Phase I/II Study of Hypofractionated Intensity-Modulated Radiotherapy for Prostate Cancer including Simultaneously Integrated Boost

Publication date: Available online 18 September 2017
Source:Practical Radiation Oncology
Author(s): Michael G. Chang, Nitai Mukhopadhyay, Diane Holdford, Vicki Skinner, Siddharth Saraiya, Drew Moghanaki, Mitchell S. Anscher
PurposeTo evaluate the safety and efficacy of moderately hypofractionated radiotherapy with simultaneous integrated boost (HSIB) IMRT that includes coverage of the seminal vesicles (SV) and pelvic lymph nodes (LN).MethodsMen with localized prostate cancer were prospectively enrolled in a phase I/II trial to receive HSIB-IMRT to the prostate, ±SV, ±pelvic LN using a risk-based method. Low-risk (LR) patients received 69.6Gy to only the prostate in 29 fractions. Intermediate- (IR) and high-risk (HR) patients received 30 fractions with 72Gy to the prostate, 54Gy to the SV, and 50.4Gy to the pelvic LN when risk of LN involvement exceeded 15% by the Roach formula. IR and HR patients received androgen deprivation therapy. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated with patient and physician reported surveys.ResultsFifty-five men were enrolled and 49 had at least one year of follow up with 19.2% LR, 40.4% IR, and 40.4% HR disease. The median age was 69years and median follow-up time was 36.9months. Twenty-six patients received pelvic nodal HSIB-IMRT. At 2years, the cumulative incidence of physician-reported late grade 2+ GU and GI toxicity were 32.6%, and 18.4% respectively. At 2-years, only 10.2% grade 2+ GU toxicities and 2.0% grade 2+ GI toxicities remained unresolved. At last follow up, the prevalence of unresolved physician-reported late grade 2+ GU and GI toxicity was 4.1% and 0%. The median patient-reported AUA-IPSS score fell from 10 at baseline to 7.5 at 2years. The 3-year biochemical relapse-free survival rate for the cohort was 96%.ConclusionsHSIB-IMRT with risk-based nodal coverage results in excellent biochemical control. While the cumulative incidence of physician-reported GU toxicity was higher than anticipated, late GI and GU toxicity was relatively transient.



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Pilot Study on the Impact of F18-Labeled Thymidine PET/CT on Gross Tumor Volume Identification and Definition for Pancreatic Cancer

Publication date: Available online 18 September 2017
Source:Practical Radiation Oncology
Author(s): Jennifer L. Pretz, Michael A. Blake, Joseph H. Killoran, Harvey J. Mamon, Jennifer Y. Wo, Andrew X. Zhu, Theodore S. Hong
PurposeAccurate target definition for radiotherapy planning in localized pancreatic cancer is critical, particularly when using strategies that omit elective coverage. Standard imaging modalities such as CT, MRI, and endoscopic ultrasound have limited concordance with pathologic evaluation. Biologic imaging with [F18]-fluorodeoxyglucose (FDG)-PET can also be difficult to interpret, as increased activity is indicative of increased glucose metabolism, rather than cellular proliferation. F18 – labeled thymidine (FLT) is a proliferative marker which exploits the expression of pyrimidine-metabolizing enzymes. We evaluate the impact of FLT-PET on pancreatic target definition for radiation planning.Methods and MaterialsPatients with biopsy proven, newly diagnosed, untreated pancreatic adenocarcinoma were enrolled on an IRB-approved prospective study. Patients were injected with FLT and scanned 20–30minutes later. Two physicians (referred to as observer 1 and observer 2) independently contoured the gross tumor volume (GTV) and involved nodes on CT scan only, and then again with the assistance of co-registered FLT-PET. Conformality index (CI), the ratio of the volumes of intersection and union, was used as the metric for volume comparison (where CI=0 represented no overlap and CI=1 represented perfect overlap).ResultsNine patients were enrolled on this study. FLT-avidity was discerned in 8 of 9 patients. Average CT-GTV volume for observers 1 and 2 was 38.1cc and 26.5cc respectively. Average FLT-GTV volume for observers 1 and 2 was 39.1cc and 25.0cc respectively. For the 8 patients with FLT-avid tumors, addition of FLT data improved concordance of GTV definition between physicians in 6 of 8 tumors. Average CI for inter-observer CT-GTV was 0.325. Addition of FLT-PET information improved average CI to 0.400.ConclusionFLT-PET improves inter-observer concordance in GTV definition. Further studies will focus on verification of these findings, pathologic verification of the FLT-PET signal, and optimization of the FLT-PET signal threshold for auto-segmentation.



http://ift.tt/2xiu7uv

Proton Craniospinal Irradiation During the Third Trimester of Pregnancy

Publication date: Available online 18 September 2017
Source:Practical Radiation Oncology
Author(s): Anusha Kalbasi, Maura Kirk, Boon-Keng Kevin Teo, Eric Diffenderfer, Xuanfeng Ding, James McDonough, Erin Murphy, Christine Hill-Kayser




http://ift.tt/2xirQzl

Phase I/II Study of Hypofractionated Intensity-Modulated Radiotherapy for Prostate Cancer including Simultaneously Integrated Boost

Publication date: Available online 18 September 2017
Source:Practical Radiation Oncology
Author(s): Michael G. Chang, Nitai Mukhopadhyay, Diane Holdford, Vicki Skinner, Siddharth Saraiya, Drew Moghanaki, Mitchell S. Anscher
PurposeTo evaluate the safety and efficacy of moderately hypofractionated radiotherapy with simultaneous integrated boost (HSIB) IMRT that includes coverage of the seminal vesicles (SV) and pelvic lymph nodes (LN).MethodsMen with localized prostate cancer were prospectively enrolled in a phase I/II trial to receive HSIB-IMRT to the prostate, ±SV, ±pelvic LN using a risk-based method. Low-risk (LR) patients received 69.6Gy to only the prostate in 29 fractions. Intermediate- (IR) and high-risk (HR) patients received 30 fractions with 72Gy to the prostate, 54Gy to the SV, and 50.4Gy to the pelvic LN when risk of LN involvement exceeded 15% by the Roach formula. IR and HR patients received androgen deprivation therapy. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated with patient and physician reported surveys.ResultsFifty-five men were enrolled and 49 had at least one year of follow up with 19.2% LR, 40.4% IR, and 40.4% HR disease. The median age was 69years and median follow-up time was 36.9months. Twenty-six patients received pelvic nodal HSIB-IMRT. At 2years, the cumulative incidence of physician-reported late grade 2+ GU and GI toxicity were 32.6%, and 18.4% respectively. At 2-years, only 10.2% grade 2+ GU toxicities and 2.0% grade 2+ GI toxicities remained unresolved. At last follow up, the prevalence of unresolved physician-reported late grade 2+ GU and GI toxicity was 4.1% and 0%. The median patient-reported AUA-IPSS score fell from 10 at baseline to 7.5 at 2years. The 3-year biochemical relapse-free survival rate for the cohort was 96%.ConclusionsHSIB-IMRT with risk-based nodal coverage results in excellent biochemical control. While the cumulative incidence of physician-reported GU toxicity was higher than anticipated, late GI and GU toxicity was relatively transient.



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Pilot Study on the Impact of F18-Labeled Thymidine PET/CT on Gross Tumor Volume Identification and Definition for Pancreatic Cancer

Publication date: Available online 18 September 2017
Source:Practical Radiation Oncology
Author(s): Jennifer L. Pretz, Michael A. Blake, Joseph H. Killoran, Harvey J. Mamon, Jennifer Y. Wo, Andrew X. Zhu, Theodore S. Hong
PurposeAccurate target definition for radiotherapy planning in localized pancreatic cancer is critical, particularly when using strategies that omit elective coverage. Standard imaging modalities such as CT, MRI, and endoscopic ultrasound have limited concordance with pathologic evaluation. Biologic imaging with [F18]-fluorodeoxyglucose (FDG)-PET can also be difficult to interpret, as increased activity is indicative of increased glucose metabolism, rather than cellular proliferation. F18 – labeled thymidine (FLT) is a proliferative marker which exploits the expression of pyrimidine-metabolizing enzymes. We evaluate the impact of FLT-PET on pancreatic target definition for radiation planning.Methods and MaterialsPatients with biopsy proven, newly diagnosed, untreated pancreatic adenocarcinoma were enrolled on an IRB-approved prospective study. Patients were injected with FLT and scanned 20–30minutes later. Two physicians (referred to as observer 1 and observer 2) independently contoured the gross tumor volume (GTV) and involved nodes on CT scan only, and then again with the assistance of co-registered FLT-PET. Conformality index (CI), the ratio of the volumes of intersection and union, was used as the metric for volume comparison (where CI=0 represented no overlap and CI=1 represented perfect overlap).ResultsNine patients were enrolled on this study. FLT-avidity was discerned in 8 of 9 patients. Average CT-GTV volume for observers 1 and 2 was 38.1cc and 26.5cc respectively. Average FLT-GTV volume for observers 1 and 2 was 39.1cc and 25.0cc respectively. For the 8 patients with FLT-avid tumors, addition of FLT data improved concordance of GTV definition between physicians in 6 of 8 tumors. Average CI for inter-observer CT-GTV was 0.325. Addition of FLT-PET information improved average CI to 0.400.ConclusionFLT-PET improves inter-observer concordance in GTV definition. Further studies will focus on verification of these findings, pathologic verification of the FLT-PET signal, and optimization of the FLT-PET signal threshold for auto-segmentation.



