Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trials

Abstract

Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who initially were treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in nine phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDIs of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In the both groups, however, the decreasing relative dose intensity (RDI) over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies.

This article is protected by copyright. All rights reserved.

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Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trials

Abstract

Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who initially were treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in nine phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDIs of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In the both groups, however, the decreasing relative dose intensity (RDI) over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hbGX4R

From bench to clinical trials the EORTC experience in biology-based clinical cancer research

Publication date: Available online 6 November 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Konstantinos Tryfonidis, Katherine Hartmann, Marie Morfouace, Denis Lacombe
For over 50years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article.



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Maspin expression and subcellular localization in invasive ductal carcinoma of the breast: Prognostic significance and relation to microvessel density

Publication date: Available online 7 November 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Duaa S. Helal, Dina M. El-Guindy
Maspin (Mammary serine protease inhibitor) is a tumor suppressor serine. Its clinical significance and role in breast carcinoma are contradictory and inconclusive. Researches demonstrated that the function of maspin differs according to its subcellular localization. This study was conducted to investigate the expression of maspin in invasive ductal carcinoma (IDC) of the breast with special emphasis on its subcellular localization and to evaluate its prognostic role in relation to clinicopathological parameters and microvessel density (MVD) of the tumor. The expression of maspin was evaluated immunohistochemically in 45 IDC cases. The positive rate of maspin expression was 73.3%. Maspin positivity was significantly related to higher tumor grade (p value = 0.041), nodal metastasis (p value = 0.044), perineural invasion (p value = 0.047), and high CD34+MVD (p value = 0.002). Nuclear maspin was detected in 36.6% whereas cytoplasmic maspin was detected in 63.4% of maspin positive cases. A significant inverse relationship was observed between nuclear maspin and high tumor grade (p value = 0.016), and nodal metastasis (p value = 0.047). These results suggest that maspin expression has a prognostic role in breast cancer. Maspin expression is related to increased angiogenesis. Subcellular localization of maspin can strongly affect cancer prognosis. Cytoplasmic maspin relates to poor prognostic parameters whereas nuclear maspin relates to good prognostic ones.



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Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25–2.92)], genistein [1.51 (1.02–2.22), daidzein [1.80 (1.18–2.75) and glycitein [1.67 (1.15–2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93–2.25), 1.65 (1.07–2.54), 1.73 (1.13–2.66) and 1.80 (1.18–2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.

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From bench to clinical trials the EORTC experience in biology-based clinical cancer research

Publication date: Available online 6 November 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Konstantinos Tryfonidis, Katherine Hartmann, Marie Morfouace, Denis Lacombe
For over 50years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article.



http://ift.tt/2jaVnXh

Maspin expression and subcellular localization in invasive ductal carcinoma of the breast: Prognostic significance and relation to microvessel density

Publication date: Available online 7 November 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Duaa S. Helal, Dina M. El-Guindy
Maspin (Mammary serine protease inhibitor) is a tumor suppressor serine. Its clinical significance and role in breast carcinoma are contradictory and inconclusive. Researches demonstrated that the function of maspin differs according to its subcellular localization. This study was conducted to investigate the expression of maspin in invasive ductal carcinoma (IDC) of the breast with special emphasis on its subcellular localization and to evaluate its prognostic role in relation to clinicopathological parameters and microvessel density (MVD) of the tumor. The expression of maspin was evaluated immunohistochemically in 45 IDC cases. The positive rate of maspin expression was 73.3%. Maspin positivity was significantly related to higher tumor grade (p value = 0.041), nodal metastasis (p value = 0.044), perineural invasion (p value = 0.047), and high CD34+MVD (p value = 0.002). Nuclear maspin was detected in 36.6% whereas cytoplasmic maspin was detected in 63.4% of maspin positive cases. A significant inverse relationship was observed between nuclear maspin and high tumor grade (p value = 0.016), and nodal metastasis (p value = 0.047). These results suggest that maspin expression has a prognostic role in breast cancer. Maspin expression is related to increased angiogenesis. Subcellular localization of maspin can strongly affect cancer prognosis. Cytoplasmic maspin relates to poor prognostic parameters whereas nuclear maspin relates to good prognostic ones.



