Lymphocytes: An Emerging Operative Indication in Surgical Oncology

Abstract

In the original article the middle initial of Nicholas D. Klemen was inadvertently omitted. On the first page of the original article, under the heading A Novel Way to Fight Cancer, there was an error in the third sentence. The corrected text is as follows: For example, the presence of T cells within tumors of colorectal origin can be a superior predictor of patient survival compared with the standard histopathologic methods currently used to stage colorectal cancer.^6,7

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Do Treatment Patterns Alter Beliefs Cancer Patients hold Regarding Oral Oncolytic Agents?

Abstract

Objective

Cancer patients, particularly those prescribed oral oncolytic medications, face treatment side effects, and temporary and permanent stoppages of treatment. This research examines how events during treatment affect patients' beliefs regarding oral oncolytic medications.

Methods

272 cancer patients initiating one of 28 oral oncolytic agents were followed for 12 weeks. Assessments of Beliefs About Medications Questionnaire (BMQ), symptoms, physical function, and depression measures were performed during telephone interviews at intake (medication start) and 4, 8, and 12 weeks. Electronic medical record audits identified dates of temporary and permanent medication stoppages. Linear mixed effects models were used for longitudinal analyses of the BMQ scores in relation to patient characteristics, symptom severity, and medication stoppages.

Results

Over the initial 12 weeks beliefs about the necessity of oral medications increased, concerns decreased, and interference of medications with daily lives increased. Permanent stoppage of a medication predicted significant declines in beliefs about its necessity over time. Male patients, those less educated, those reporting higher symptom severity, and experiencing temporary stoppages had greater concerns. Interference of medications with daily life was higher for males, increased with higher symptom severity, and differed by drug category.

Conclusions

Patients' beliefs in the necessity of their oral medication were affected only by a permanent drug stoppage. Symptom severity, education, and patient sex affected patients' beliefs about their concerns with their medications, and the interference medications posed for their daily lives. Interventions may need to target the distinct dimensions of beliefs during treatment with oral oncolytic agents.

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Relation of Social Constraints on Disclosure to Adjustment among Chinese American Cancer Survivors: A Multi-Processes Approach

Abstract

Purpose

The present study examines the association between social constraints and depressive symptoms among Chinese American breast cancer survivors, and the mechanism underling this association. A multi-processes model is tested to examine the mediating roles of ambivalence over emotional expression (AEE), avoidance, intrusive thoughts, and social support in the association between social constraints and depressive symptoms among Chinese American breast cancer survivors.

Methods

Ninety-six Chinese American breast cancer survivors were recruited from Chinese community organizations. They were asked to complete a questionnaire package that assessed social constraints, AEE, avoidance, intrusive thoughts, social support, depressive symptoms, and demographic information. Path analysis was conducted to test the hypothesized model.

Results

The overall and specific indirect effects of social constraints on depressive symptoms through AEE, avoidance, intrusive thoughts, and social support are significant. When the mediators are controlled for, the direct effect of social constraints on depressive symptoms is no longer significant.

Conclusions

A multi-processes model of social constraints and depressive symptoms is tested in a sample of Chinese American breast cancer survivors. The findings suggest that the existence of multiple pathways, through which social constraints may associate with depressive symptoms among Chinese American breast cancer survivors.

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Do Treatment Patterns Alter Beliefs Cancer Patients hold Regarding Oral Oncolytic Agents?

Abstract

Objective

Cancer patients, particularly those prescribed oral oncolytic medications, face treatment side effects, and temporary and permanent stoppages of treatment. This research examines how events during treatment affect patients' beliefs regarding oral oncolytic medications.

Methods

272 cancer patients initiating one of 28 oral oncolytic agents were followed for 12 weeks. Assessments of Beliefs About Medications Questionnaire (BMQ), symptoms, physical function, and depression measures were performed during telephone interviews at intake (medication start) and 4, 8, and 12 weeks. Electronic medical record audits identified dates of temporary and permanent medication stoppages. Linear mixed effects models were used for longitudinal analyses of the BMQ scores in relation to patient characteristics, symptom severity, and medication stoppages.

Results

Over the initial 12 weeks beliefs about the necessity of oral medications increased, concerns decreased, and interference of medications with daily lives increased. Permanent stoppage of a medication predicted significant declines in beliefs about its necessity over time. Male patients, those less educated, those reporting higher symptom severity, and experiencing temporary stoppages had greater concerns. Interference of medications with daily life was higher for males, increased with higher symptom severity, and differed by drug category.

Conclusions

Patients' beliefs in the necessity of their oral medication were affected only by a permanent drug stoppage. Symptom severity, education, and patient sex affected patients' beliefs about their concerns with their medications, and the interference medications posed for their daily lives. Interventions may need to target the distinct dimensions of beliefs during treatment with oral oncolytic agents.

http://ift.tt/2yhUrlE

Relation of Social Constraints on Disclosure to Adjustment among Chinese American Cancer Survivors: A Multi-Processes Approach

Abstract

Purpose

The present study examines the association between social constraints and depressive symptoms among Chinese American breast cancer survivors, and the mechanism underling this association. A multi-processes model is tested to examine the mediating roles of ambivalence over emotional expression (AEE), avoidance, intrusive thoughts, and social support in the association between social constraints and depressive symptoms among Chinese American breast cancer survivors.

Methods

Ninety-six Chinese American breast cancer survivors were recruited from Chinese community organizations. They were asked to complete a questionnaire package that assessed social constraints, AEE, avoidance, intrusive thoughts, social support, depressive symptoms, and demographic information. Path analysis was conducted to test the hypothesized model.

Results

The overall and specific indirect effects of social constraints on depressive symptoms through AEE, avoidance, intrusive thoughts, and social support are significant. When the mediators are controlled for, the direct effect of social constraints on depressive symptoms is no longer significant.