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Proton Craniospinal Irradiation During the Third Trimester of Pregnancy

Publication date: Available online 18 September 2017
Source:Practical Radiation Oncology
Author(s): Anusha Kalbasi, Maura Kirk, Boon-Keng Kevin Teo, Eric Diffenderfer, Xuanfeng Ding, James McDonough, Erin Murphy, Christine Hill-Kayser




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Peripheral T-cell lymphomas:focusing on novel agents in relapsed and refractory disease

Publication date: Available online 17 September 2017
Source:Cancer Treatment Reviews
Author(s): Alessandro Broccoli, Lisa Argnani, Pier Luigi Zinzani
Patients with relapsed or refractory peripheral T-cell lymphoma display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory PTCL. Four recently approved compounds are used as single agents: pralatrexate, a novel antifolate agent; romidepsin and belinostat, both histone deacetylase (HDAC) inhibitors; brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody. Several other molecules have demonstrated their activity in the same context: gemcitabine, bendamustine, lenalidomide, duvelisib, copanlisib, alisertib, mogamulizumab, selinexor and ARGX-110. Robust preclinical observations strongly support chemo-free combinations, which are expected to enhance the quality and duration of responses in pretreated patients and in those who are unable to receive a stem cell transplantation.



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Trends in active surveillance for very low-risk prostate cancer: do guidelines influence modern practice?

Abstract

As recommended by current NCCN guidelines, patients with very low-risk prostate cancer may be treated with active surveillance (AS), but this may be underutilized. Using the National Cancer Database (NCDB), we identified men (2010–2013) with biopsy-proven, very low-risk prostate cancer that met AS criteria as suggested by Epstein (stage ≤ T1c; Gleason score (GS) ≤ 6; PSA < 10; and ≤2 [or <33%] positive biopsy cores) and aged ≤76, and low comorbidity index (Charlson-Deyo score = 0). For those patients meeting this criteria, we performed generalized estimation equation (GEE) method with incorporation of correlation in patients clustered within facility to determine the likelihood of undergoing AS. Among the 448 773 patients in the NCDB with low-risk prostate cancer, 40 839 patients met the inclusion criteria. AS was utilized in 5798 patients (14.2%), while within the very low-risk patients receiving treatment, up to 52.2% received radical prostatectomy. In univariate analyses, AS utilization was associated with older age, uninsured status (compared to private insurance), farther distance from facility, academic/research institutions and particularly in the New England region (all P < 0.01). After adjustments of other predictors in multivariate analysis, patients preferentially received AS if they were older (all OR's > 1 compared to younger groups), uninsured (vs. any insurance type, OR's > 1); or treated at academic/research center (OR > 1). The overall use of AS increased from 11.6% (2010) to 27.3% (2013). We found a low, but rising rate of AS in a nationally representative group of very low-risk prostate cancer patients. Disparities in the use of AS may be targeted to improve adherence to national guidelines.

This article demonstrates one of the largest series examining the role of active surveillance in patients with very low-risk prostate cancer. Our results in disparities and trends in recommendations for active surveillance reveal an important aspect of cancer care in the management of this disease entity.

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Trends in active surveillance for very low-risk prostate cancer: do guidelines influence modern practice?

Abstract

As recommended by current NCCN guidelines, patients with very low-risk prostate cancer may be treated with active surveillance (AS), but this may be underutilized. Using the National Cancer Database (NCDB), we identified men (2010–2013) with biopsy-proven, very low-risk prostate cancer that met AS criteria as suggested by Epstein (stage ≤ T1c; Gleason score (GS) ≤ 6; PSA < 10; and ≤2 [or <33%] positive biopsy cores) and aged ≤76, and low comorbidity index (Charlson-Deyo score = 0). For those patients meeting this criteria, we performed generalized estimation equation (GEE) method with incorporation of correlation in patients clustered within facility to determine the likelihood of undergoing AS. Among the 448 773 patients in the NCDB with low-risk prostate cancer, 40 839 patients met the inclusion criteria. AS was utilized in 5798 patients (14.2%), while within the very low-risk patients receiving treatment, up to 52.2% received radical prostatectomy. In univariate analyses, AS utilization was associated with older age, uninsured status (compared to private insurance), farther distance from facility, academic/research institutions and particularly in the New England region (all P < 0.01). After adjustments of other predictors in multivariate analysis, patients preferentially received AS if they were older (all OR's > 1 compared to younger groups), uninsured (vs. any insurance type, OR's > 1); or treated at academic/research center (OR > 1). The overall use of AS increased from 11.6% (2010) to 27.3% (2013). We found a low, but rising rate of AS in a nationally representative group of very low-risk prostate cancer patients. Disparities in the use of AS may be targeted to improve adherence to national guidelines.

This article demonstrates one of the largest series examining the role of active surveillance in patients with very low-risk prostate cancer. Our results in disparities and trends in recommendations for active surveillance reveal an important aspect of cancer care in the management of this disease entity.

http://ift.tt/2hegSlh

Serous retinal detachment after panretinal photocoagulation for proliferative diabetic retinopathy: a case report

Proliferative diabetic retinopathy is a major cause of visual impairment in working-age adults worldwide. Panretinal photocoagulation is a cornerstone in its management; however, it may include a range of side...

http://ift.tt/2wsuIuX

Cancers, Vol. 9, Pages 126: The Impact of DNA Repair Pathways in Cancer Biology and Therapy

Cancers, Vol. 9, Pages 126: The Impact of DNA Repair Pathways in Cancer Biology and Therapy

Cancers doi: 10.3390/cancers9090126

Authors: Anatoly Nikolaev Eddy Yang

Genomic instability is one of the key hallmarks of cancer progression [1].[...]

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Cancers, Vol. 9, Pages 126: The Impact of DNA Repair Pathways in Cancer Biology and Therapy

Cancers, Vol. 9, Pages 126: The Impact of DNA Repair Pathways in Cancer Biology and Therapy

Cancers doi: 10.3390/cancers9090126

Authors: Anatoly Nikolaev Eddy Yang

Genomic instability is one of the key hallmarks of cancer progression [1].[...]

http://ift.tt/2fgnz9v

Personal use of hair dyes and risk of leukemia: a systematic literature review and meta-analysis

Abstract

The objective of this study was to examine the association between personal use of hair dyes and the risk of leukemia. We conducted a systematic literature review of epidemiology studies reporting leukemia-specific cancer risks among hair dye users, and estimated the meta-relative risk (meta-RR) and corresponding 95% confidence interval (95% CI) of leukemia, comparing hair dye users to nonusers. When data from all 20 studies that met the inclusion criteria were combined, ever use of hair dye was associated with a nonstatistically significant increased risk of leukemia, meta-RR = 1.09 (95% CI: 0.97–1.22). When restricted to studies that adjusted for smoking, ever use of hair dye was not associated with leukemia, meta-RR = 0.99 (95% CI: 0.76–1.29). A statistically significant increased risk of leukemia was associated with permanent hair dye use (meta-RR = 1.19 [95% CI: 1.07–1.33]), dark hair dye use (meta-RR = 1.29 [95% CI: 1.11–1.50]), hair dye use among males (meta-RR = 1.42 [95% CI: 1.01–2.00]), hair dye use pre-1980 (meta-RR = 1.49 [95% CI: 1.21–1.83]), and hair dye use for ≥15 years (meta-RR = 1.35 [95% CI: 1.13–1.62]). Overall, findings suggest that ever use of hair dye is not a significant risk factor for leukemia. Certain hair dye use characteristics were associated with a statistically significant increased risk, but further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.