http://ift.tt/2ArLCrP

Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25–2.92)], genistein [1.51 (1.02–2.22), daidzein [1.80 (1.18–2.75) and glycitein [1.67 (1.15–2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93–2.25), 1.65 (1.07–2.54), 1.73 (1.13–2.66) and 1.80 (1.18–2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.

http://ift.tt/2hT5H2J

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Abstract

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer. However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and pancreatic cancer incidence in European populations.

We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident pancreatic cancer cases (EPIC n=626; HUNT2 n=112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D₂ and 25(OH)D₃ combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI).

Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53); and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with pancreatic cancer risk (p for trend = 0.23).

Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of pancreatic cancer risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant. This article is protected by copyright. All rights reserved.

http://ift.tt/2hdNDzz

Risk of skin cancer among patients with myotonic dystrophy type 1 based on Primary care physician data from the United Kingdom Clinical Practice Research Datalink

Abstract

Myotonic dystrophy type 1 (DM1) is an inherited multisystem neuromuscular disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. Recent evidence documents that DM1 patients have an increased risk of certain cancers, but whether skin cancer risks are elevated is unclear. Using the U.K. Clinical Practice Research Datalink (CPRD), we identified 1,061 DM1 patients and 15,119 DM1-free individuals matched on gender, birth year (±2 years), attending practice, and registration year (±1 year). We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of DM1 diagnosis with skin cancer risk using Cox proportional hazards models, for all skin cancers combined and by histological subtype. Follow-up started at the latest of the age at practice registration, DM1 diagnosis/control selection or January 1st 1988, and ended at the earliest of the age at first skin cancer diagnosis, death, transfer out of the practice, last date of data collection or the end of the CPRD record (October 31, 2016). During a median follow-up of 3.6 years, 35 DM1 patients and 108 matched DM1-free individuals developed a skin cancer. DM1 patients had an increased risk of skin cancer overall (HR=5.44, 95% CI=3.33-8.89, p<.0001), and basal cell carcinoma (BCC) (HR=5.78, 95% CI=3.36-9.92, p<.0001). Risks did not differ by gender, or age at DM1 diagnosis (P-heterogeneity>0.5). Our data confirm suggested associations between DM1 and skin neoplasms with the highest risk seen for BCC. Patients are advised to minimize ultraviolet light exposure and seek medical advice for suspicious lesions. This article is protected by copyright. All rights reserved.

http://ift.tt/2iECPLd

Biweekly cisplatin and gemcitabine in patients advanced biliary tract cancer

Abstract

Treatment with cisplatin with gemcitabine (CG) demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1000mg/m²/min) and cisplatin 20mg/m² on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%) and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%) and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies. This article is protected by copyright. All rights reserved.

http://ift.tt/2iECMiv

Midlife metabolic factors and prostate cancer risk in later life

Abstract

Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n=9,097, enrolled 1967-1987) were followed for incident (n=1,084 total; n=378 advanced; n=148 high-grade) and fatal (n=340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m²; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mmHg or taking anti-hypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dL or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides was associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs. 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p-trend=0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2hezCSh

A comprehensive analysis of polymorphic variants in steroid hormone and IGF-1 metabolism and risk of in situ breast cancer: results from the Breast and Prostate Cancer Cohort (BPC3) Consortium

Abstract

We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and IGF-1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was done using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (OR_hom=3.05, 95%CI = 1.72-5.44, P_hom= 1.47 × 10⁻⁴), MAST2-rs12124649 (OR_hom=1.73, 95% CI =1.18-2.54, P_hom= 5.24 × 10⁻³), and INSR-rs10500204 (OR_hom= 1.96, 95% CI =1.44-2.67, P_hom=1.68 × 10⁻⁵) were associated with increased risk of BCIS; however only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (OR_hom=1.78, 95% CI =1.30-2.44, P_hom= 3.23 × 10⁻⁴).