Conclusions

A multi-processes model of social constraints and depressive symptoms is tested in a sample of Chinese American breast cancer survivors. The findings suggest that the existence of multiple pathways, through which social constraints may associate with depressive symptoms among Chinese American breast cancer survivors.

http://ift.tt/2AxCHJf

The role of postmastectomy radiotherapy in patients with stage II breast cancer

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Patient-reported outcomes enhance the survival prediction of traditional disease risk classifications: An international study in patients with myelodysplastic syndromes

BACKGROUND

Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well-established clinical risk classification: the International Prognostic Scoring System (IPSS).

METHODS

A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).

RESULTS

A new prognostic index was developed: the FA-IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients.

CONCLUSIONS

The FA-IPSS(h) is a novel patient-centered prognostic index that includes patients' self-reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2017. © 2017 American Cancer Society.

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Travel distance and stereotactic body radiotherapy for localized prostate cancer

BACKGROUND

Definitive stereotactic body radiotherapy (SBRT) represents an emerging and debated treatment option for patients with prostate cancer, with potential economic savings and reports of short-term efficacy since 2006. The current study sought to define national trends in definitive prostate SBRT use and determine whether patterns vary by travel distance for treatment.

METHODS

The National Cancer Data Base identified 181,544 men with localized prostate cancer who were treated with definitive external beam radiotherapy from 2004 through 2012. Joinpoint regression analyzed definitive prostate SBRT trends over time, whereas multivariable logistic regression defined the odds for its receipt by travel distance for treatment.

RESULTS

Definitive prostate SBRT use increased from 1.8% in 2004 to 5.9% in 2012 (P for trend <.0001), with a joinpoint for increased use noted in 2006 (P<.0001). Higher SBRT use was found to be associated with longer travel distance for treatment, younger age, white race, more affluent zip code of residence, academic treatment center, favorable disease characteristics, and fewer comorbidities (all P<.0001). Compared with travel distances <25 miles for treatment, travel distances of 25 to 50 miles and >50 miles were associated with increasing adjusted odds of receipt of definitive prostate SBRT (1.63 [95% confidence interval, 1.51-1.76] and 2.35 [95% confidence interval, 2.14-2.57], respectively; both P < .0001).

CONCLUSIONS

Definitive prostate SBRT use increased more than 3-fold since 2004, with a significant increase in use coinciding with early reports of short-term efficacy. Long-distance travel for treatment was associated with greater than twice the odds of receipt of definitive prostate SBRT compared with short-distance travel, suggesting that treatment decisions with unknown long-term clinical implications may be strongly driven by sociodemographic factors. Cancer 2017. © 2017 American Cancer Society.

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Body composition in long-term survivors of acute lymphoblastic leukemia diagnosed in childhood and adolescence: A focus on sarcopenic obesity

BACKGROUND

The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity.

METHODS

A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index.

RESULTS

The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height²), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height²) was –0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity.

CONCLUSIONS

Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2017. © 2017 American Cancer Society.

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Comparative effectiveness of prostate cancer screening between the ages of 55 and 69 years followed by active surveillance

BACKGROUND

Because of the recent grade C draft recommendation by the US Preventive Services Task Force (USPSTF) for prostate cancer screening between the ages of 55 and 69 years, there is a need to determine whether this could be cost-effective in a US population setting.

METHODS

This study used a microsimulation model of screening and active surveillance (AS), based on data from the European Randomized Study of Screening for Prostate Cancer and the Surveillance, Epidemiology, and End Results Program, for the natural history of prostate cancer and Johns Hopkins AS cohort data to inform the probabilities of referral to treatment during AS. A cohort of 10 million men, based on US life tables, was simulated. The lifetime costs and effects of screening between the ages of 55 and 69 years with different screening frequencies and AS protocols were projected, and their cost-effectiveness was determined.

RESULTS

Quadrennial screening between the ages of 55 and 69 years (55, 59, 63, and 67 years) with AS for men with low-risk cancers (ie, those with a Gleason score of 6 or lower) and yearly biopsies or triennial biopsies resulted in an incremental cost per quality-adjusted life-year (QALY) of $51,918 or $69,380, respectively. Most policies in which screening was followed by immediate treatment were dominated. In most sensitivity analyses, this study found a policy with which the cost per QALY remained below $100,000.

CONCLUSIONS

Prostate-specific antigen–based prostate cancer screening in the United States between the ages of 55 and 69 years, as recommended by the USPSTF, may be cost-effective at a $100,000 threshold but only with a quadrennial screening frequency and with AS offered to all low-risk men. Cancer 2017. © 2017 American Cancer Society.

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Prostate cancer screening with prostate-specific antigen: Where are we going?

Current prostate-specific antigen screening is not cost-effective from a public health perspective. A new algorithm using genetic testing and imaging has yet to be developed. See also pages 000-000.

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Erratum: Chang Y-J, Wang Y, Mo X-D, et al. Optimal dose of rabbit thymoglobulin in conditioning regimens for unmanipulated, haploidentical, hematopoietic stem cell transplantation: Long-term outcomes of a prospective randomized trial. Cancer. 2017;123: 2881-2892.

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The role of postmastectomy radiotherapy in patients with stage II breast cancer

http://ift.tt/2AOphoK

Patient-reported outcomes enhance the survival prediction of traditional disease risk classifications: An international study in patients with myelodysplastic syndromes

BACKGROUND

Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well-established clinical risk classification: the International Prognostic Scoring System (IPSS).

METHODS

A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).

RESULTS

A new prognostic index was developed: the FA-IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients.

CONCLUSIONS

The FA-IPSS(h) is a novel patient-centered prognostic index that includes patients' self-reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2BX74oF