The purpose of this study was to synthesize and examine the evidence on the relative risk of leukemia among hair dye users under various exposure scenarios. Findings suggest that personal hair dye use is not a significant risk factor for leukemia when data from all studies were combined. Upon stratification, permanent hair dye use, dark hair dye use, hair dye use pre-1980, hair dye use among males, and hair dye use for ≥15 years were associated with a statistically significant increased risk of leukemia. Further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.

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Relationship of tumor PD-L1 (CD274) expression with lower mortality in lung high-grade neuroendocrine tumor

Abstract

Programmed death-ligand 1 (PD-L1) promotes immunosuppression by binding to PD-1 on T lymphocytes. Although tumor PD-L1 expression is a potential predictive marker of clinical response to anti-PD-1/PD-L1 therapy, little is known about its association with clinicopathological features, including prognosis, in high-grade neuroendocrine tumors (HGNETs), including small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC), of the lung. We immunohistochemically examined the membranous of expression of PD-L1 in 115 consecutive surgical cases of lung HGNET (74 SCLC cases and 41 LCNEC cases). We examined the prognostic association of tumor PD-L1 positivity using the log-rank test as well as Cox proportional hazards regression models to calculate the hazard ratio (HR) for mortality. Programmed death-ligand 1 immunostaining (at least 5% tumor cells) was observed in 25 (21%) of the 115 HGNET cases. In a univariable analysis, PD-L1 positivity was associated with lower lung cancer-specific (univariable HR = 0.23; 95% confidence interval [CI] = 0.056–0.64; P = 0.0028) and overall (univariable HR = 0.28; 95% CI = 0.11–0.60; P = 0.0005) mortality. Additionally, in a multivariable analysis, PD-L1 positivity was independently associated with lower lung cancer-specific (multivariable HR = 0.24; 95% CI = 0.058–0.67; P = 0.0039) and overall (multivariable HR = 0.29; 95% CI = 0.11–0.61; P = 0.0006) mortality. Our study demonstrated the prevalence of PD-L1 positivity in lung HGNET cases, and the independent association of tumor PD-L1 positivity with lower mortality in lung HGNET cases. Further studies are needed to confirm our findings.

High-grade neuroendocrine tumor (HGNET) (small cell lung carcinoma and large cell neuroendocrine carcinoma) is the most aggressive histological subtype of lung cancer, and immunotherapies, including anti-PD-1/Programmed death-ligand 1 (PD-L1) therapy, are emerging and promising. The prevalence of PD-L1 positivity in lung HGNET is shown. PD-L1 positivity is associated with lower mortality in lung HGNET.

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Clinical predictive factors of long-term survival after curative resection of pancreatic cancer: a retrospective study

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to have the poorest prognosis of all gastrointestinal malignancies, even after the tumor has been completely resected. However, only a proportion of patients achieve 5-year survival after resection. The factors predictive of achieving 5-year survival remain unclear. The aim of this study was to investigate the pre- and postoperative clinicopathological characteristics of PDAC patients with a >5-year survival after curative resection. We retrospectively reviewed patients who underwent pancreatectomy for PDAC between January 1995 and December 2011. Logistic regression analysis was performed to determine the predictive factors for 5-year survival. One hundred and fifty-one patients were enrolled, including 38 patients with 5-year survival (actual 5-year survival rate, 25.2%). The independent preoperative factors predictive of achieving 5-year survival included serum albumin levels (odds ratio [OR]: 5.06, 95.0% confidence interval [CI]: 1.49–17.19; P = 0.009) and neoadjuvant chemoradiotherapy (OR: 3.02, 95.0% CI: 1.00–9.08; P = 0.049). Venous infiltration (OR: 2.99, 95.0% CI: 1.09–8.25; P = 0.034), liver recurrence (OR: 0.17, 95.0% CI: 0.04–0.69; P = 0.013), and perioperative portal vein infusion chemotherapy (OR: 3.06, 95.0% CI: 1.09–8.25; P = 0.028) were found to be independent postoperative predictive factors for achieving 5-year survival. Serum albumin levels could be a biomarker for predicting the prognosis of PDAC patients after curative resection. Liver recurrence and perioperative portal vein infusion chemotherapy were independent postoperative factors, suggesting that perioperative portal vein infusion chemotherapy could be promising for improving the survival rate of PDAC patients after curative resection.

Relationship between neoadjuvant chemoradiotherapy (NACRT) and (A) postoperative disease-free survival (DFS) and (B) postoperative overall survival (OS) and relationship between perioperative adjuvant portal vein infusion (PVI) chemotherapy and (C) postoperative DFS and (D) postoperative OS.

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Comparison of multi-leaf collimator tracking and treatment-couch tracking during stereotactic body radiation therapy of prostate cancer

Motion mitigation during prostate stereotactic body radiation therapy (SBRT) ensures optimal target coverage while reducing the risk of overdosage of nearby organs. The geometrical and dosimetrical performance of motion mitigation with the multileaf-collimator (MLC tracking) or the treatment couch (couch tracking) were compared.

http://ift.tt/2yaMM9d

Personal use of hair dyes and risk of leukemia: a systematic literature review and meta-analysis

Abstract

The objective of this study was to examine the association between personal use of hair dyes and the risk of leukemia. We conducted a systematic literature review of epidemiology studies reporting leukemia-specific cancer risks among hair dye users, and estimated the meta-relative risk (meta-RR) and corresponding 95% confidence interval (95% CI) of leukemia, comparing hair dye users to nonusers. When data from all 20 studies that met the inclusion criteria were combined, ever use of hair dye was associated with a nonstatistically significant increased risk of leukemia, meta-RR = 1.09 (95% CI: 0.97–1.22). When restricted to studies that adjusted for smoking, ever use of hair dye was not associated with leukemia, meta-RR = 0.99 (95% CI: 0.76–1.29). A statistically significant increased risk of leukemia was associated with permanent hair dye use (meta-RR = 1.19 [95% CI: 1.07–1.33]), dark hair dye use (meta-RR = 1.29 [95% CI: 1.11–1.50]), hair dye use among males (meta-RR = 1.42 [95% CI: 1.01–2.00]), hair dye use pre-1980 (meta-RR = 1.49 [95% CI: 1.21–1.83]), and hair dye use for ≥15 years (meta-RR = 1.35 [95% CI: 1.13–1.62]). Overall, findings suggest that ever use of hair dye is not a significant risk factor for leukemia. Certain hair dye use characteristics were associated with a statistically significant increased risk, but further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.

The purpose of this study was to synthesize and examine the evidence on the relative risk of leukemia among hair dye users under various exposure scenarios. Findings suggest that personal hair dye use is not a significant risk factor for leukemia when data from all studies were combined. Upon stratification, permanent hair dye use, dark hair dye use, hair dye use pre-1980, hair dye use among males, and hair dye use for ≥15 years were associated with a statistically significant increased risk of leukemia. Further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.

http://ift.tt/2xdRYdj

Relationship of tumor PD-L1 (CD274) expression with lower mortality in lung high-grade neuroendocrine tumor

Abstract

Programmed death-ligand 1 (PD-L1) promotes immunosuppression by binding to PD-1 on T lymphocytes. Although tumor PD-L1 expression is a potential predictive marker of clinical response to anti-PD-1/PD-L1 therapy, little is known about its association with clinicopathological features, including prognosis, in high-grade neuroendocrine tumors (HGNETs), including small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC), of the lung. We immunohistochemically examined the membranous of expression of PD-L1 in 115 consecutive surgical cases of lung HGNET (74 SCLC cases and 41 LCNEC cases). We examined the prognostic association of tumor PD-L1 positivity using the log-rank test as well as Cox proportional hazards regression models to calculate the hazard ratio (HR) for mortality. Programmed death-ligand 1 immunostaining (at least 5% tumor cells) was observed in 25 (21%) of the 115 HGNET cases. In a univariable analysis, PD-L1 positivity was associated with lower lung cancer-specific (univariable HR = 0.23; 95% confidence interval [CI] = 0.056–0.64; P = 0.0028) and overall (univariable HR = 0.28; 95% CI = 0.11–0.60; P = 0.0005) mortality. Additionally, in a multivariable analysis, PD-L1 positivity was independently associated with lower lung cancer-specific (multivariable HR = 0.24; 95% CI = 0.058–0.67; P = 0.0039) and overall (multivariable HR = 0.29; 95% CI = 0.11–0.61; P = 0.0006) mortality. Our study demonstrated the prevalence of PD-L1 positivity in lung HGNET cases, and the independent association of tumor PD-L1 positivity with lower mortality in lung HGNET cases. Further studies are needed to confirm our findings.