The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further. This article is protected by copyright. All rights reserved.

http://ift.tt/2hbxDOp

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Abstract

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer. However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and pancreatic cancer incidence in European populations.

We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident pancreatic cancer cases (EPIC n=626; HUNT2 n=112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D₂ and 25(OH)D₃ combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI).

Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53); and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with pancreatic cancer risk (p for trend = 0.23).

Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of pancreatic cancer risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2hdNDzz
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Risk of skin cancer among patients with myotonic dystrophy type 1 based on Primary care physician data from the United Kingdom Clinical Practice Research Datalink

Abstract

Myotonic dystrophy type 1 (DM1) is an inherited multisystem neuromuscular disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. Recent evidence documents that DM1 patients have an increased risk of certain cancers, but whether skin cancer risks are elevated is unclear. Using the U.K. Clinical Practice Research Datalink (CPRD), we identified 1,061 DM1 patients and 15,119 DM1-free individuals matched on gender, birth year (±2 years), attending practice, and registration year (±1 year). We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of DM1 diagnosis with skin cancer risk using Cox proportional hazards models, for all skin cancers combined and by histological subtype. Follow-up started at the latest of the age at practice registration, DM1 diagnosis/control selection or January 1st 1988, and ended at the earliest of the age at first skin cancer diagnosis, death, transfer out of the practice, last date of data collection or the end of the CPRD record (October 31, 2016). During a median follow-up of 3.6 years, 35 DM1 patients and 108 matched DM1-free individuals developed a skin cancer. DM1 patients had an increased risk of skin cancer overall (HR=5.44, 95% CI=3.33-8.89, p<.0001), and basal cell carcinoma (BCC) (HR=5.78, 95% CI=3.36-9.92, p<.0001). Risks did not differ by gender, or age at DM1 diagnosis (P-heterogeneity>0.5). Our data confirm suggested associations between DM1 and skin neoplasms with the highest risk seen for BCC. Patients are advised to minimize ultraviolet light exposure and seek medical advice for suspicious lesions. This article is protected by copyright. All rights reserved.

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

Midlife metabolic factors and prostate cancer risk in later life

Abstract

Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n=9,097, enrolled 1967-1987) were followed for incident (n=1,084 total; n=378 advanced; n=148 high-grade) and fatal (n=340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m²; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mmHg or taking anti-hypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dL or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides was associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs. 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p-trend=0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer. This article is protected by copyright. All rights reserved.

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

Biweekly cisplatin and gemcitabine in patients advanced biliary tract cancer

Abstract

Treatment with cisplatin with gemcitabine (CG) demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1000mg/m²/min) and cisplatin 20mg/m² on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%) and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%) and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies. This article is protected by copyright. All rights reserved.

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

A comprehensive analysis of polymorphic variants in steroid hormone and IGF-1 metabolism and risk of in situ breast cancer: results from the Breast and Prostate Cancer Cohort (BPC3) Consortium

Abstract

We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and IGF-1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was done using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (OR_hom=3.05, 95%CI = 1.72-5.44, P_hom= 1.47 × 10⁻⁴), MAST2-rs12124649 (OR_hom=1.73, 95% CI =1.18-2.54, P_hom= 5.24 × 10⁻³), and INSR-rs10500204 (OR_hom= 1.96, 95% CI =1.44-2.67, P_hom=1.68 × 10⁻⁵) were associated with increased risk of BCIS; however only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (OR_hom=1.78, 95% CI =1.30-2.44, P_hom= 3.23 × 10⁻⁴).

The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further. This article is protected by copyright. All rights reserved.