High-grade neuroendocrine tumor (HGNET) (small cell lung carcinoma and large cell neuroendocrine carcinoma) is the most aggressive histological subtype of lung cancer, and immunotherapies, including anti-PD-1/Programmed death-ligand 1 (PD-L1) therapy, are emerging and promising. The prevalence of PD-L1 positivity in lung HGNET is shown. PD-L1 positivity is associated with lower mortality in lung HGNET.

http://ift.tt/2yaMpLR

Clinical predictive factors of long-term survival after curative resection of pancreatic cancer: a retrospective study

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to have the poorest prognosis of all gastrointestinal malignancies, even after the tumor has been completely resected. However, only a proportion of patients achieve 5-year survival after resection. The factors predictive of achieving 5-year survival remain unclear. The aim of this study was to investigate the pre- and postoperative clinicopathological characteristics of PDAC patients with a >5-year survival after curative resection. We retrospectively reviewed patients who underwent pancreatectomy for PDAC between January 1995 and December 2011. Logistic regression analysis was performed to determine the predictive factors for 5-year survival. One hundred and fifty-one patients were enrolled, including 38 patients with 5-year survival (actual 5-year survival rate, 25.2%). The independent preoperative factors predictive of achieving 5-year survival included serum albumin levels (odds ratio [OR]: 5.06, 95.0% confidence interval [CI]: 1.49–17.19; P = 0.009) and neoadjuvant chemoradiotherapy (OR: 3.02, 95.0% CI: 1.00–9.08; P = 0.049). Venous infiltration (OR: 2.99, 95.0% CI: 1.09–8.25; P = 0.034), liver recurrence (OR: 0.17, 95.0% CI: 0.04–0.69; P = 0.013), and perioperative portal vein infusion chemotherapy (OR: 3.06, 95.0% CI: 1.09–8.25; P = 0.028) were found to be independent postoperative predictive factors for achieving 5-year survival. Serum albumin levels could be a biomarker for predicting the prognosis of PDAC patients after curative resection. Liver recurrence and perioperative portal vein infusion chemotherapy were independent postoperative factors, suggesting that perioperative portal vein infusion chemotherapy could be promising for improving the survival rate of PDAC patients after curative resection.

Relationship between neoadjuvant chemoradiotherapy (NACRT) and (A) postoperative disease-free survival (DFS) and (B) postoperative overall survival (OS) and relationship between perioperative adjuvant portal vein infusion (PVI) chemotherapy and (C) postoperative DFS and (D) postoperative OS.

http://ift.tt/2jEXe6A

Evaluation of stopping-power prediction by dual- and single-energy computed tomography in an anthropomorphic ground-truth phantom

Publication date: Available online 17 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Patrick Wohlfahrt, Christian Möhler, Christian Richter, Steffen Greilich
PurposeTo determine the accuracy of particle range prediction for proton and heavier ion radiotherapy based on dual-energy computed tomography (DECT) in a realistic inhomogeneous geometry and to compare it to the state-of-the-art clinical approach.Methods and MaterialsA 3D ground-truth map of stopping-power ratios (SPRs) was created for an anthropomorphic head phantom by assigning measured SPR values to segmented structures in a high-resolution CT scan. This reference map was validated independently comparing proton transmission measurements to Monte Carlo transport simulations.Two DECT-based methods for direct SPR prediction via the Bethe formula (DirectSPR) and two established approaches based on Hounsfield look-up tables (HLUTs) were chosen for evaluation. SPR predictions from the four investigated methods were compared to the reference, employing material-specific voxel statistics and 2D gamma analysis. Furthermore, range deviations were analyzed in an exemplary proton treatment plan.ResultsThe established reference SPR map was successfully validated for the discrimination of SPR and range differences well below 0.3% and 1 mm respectively, even in complex inhomogeneous settings. For the phantom materials of larger volume (mainly brain, soft tissue), the investigated methods were overall able to predict SPR within 1% median deviation. The DirectSPR methods generally performed better than the HLUT approaches. For smaller phantom parts (such as cortical bone, air cavities), all methods were affected by image smoothing, leading to considerable SPR under- or overestimation. This effect was superimposed on the general SPR prediction accuracy in the exemplary treatment plan.ConclusionsDirectSPR predictions proved to be more robust with high accuracy in particular for larger volumes. In contrast, HLUT approaches exhibited a fortuitous component. The evaluation of accuracy in a realistic phantom with validated ground-truth SPR represents a crucial step towards possible clinical application of DECT-based SPR prediction methods.



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A Population-Based Study of Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Vestibular Schwannoma: Long-Term Outcomes and Toxicities

Publication date: Available online 17 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Andrea Lo, Gareth Ayre, Roy Ma, Fred Hsu, Ryojo Akagami, Michael McKenzie, Boris Valev, Ermias Gete, Isabelle Vallieres, Alan Nichol
PurposeThe purpose of the study is to examine long-term local control of vestibular schwannoma (VS) and side effects in patients treated with stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) in XX-region.Methods and MaterialsFrom August 1998 to May 2009, 207 patients were treated with radiation therapy (RT) at XX-center; 136 (66%) received SRS and 71 (34%) received SRT. Dose prescriptions were 50Gy/25 for SRT and 12Gy/1 for SRS. Our multidisciplinary provincial neuro-stereotactic conference recommended SRT for tumors >3cm and for patients with serviceable hearing (Gardner-Robertson Class I & II).ResultsMedian follow-up was 7.7 years to the last MRI and 6.4 years to the last clinical assessment. Local control for SRS vs. SRT was 94% vs. 87% at 5 years and 90% vs. 85% at 10 years (P=0.2). Five- and 10-year actuarial rates of RT-induced trigeminal nerve dysfunction (TND) were 25% and 25% after SRS, compared to 7% and 12% after SRT (P=0.01). Five- and 10-year actuarial rates of RT-induced facial nerve dysfunction were 15% and 15% after SRS, vs. 13% and 15% after SRT (P=0.93). In the 49 patients with serviceable hearing at baseline who were treated with SRT, hearing preservation was 55% at 3 years, 37% at 5 years, and 29% at 7 years. In multivariable analysis, better pre-treatment ipsilateral pure tone average was significantly associated with hearing preservation (HR 1.03; 95% CI 1.00-1.07; P=0.04).ConclusionsBoth SRS and SRT provided excellent long-term local control of VS. SRS was associated with higher rates of trigeminal nerve dysfunction. Even with a fractionated course, hearing preservation declined steadily with long-term audiometric follow-up.



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Evaluation of stopping-power prediction by dual- and single-energy computed tomography in an anthropomorphic ground-truth phantom

Publication date: Available online 17 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Patrick Wohlfahrt, Christian Möhler, Christian Richter, Steffen Greilich
PurposeTo determine the accuracy of particle range prediction for proton and heavier ion radiotherapy based on dual-energy computed tomography (DECT) in a realistic inhomogeneous geometry and to compare it to the state-of-the-art clinical approach.Methods and MaterialsA 3D ground-truth map of stopping-power ratios (SPRs) was created for an anthropomorphic head phantom by assigning measured SPR values to segmented structures in a high-resolution CT scan. This reference map was validated independently comparing proton transmission measurements to Monte Carlo transport simulations.Two DECT-based methods for direct SPR prediction via the Bethe formula (DirectSPR) and two established approaches based on Hounsfield look-up tables (HLUTs) were chosen for evaluation. SPR predictions from the four investigated methods were compared to the reference, employing material-specific voxel statistics and 2D gamma analysis. Furthermore, range deviations were analyzed in an exemplary proton treatment plan.ResultsThe established reference SPR map was successfully validated for the discrimination of SPR and range differences well below 0.3% and 1 mm respectively, even in complex inhomogeneous settings. For the phantom materials of larger volume (mainly brain, soft tissue), the investigated methods were overall able to predict SPR within 1% median deviation. The DirectSPR methods generally performed better than the HLUT approaches. For smaller phantom parts (such as cortical bone, air cavities), all methods were affected by image smoothing, leading to considerable SPR under- or overestimation. This effect was superimposed on the general SPR prediction accuracy in the exemplary treatment plan.ConclusionsDirectSPR predictions proved to be more robust with high accuracy in particular for larger volumes. In contrast, HLUT approaches exhibited a fortuitous component. The evaluation of accuracy in a realistic phantom with validated ground-truth SPR represents a crucial step towards possible clinical application of DECT-based SPR prediction methods.



http://ift.tt/2xaE6ms

A Population-Based Study of Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Vestibular Schwannoma: Long-Term Outcomes and Toxicities

Publication date: Available online 17 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Andrea Lo, Gareth Ayre, Roy Ma, Fred Hsu, Ryojo Akagami, Michael McKenzie, Boris Valev, Ermias Gete, Isabelle Vallieres, Alan Nichol
PurposeThe purpose of the study is to examine long-term local control of vestibular schwannoma (VS) and side effects in patients treated with stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) in XX-region.Methods and MaterialsFrom August 1998 to May 2009, 207 patients were treated with radiation therapy (RT) at XX-center; 136 (66%) received SRS and 71 (34%) received SRT. Dose prescriptions were 50Gy/25 for SRT and 12Gy/1 for SRS. Our multidisciplinary provincial neuro-stereotactic conference recommended SRT for tumors >3cm and for patients with serviceable hearing (Gardner-Robertson Class I & II).ResultsMedian follow-up was 7.7 years to the last MRI and 6.4 years to the last clinical assessment. Local control for SRS vs. SRT was 94% vs. 87% at 5 years and 90% vs. 85% at 10 years (P=0.2). Five- and 10-year actuarial rates of RT-induced trigeminal nerve dysfunction (TND) were 25% and 25% after SRS, compared to 7% and 12% after SRT (P=0.01). Five- and 10-year actuarial rates of RT-induced facial nerve dysfunction were 15% and 15% after SRS, vs. 13% and 15% after SRT (P=0.93). In the 49 patients with serviceable hearing at baseline who were treated with SRT, hearing preservation was 55% at 3 years, 37% at 5 years, and 29% at 7 years. In multivariable analysis, better pre-treatment ipsilateral pure tone average was significantly associated with hearing preservation (HR 1.03; 95% CI 1.00-1.07; P=0.04).ConclusionsBoth SRS and SRT provided excellent long-term local control of VS. SRS was associated with higher rates of trigeminal nerve dysfunction. Even with a fractionated course, hearing preservation declined steadily with long-term audiometric follow-up.



http://ift.tt/2fwVBmR

Exploiting drug addiction mechanisms to select against MAPKi-resistant melanoma [Research Articles]

Melanoma resistant to MAPK inhibitor(s) (MAPKi) displays loss-of-fitness upon experimental MAPKi withdrawal and, clinically, may be re-sensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi-addiction in MAPKi-resistant MUTBRAF or MUTNRAS melanoma. MAPKi-addiction phenotypes evident upon drug-withdrawal spanned transient cell-cycle slow-down to cell-death responses, the latter of which required a robust p-ERK rebound. Generally, drug withdrawal-induced p-ERK rebound up-regulated p38-FRA1-JUNB-CDKN1A and down-regulated proliferation, but only a robust p-ERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi-addiction across-the-board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant MUTNRAS or atypical MUTBRAF melanoma, treatment with a type I RAF inhibitor intensified p-ERK rebound elicited by MEKi-withdrawal, thereby promoting a cell-death predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi-addiction.

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How Ribosomes Translate Cancer [Reviews]

A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis—from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on "onco-ribosomes" as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention.

Significance: The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies. Cancer Discov; 7(10); 1–19. ©2017 AACR.

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A transposon screen identifies loss of primary cilia as a mechanism of resistance to Smo inhibitors [Research Articles]

Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway-dependent cancers, the scope of mechanisms enabling resistance to Smo-inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to Smo-inhibitors and maintains a "persister" state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal novel patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

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In silico modeling of immunotherapy and stroma-targeting therapies in human colorectal cancer

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n=20) including tumor cells, lymphocytes, stroma and necrosis to generate a multi-agent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n=37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n=261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, p=0.0219) as compared with high stroma and low lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in pre-established tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions which target the colorectal cancer microenvironment.

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MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and non-invasive magnetic resonance spectroscopy

Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle-related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by co-administration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. 

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Upregulation of Cystathionine-{beta}-synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

The transsulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-kappaB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immune compromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/-) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis.

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MetaLnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway

Long non-coding RNAs participate in carcinogenesis and tumor progression in lung cancer. Here we report the identification of a lncRNA signature associated with metastasis of non-small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a co-activator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC.

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Mitosis-mediated intravasation in a tissue-engineered tumor-microvessel platform

Intravasation involves the migration of tumor cells across the local endothelium and escape into vessel flow. While tumor cell invasiveness has been correlated to increased intravasation, the details of transendothelial migration and detachment into circulation are still unclear. Here we analyzed the intravasation of invasive human breast cancer cells within a tissue-engineered microvessel model of the tumor microenvironment. Using live-cell fluorescence microscopy, we captured 2,330 hours of tumor cell interactions with functional microvessels and provide evidence for a mitosis-mediated mechanism where tumor cells located along the vessel periphery are able to disrupt the vessel endothelium through cell division and detach into circulation. This model provides a framework for understanding the physical and biological parameters of the tumor microenvironment that mediate intravasation of tumor cells across an intact endothelium.

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Anti-CD137 suppresses tumor growth by blocking reverse signaling by CD137 ligand

CD137 (4-1BB) is a T cell co-stimulatory molecule and agonstic CD137 antibodies are currently being evaluated in clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL-12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFN-γ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL-12 and IFN-γ which promoted intratumoral differentiation of IFN-γ-producing Tc1, IL-12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance.

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Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer

The PPARG gene encoding the nuclear receptor PPAR-gamma is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene which encodes the heterodimeric partner of PPAR-gamma. Here we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer.

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Caveolae-Mediated Endocytosis is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for trans-endothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above which respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells where Cav-1 was attenuated exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs.

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Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies

FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared to either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition.

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TET-mediated sequestration of miR-26 drives EZH2 expression and gastric carcinogenesis

DNA demethylases of the TET family function as tumor suppressors in various human cancers but their pathogenic contributions and mechanisms of action in gastric carcinogenesis and progression remain unclear. Here we report that TET is transcriptionally upregulated in gastric cancer (GC) where it correlates with poor prognosis. Mechanistic investigations revealed that TET facilitated gastric carcinogenesis through a non-coding function of the 3'UTR which interacted with miR-26. This interaction resulted in sequestration of miR-26 from its target EZH2, which released the suppression on EZH2, and thereby leaded to EZH2 overexpression in gastric cancer. Our findings uncover a novel non-coding function for TET family proteins in facilitating gastric carcinogenesis.

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In silico modeling of immunotherapy and stroma-targeting therapies in human colorectal cancer

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n=20) including tumor cells, lymphocytes, stroma and necrosis to generate a multi-agent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n=37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n=261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, p=0.0219) as compared with high stroma and low lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in pre-established tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions which target the colorectal cancer microenvironment.

http://ift.tt/2jFACmp

MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and non-invasive magnetic resonance spectroscopy

Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle-related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by co-administration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. 

http://ift.tt/2xM6onN

Upregulation of Cystathionine-{beta}-synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

The transsulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-kappaB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immune compromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/-) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis.

http://ift.tt/2jFnVrv

MetaLnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway

Long non-coding RNAs participate in carcinogenesis and tumor progression in lung cancer. Here we report the identification of a lncRNA signature associated with metastasis of non-small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a co-activator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC.

http://ift.tt/2xM6kEz

Mitosis-mediated intravasation in a tissue-engineered tumor-microvessel platform

Intravasation involves the migration of tumor cells across the local endothelium and escape into vessel flow. While tumor cell invasiveness has been correlated to increased intravasation, the details of transendothelial migration and detachment into circulation are still unclear. Here we analyzed the intravasation of invasive human breast cancer cells within a tissue-engineered microvessel model of the tumor microenvironment. Using live-cell fluorescence microscopy, we captured 2,330 hours of tumor cell interactions with functional microvessels and provide evidence for a mitosis-mediated mechanism where tumor cells located along the vessel periphery are able to disrupt the vessel endothelium through cell division and detach into circulation. This model provides a framework for understanding the physical and biological parameters of the tumor microenvironment that mediate intravasation of tumor cells across an intact endothelium.

http://ift.tt/2jFnTzT

Anti-CD137 suppresses tumor growth by blocking reverse signaling by CD137 ligand

CD137 (4-1BB) is a T cell co-stimulatory molecule and agonstic CD137 antibodies are currently being evaluated in clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL-12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFN-γ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL-12 and IFN-γ which promoted intratumoral differentiation of IFN-γ-producing Tc1, IL-12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance.

http://ift.tt/2xM6ifV

Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer

The PPARG gene encoding the nuclear receptor PPAR-gamma is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene which encodes the heterodimeric partner of PPAR-gamma. Here we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer.

http://ift.tt/2jFnQUJ

Caveolae-Mediated Endocytosis is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for trans-endothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above which respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells where Cav-1 was attenuated exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs.

http://ift.tt/2jE3DPh

Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies

FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared to either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition.

http://ift.tt/2xMzpzL

TET-mediated sequestration of miR-26 drives EZH2 expression and gastric carcinogenesis

DNA demethylases of the TET family function as tumor suppressors in various human cancers but their pathogenic contributions and mechanisms of action in gastric carcinogenesis and progression remain unclear. Here we report that TET is transcriptionally upregulated in gastric cancer (GC) where it correlates with poor prognosis. Mechanistic investigations revealed that TET facilitated gastric carcinogenesis through a non-coding function of the 3'UTR which interacted with miR-26. This interaction resulted in sequestration of miR-26 from its target EZH2, which released the suppression on EZH2, and thereby leaded to EZH2 overexpression in gastric cancer. Our findings uncover a novel non-coding function for TET family proteins in facilitating gastric carcinogenesis.

http://ift.tt/2jFnGwB

Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

Oncogenesis 6, e379 (September 2017). doi:10.1038/oncsis.2017.78

Authors: A Di Matteo, M Franceschini, A Paiardini, A Grottesi, S Chiarella, S Rocchio, C Di Natale, D Marasco, L Vitagliano, C Travaglini-Allocatelli & L Federici

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Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

Oncogenesis 6, e378 (September 2017). doi:10.1038/oncsis.2017.77

Authors: N Woolf, B E Pearson, P A Bondzie, R D Meyer, M Lavaei, A C Belkina, V Chitalia & N Rahimi

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Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

Oncogenesis 6, e379 (September 2017). doi:10.1038/oncsis.2017.78

Authors: A Di Matteo, M Franceschini, A Paiardini, A Grottesi, S Chiarella, S Rocchio, C Di Natale, D Marasco, L Vitagliano, C Travaglini-Allocatelli & L Federici

http://ift.tt/2f5HRih

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

Oncogenesis 6, e378 (September 2017). doi:10.1038/oncsis.2017.77

Authors: N Woolf, B E Pearson, P A Bondzie, R D Meyer, M Lavaei, A C Belkina, V Chitalia & N Rahimi

http://ift.tt/2f5HPa9

Determination of PD-L1 expression in effusions from mesothelioma by immuno-cytochemical staining

BACKGROUND

Malignant mesothelioma (MM) is an aggressive, fatal tumor. Current therapeutic options only marginally improve survival. Programmed cell death ligand 1 (PD-L1) is a dominant mediator of immunosuppression, binding to programmed cell death 1 (PD-1). PD-L1 is up-regulated in cancer cells, and the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion, thus providing a target for antitumor therapy. Further, a correlation between PD-L1 expression and prognosis has been reported. Studies performed on histological material have revealed expression of PD-L1 in MM, but no study has been performed on MM effusions thus far.

METHODS

PD-L1 expression was determined by a commercially available antibody (clone 28-8) in 74 formalin-fixed, paraffin-embedded cell blocks from body effusions obtained at diagnosis from patients with MM. The presence of MM cells was confirmed with CK5/6, calretinin, and EMA and the admixture of macrophages was assessed with CD68. Only cases containing more than 100 tumor cells were assessed. Membranous staining in tumor cells was considered positive. Survival time was calculated from the appearance of the first malignant effusion until death.

RESULTS

Reactivity was observed in 23 of 61 (38%) of cases and was classified as ≥1%-5% (n = 9 cases), >5%-10% (n = 4 cases), >10%-50% (n = 4 cases), and >50% (n = 6 cases) positive cells. Survival times did not differ significantly between patients with PD-L1–positive and PD-L1–negative tumors.

CONCLUSION

MM effusions are suitable for immune-cytochemical assessment of PD-L1 expression in malignant cells and the results are similar to those reported for histological specimens. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2xLGOQ7

Determination of PD-L1 expression in effusions from mesothelioma by immuno-cytochemical staining

BACKGROUND

Malignant mesothelioma (MM) is an aggressive, fatal tumor. Current therapeutic options only marginally improve survival. Programmed cell death ligand 1 (PD-L1) is a dominant mediator of immunosuppression, binding to programmed cell death 1 (PD-1). PD-L1 is up-regulated in cancer cells, and the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion, thus providing a target for antitumor therapy. Further, a correlation between PD-L1 expression and prognosis has been reported. Studies performed on histological material have revealed expression of PD-L1 in MM, but no study has been performed on MM effusions thus far.

METHODS

PD-L1 expression was determined by a commercially available antibody (clone 28-8) in 74 formalin-fixed, paraffin-embedded cell blocks from body effusions obtained at diagnosis from patients with MM. The presence of MM cells was confirmed with CK5/6, calretinin, and EMA and the admixture of macrophages was assessed with CD68. Only cases containing more than 100 tumor cells were assessed. Membranous staining in tumor cells was considered positive. Survival time was calculated from the appearance of the first malignant effusion until death.

RESULTS

Reactivity was observed in 23 of 61 (38%) of cases and was classified as ≥1%-5% (n = 9 cases), >5%-10% (n = 4 cases), >10%-50% (n = 4 cases), and >50% (n = 6 cases) positive cells. Survival times did not differ significantly between patients with PD-L1–positive and PD-L1–negative tumors.

CONCLUSION

MM effusions are suitable for immune-cytochemical assessment of PD-L1 expression in malignant cells and the results are similar to those reported for histological specimens. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Surgery for T4 lung cancer invading the thoracic aorta: Do we push the limits?

Background

Few investigators have described en bloc resection of non-small cell lung cancer (NSCLC) invading the aorta.

Aim of Study

Analysis of outcome and prognostic factors for en bloc resections of NSCLC invading the aorta.

Methods

Thirty-five patients (27 males, 8 females; mean age 63 ± 8.6 years) were operated between 1994 and 2015 in four European Centers. Histology: 12 (34.3%) squamous cell carcinoma, and 6 (17.1%) undifferentiated/large cell carcinoma. The site of aortic infiltration was the descending thoracic aorta in 24 (68.6%) patients, the aortic arch in 9 (25.7%), and the aortic arch and supraortic trunks in 2 (5.7%).

Results

Lung resection consisted of pneumonectomy in 19 (54.3%) patients and lobectomy in 16 (45.7%). Aortic resection management was undertaken by endograft positioning (37.1%), subadventitial dissection (37.1%), cardiopulmonary/aorto-aortic bypass (17.2%), and direct clamping (8.6%). A tubular graft replacement was carried out in five cases, a synthetic patch repair in 6. Mortality was 2.9%, morbidity 37.1%. Patients undergoing pneumonectomy had a significantly higher morbidity rate compared with lobectomy (52% vs 18.7%; P = 0.003), although patients managed with aortic endografting had a lower complication rate. Median overall and disease-free survival rates were 31.3 and 22.2 months, respectively. Gender and site of aortic infiltration were independent prognostic factors.

Conclusions

Resection of NSCLC combined with an infiltrated aorta is a challenging procedure that can be performed with reasonable morbidity and mortality in highly selected patients.

http://ift.tt/2xgu1Dr

NFBD1/MDC1 participates in the regulation of proliferation and apoptosis in human laryngeal squamous cell carcinoma

Abstract

Purpose

The objective of the study was to investigate the role of NFBD1 in the proliferation and apoptosis of laryngeal squamous cell carcinoma (LSCC) cells.

Methods

Immunohistochemistry (IHC) and qRT-PCR was employed to determine the expressions of NFBD1 protein and mRNA in LSCC tissues and adjacent noncancerous tissues. After the downregulation of NFBD1 expression, the colony formation assay, MTS assay and apoptosis assay were used to investigate the changes in the proliferation and apoptosis of Hep2 cells. The mechanisms by which silencing NFBD1 promote apoptosis of Hep2 cells were examined by western blotting. Furthermore, xenograft models were used to evaluate the proliferation of Hep2 cells in vivo.

Results

NFBD1 protein was upregulated in 55.6% of LSCC cancer tissues compared with adjacent normal tissues (26.7%). NFBD1 knockdown in Hep2 cells significantly impacted proliferation and apoptosis, and silencing NFBD1 might promote apoptosis of Hep2 cells by activating the mitochondrial apoptotic pathway. Xenograft models showed that silencing NFBD1 also significantly inhibited tumor growth.

Conclusions

Our data highlight that NFBD1 participates in the regulation of proliferation and apoptosis in LSCC, and suggest that NFBD1 could be a promising therapy target.

http://ift.tt/2w307jj

NFBD1/MDC1 participates in the regulation of proliferation and apoptosis in human laryngeal squamous cell carcinoma

Abstract

Purpose

The objective of the study was to investigate the role of NFBD1 in the proliferation and apoptosis of laryngeal squamous cell carcinoma (LSCC) cells.

Methods

Immunohistochemistry (IHC) and qRT-PCR was employed to determine the expressions of NFBD1 protein and mRNA in LSCC tissues and adjacent noncancerous tissues. After the downregulation of NFBD1 expression, the colony formation assay, MTS assay and apoptosis assay were used to investigate the changes in the proliferation and apoptosis of Hep2 cells. The mechanisms by which silencing NFBD1 promote apoptosis of Hep2 cells were examined by western blotting. Furthermore, xenograft models were used to evaluate the proliferation of Hep2 cells in vivo.

Results

NFBD1 protein was upregulated in 55.6% of LSCC cancer tissues compared with adjacent normal tissues (26.7%). NFBD1 knockdown in Hep2 cells significantly impacted proliferation and apoptosis, and silencing NFBD1 might promote apoptosis of Hep2 cells by activating the mitochondrial apoptotic pathway. Xenograft models showed that silencing NFBD1 also significantly inhibited tumor growth.

Conclusions

Our data highlight that NFBD1 participates in the regulation of proliferation and apoptosis in LSCC, and suggest that NFBD1 could be a promising therapy target.

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Inhibitory Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) in Thyroid Cancer

Abstract

Growth hormone-releasing hormone (GHRH) is a peptide hormone secreted by the hypothalamus that regulates the synthesis and secretion of growth hormone (GH) in the pituitary. The extra-hypothalamic GHRH and its cognate receptors (GHRHR and splice variants) play a mitogenic role by stimulating cell proliferation and preventing apoptotic cell death. It is well established that GHRH antagonists inhibit the growth, tumorigenicity, and metastasis of various human malignancies. In this work, we studied the effect of two new GHRH antagonists, MIA602 and MIA690, on thyroid cancer. We studied the effect of MIA602 and MIA690 on thyroid cancer in vitro, using human thyroid cancer cell lines, and in vivo, using chicken embryo chorioallantoic membrane (CAM) assays. We found that mRNA for GHRH and GHRH receptor is expressed in thyroid cell lines and in samples of thyroid tumors. Immunohistochemistry confirmed the expression of GHRHR protein in specimens of thyroid tumor. We observed that GHRH antagonists inhibited the growth and increased apoptosis of thyroid cancer cells. In vivo, the antagonists inhibited growth and angiogenesis of engrafted thyroid tumors. Our results suggest that GHRH expression may play a role in growth of thyroid cancer and that GHRH antagonists can be a therapeutic option for thyroid cancer patients.

http://ift.tt/2wBjpLO

Inhibitory Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) in Thyroid Cancer

Abstract

Growth hormone-releasing hormone (GHRH) is a peptide hormone secreted by the hypothalamus that regulates the synthesis and secretion of growth hormone (GH) in the pituitary. The extra-hypothalamic GHRH and its cognate receptors (GHRHR and splice variants) play a mitogenic role by stimulating cell proliferation and preventing apoptotic cell death. It is well established that GHRH antagonists inhibit the growth, tumorigenicity, and metastasis of various human malignancies. In this work, we studied the effect of two new GHRH antagonists, MIA602 and MIA690, on thyroid cancer. We studied the effect of MIA602 and MIA690 on thyroid cancer in vitro, using human thyroid cancer cell lines, and in vivo, using chicken embryo chorioallantoic membrane (CAM) assays. We found that mRNA for GHRH and GHRH receptor is expressed in thyroid cell lines and in samples of thyroid tumors. Immunohistochemistry confirmed the expression of GHRHR protein in specimens of thyroid tumor. We observed that GHRH antagonists inhibited the growth and increased apoptosis of thyroid cancer cells. In vivo, the antagonists inhibited growth and angiogenesis of engrafted thyroid tumors. Our results suggest that GHRH expression may play a role in growth of thyroid cancer and that GHRH antagonists can be a therapeutic option for thyroid cancer patients.

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Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer

Abstract

Background

Recent observations revealed Foxp3 participated in the development of cervical cancer. Furthermore, Foxp3 has a vital function in the lymphatic metastasis of cervical cancer. However, it is unclear whether Foxp3 is correlated with lymphangiogenesis of cervical cancer.

Methods

In this experiment, expression of Foxp3 and VEGF-C was detected in 50 cervical cancer samples by immunohistochemistry. In addition, we evaluated the association between Foxp3 and VEGF-C expression and lymphangiogenesis of cervical cancer evaluated by lymphatic vessel density.

Results

These data demonstrate Foxp3 is positively correlated with VEGF-C expression. Furthermore, Foxp3 is associated with lymphangiogenesis of cervical cancer.

Conclusions

These results revealed Foxp3 play an important role in lymphangiogenesis of cervical cancer.

Trial registration

Gunagdong Medical University, PJ2013049

http://ift.tt/2wpvpVQ

Clinical outcome of laparoscopic complete mesocolic excision in the treatment of right colon cancer

Abstract

Background

This study aimed to investigate the clinical outcome of complete mesocolic excision (CME) with a caudal-to-cranial medial approach in the treatment of right colon cancer.

Methods

The clinical data of 172 patients who underwent laparoscopic CME for right colon cancer and were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to April 2015 were retrospectively analyzed. The 3-year disease-free survival (DFS) and overall survival (OS) in relation to gender, age, history of abdominal surgery, tumor size, complications, and tumor–node–metastasis (TNM) classification were analyzed using the Kaplan–Meier survival curves.

Results

A total of 172 patients with 94 males and 78 females were included. The average surgical time was 113.5 ± 34.4 min, blood loss was 74.2 ± 28.1 mL, and the number of lymph nodes retrieved was 23.3 ± 9.2. No readmission or death occurred within 30 days after surgery. Postoperative complications occurred in 16.3% of the patients, which included wound infection (3 patients), chylous fistula (22 patients), anastomotic leakage (1 patient), anastomotic bleeding (1 patient), and lung infection (1 patient). The 3-year DFS and OS were 81.7 and 89.1%, respectively. The rate of DFS and OS was significantly higher in stages I and II compared with that in stage III (P < 0.05), and in stages IIIA and IIIB compared with that in stage IIIC (P < 0.05).

Conclusions

Laparoscopic CME with a caudal-to-cranial medial approach in the treatment of right colon cancer had good short-term efficacy and satisfactory oncological outcome.

http://ift.tt/2ylGDIi

Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer

Abstract

Background

Recent observations revealed Foxp3 participated in the development of cervical cancer. Furthermore, Foxp3 has a vital function in the lymphatic metastasis of cervical cancer. However, it is unclear whether Foxp3 is correlated with lymphangiogenesis of cervical cancer.

Methods

In this experiment, expression of Foxp3 and VEGF-C was detected in 50 cervical cancer samples by immunohistochemistry. In addition, we evaluated the association between Foxp3 and VEGF-C expression and lymphangiogenesis of cervical cancer evaluated by lymphatic vessel density.

Results

These data demonstrate Foxp3 is positively correlated with VEGF-C expression. Furthermore, Foxp3 is associated with lymphangiogenesis of cervical cancer.

Conclusions

These results revealed Foxp3 play an important role in lymphangiogenesis of cervical cancer.

Trial registration

Gunagdong Medical University, PJ2013049

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Clinical outcome of laparoscopic complete mesocolic excision in the treatment of right colon cancer

Abstract

Background

This study aimed to investigate the clinical outcome of complete mesocolic excision (CME) with a caudal-to-cranial medial approach in the treatment of right colon cancer.

Methods

The clinical data of 172 patients who underwent laparoscopic CME for right colon cancer and were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to April 2015 were retrospectively analyzed. The 3-year disease-free survival (DFS) and overall survival (OS) in relation to gender, age, history of abdominal surgery, tumor size, complications, and tumor–node–metastasis (TNM) classification were analyzed using the Kaplan–Meier survival curves.

Results

A total of 172 patients with 94 males and 78 females were included. The average surgical time was 113.5 ± 34.4 min, blood loss was 74.2 ± 28.1 mL, and the number of lymph nodes retrieved was 23.3 ± 9.2. No readmission or death occurred within 30 days after surgery. Postoperative complications occurred in 16.3% of the patients, which included wound infection (3 patients), chylous fistula (22 patients), anastomotic leakage (1 patient), anastomotic bleeding (1 patient), and lung infection (1 patient). The 3-year DFS and OS were 81.7 and 89.1%, respectively. The rate of DFS and OS was significantly higher in stages I and II compared with that in stage III (P < 0.05), and in stages IIIA and IIIB compared with that in stage IIIC (P < 0.05).

Conclusions

Laparoscopic CME with a caudal-to-cranial medial approach in the treatment of right colon cancer had good short-term efficacy and satisfactory oncological outcome.

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The Utility of FDG PET/CT in IgG4-Related Disease with a Focus on Coronary Artery Involvement

Abstract

Purpose

Our case series aims to study the growing use of FDG PET/CT in diagnostic evaluation and follow up of IgG4-RD with emphasis on patients presenting with coronary artery involvement.

Methods

We conducted a search on the nuclear medicine and rheumatology service databases and identified patients with histologically proven IgG4-RD with FDG PET/CT performed at the Singapore General Hospital. The radiological, clinical, and laboratory findings of these patients were analyzed retrospectively.

Results

The series included ten male and two female patients. The commonest organ involved (five patients) was the pancreas. In three patients, coronary artery involvement manifested as soft tissue masses surrounding the arterial lumens. In these patients, histological diagnosis was established from alternative biopsy sites with abnormal metabolic activity on FDG PET/CT.

Correlation between laboratory and metabolic imaging findings was not statistically significant in our series.

Four patients had follow-up FDG PET/CT; three showed interval reduction in metabolic activity to baseline. One showed persistent abnormal metabolic activity before a rise in IgG4 levels. The metabolic imaging response was used to guide steroid dose.

Conclusions

FDG PET/CT is a useful tool in evaluation and follow-up of IgG4-RD, particularly in identifying alternative biopsy sites in patients who present with coronary artery involvement. Hypermetabolic coronary artery masses on FDG PET/CT should raise clinical suspicion of IgG4-RD. As the coronary artery masses may not show decrease in size after treatment, FDG PET/CT is also useful for metabolic response assessment.

http://ift.tt/2fuu2dZ

The Utility of FDG PET/CT in IgG4-Related Disease with a Focus on Coronary Artery Involvement

Abstract

Purpose

Our case series aims to study the growing use of FDG PET/CT in diagnostic evaluation and follow up of IgG4-RD with emphasis on patients presenting with coronary artery involvement.

Methods

We conducted a search on the nuclear medicine and rheumatology service databases and identified patients with histologically proven IgG4-RD with FDG PET/CT performed at the Singapore General Hospital. The radiological, clinical, and laboratory findings of these patients were analyzed retrospectively.

Results

The series included ten male and two female patients. The commonest organ involved (five patients) was the pancreas. In three patients, coronary artery involvement manifested as soft tissue masses surrounding the arterial lumens. In these patients, histological diagnosis was established from alternative biopsy sites with abnormal metabolic activity on FDG PET/CT.

Correlation between laboratory and metabolic imaging findings was not statistically significant in our series.

Four patients had follow-up FDG PET/CT; three showed interval reduction in metabolic activity to baseline. One showed persistent abnormal metabolic activity before a rise in IgG4 levels. The metabolic imaging response was used to guide steroid dose.

Conclusions

FDG PET/CT is a useful tool in evaluation and follow-up of IgG4-RD, particularly in identifying alternative biopsy sites in patients who present with coronary artery involvement. Hypermetabolic coronary artery masses on FDG PET/CT should raise clinical suspicion of IgG4-RD. As the coronary artery masses may not show decrease in size after treatment, FDG PET/CT is also useful for metabolic response assessment.

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Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

http://ift.tt/2wqQYFy

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

http://ift.tt/2yk7CUy

Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

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

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

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Prediction of neoadjuvant chemotherapy response using diffuse optical spectroscopy in breast cancer

Abstract

Purpose

Near-infrared diffuse optical spectroscopy (DOS) has been recently used to predict neoadjuvant chemotherapy response (NAC). In the present study, we explore the change in blood-oxygen content using DOS to predict NAC response against breast cancer.

Materials and methods

A total of 20 patients were enrolled and underwent DOS scan with blood-oxygen detection before each treatment cycle. The first DOS scan was performed before NAC treatment (pretreatment), and subsequent scans were performed after each NAC treatment circle. Changes in blood content and oxygen content by DOS were evaluated and compared with tumor size, and their changes were analyzed in response versus nonresponse group.

Results

Thirteen patients were classified into response and seven patients into nonresponse group. The tumor blood content value (−1.06 ± 0.43) and oxygen content value (0.48 ± 0.17) of DOS at pretreatment was significantly different from presurgery in response group (P < 0.05), but not in nonresponse group. In response group, the percentage change in blood content (median 91.19%) was significantly larger than tumor size (median 48.89%) (P = 0.0035), while in oxygen content (median 47.11%) is not (P = 0.2815). Comparing each cycle, the percentage change in blood content could distinguish responder from non-responder as early as after the first treatment cycle (19.1 versus 6.6%, P = 0.0265). Blood content percentage sensitivity was 76.9% and specificity was 85.7% (AUC 0.912), while oxygen content percentage sensitivity was 76.9% and specificity was 71.4% (AUC 0.797).

Conclusion

Both blood and oxygen content measured by DOS could be used to discriminate responder to the treatment versus non-responder. Among the two, percentage change of blood content was more precise and earlier than that of oxygen content to predicted breast tumor response. The percentage change in blood content could distinguish responder from non-responder after the first treatment cycle.

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Prediction of neoadjuvant chemotherapy response using diffuse optical spectroscopy in breast cancer

Abstract

Purpose

Near-infrared diffuse optical spectroscopy (DOS) has been recently used to predict neoadjuvant chemotherapy response (NAC). In the present study, we explore the change in blood-oxygen content using DOS to predict NAC response against breast cancer.

Materials and methods

A total of 20 patients were enrolled and underwent DOS scan with blood-oxygen detection before each treatment cycle. The first DOS scan was performed before NAC treatment (pretreatment), and subsequent scans were performed after each NAC treatment circle. Changes in blood content and oxygen content by DOS were evaluated and compared with tumor size, and their changes were analyzed in response versus nonresponse group.

Results

Thirteen patients were classified into response and seven patients into nonresponse group. The tumor blood content value (−1.06 ± 0.43) and oxygen content value (0.48 ± 0.17) of DOS at pretreatment was significantly different from presurgery in response group (P < 0.05), but not in nonresponse group. In response group, the percentage change in blood content (median 91.19%) was significantly larger than tumor size (median 48.89%) (P = 0.0035), while in oxygen content (median 47.11%) is not (P = 0.2815). Comparing each cycle, the percentage change in blood content could distinguish responder from non-responder as early as after the first treatment cycle (19.1 versus 6.6%, P = 0.0265). Blood content percentage sensitivity was 76.9% and specificity was 85.7% (AUC 0.912), while oxygen content percentage sensitivity was 76.9% and specificity was 71.4% (AUC 0.797).

Conclusion

Both blood and oxygen content measured by DOS could be used to discriminate responder to the treatment versus non-responder. Among the two, percentage change of blood content was more precise and earlier than that of oxygen content to predicted breast tumor response. The percentage change in blood content could distinguish responder from non-responder after the first treatment cycle.

http://ift.tt/2xsSVQL

FDA Approves Inotuzumab for Adults with B-Cell Acute Lymphoblastic Leukemia

FDA has approved inotuzumab (Besponsa®) for some adults with B-cell acute lymphoblastic leukemia (ALL). The approval covers patients with B-cell ALL whose disease has relapsed or is refractory to standard chemotherapy.

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FDA Approves Inotuzumab for Adults with B-Cell Acute Lymphoblastic Leukemia

FDA has approved inotuzumab (Besponsa®) for some adults with B-cell acute lymphoblastic leukemia (ALL). The approval covers patients with B-cell ALL whose disease has relapsed or is refractory to standard chemotherapy.

http://ift.tt/2xarBoj