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Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses

The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. Cancer Res; 77(22); 1–11. ©2017 AACR.

http://ift.tt/2m2iunV

Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses

The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. Cancer Res; 77(22); 1–11. ©2017 AACR.

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Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma

The incidence of cutaneous melanoma has continued to increase in recent years. For early-stage melanoma, surgical resection is the standard treatment and is associated with an excellent long-term prognosis, with 5-year survival rates of 98% for stage I disease and 90% for stage II disease. However,…

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Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma

The incidence of cutaneous melanoma has continued to increase in recent years. For early-stage melanoma, surgical resection is the standard treatment and is associated with an excellent long-term prognosis, with 5-year survival rates of 98% for stage I disease and 90% for stage II disease. However,…

http://ift.tt/2eYhcY8

BAP1 is a novel target in HPV negative head and neck cancer.

Purpose: This study examined the potential role of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) in radioresistance in head and neck squamous cell cancer (HNSCC). Experimental Design: We overexpressed, knocked down, and rescued BAP1 expression in six HNSCC cell lines, three human papillomavirus (HPV) -negative and HPV-positive, and examined the effects on radiosensitivity in vitro and in HNSCC mouse xenograft models. Radiosensitivity was assessed by clonogenic cell survival and tumor growth delay assays; changes in protein expression were analyzed by immunofluorescence staining and western blotting. We also analyzed The Cancer Genome Atlas HNSCC database to test for associations between BAP1 expression and outcome in patients. Results. Overexpression of BAP1 induced radioresistance in both cell lines and xenograft models; conversely, BAP1 knockdown led to increased ubiquitination of histone H2A, which has been implicated in DNA repair. We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on -H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying homologous recombination. Finally, in patients with HNSCCC, overexpression of BAP1 was associated with higher failure rates after radiation therapy. Conclusions. BAP1 can induce radioresistance in HNSCC cells, possibly via deubiquitination of H2Aub and modulation of HR, and was associated with poor outcomes in patients with HNSCC. BAP1 may be a potential therapeutic target in HNSCC.

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Muscadine Grape Skin Extract in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial

Purpose: MPX, a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. Experimental Design: This was a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR PCa, powered to detect a prostate specific antigen doubling time (PSADT) difference of 6 months (low-dose) and 12 months (high-dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500mg MPX (low), 4000mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation and polyphenol pharmacokinetics. Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (p=0.81): control 0.9 months (n=20, range -6.7 to 83.1), low-dose 1.5 months (n=52, range: -10.3 to 87.2), high-dose 0.9 months (n=40, range: -27.3 to 88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms) (6.4 months, p=0.02), but not in control (1.8 months, p=0.25). Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study.

http://ift.tt/2m1x2nH

BAP1 is a novel target in HPV negative head and neck cancer.

Purpose: This study examined the potential role of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) in radioresistance in head and neck squamous cell cancer (HNSCC). Experimental Design: We overexpressed, knocked down, and rescued BAP1 expression in six HNSCC cell lines, three human papillomavirus (HPV) -negative and HPV-positive, and examined the effects on radiosensitivity in vitro and in HNSCC mouse xenograft models. Radiosensitivity was assessed by clonogenic cell survival and tumor growth delay assays; changes in protein expression were analyzed by immunofluorescence staining and western blotting. We also analyzed The Cancer Genome Atlas HNSCC database to test for associations between BAP1 expression and outcome in patients. Results. Overexpression of BAP1 induced radioresistance in both cell lines and xenograft models; conversely, BAP1 knockdown led to increased ubiquitination of histone H2A, which has been implicated in DNA repair. We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on -H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying homologous recombination. Finally, in patients with HNSCCC, overexpression of BAP1 was associated with higher failure rates after radiation therapy. Conclusions. BAP1 can induce radioresistance in HNSCC cells, possibly via deubiquitination of H2Aub and modulation of HR, and was associated with poor outcomes in patients with HNSCC. BAP1 may be a potential therapeutic target in HNSCC.

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Muscadine Grape Skin Extract in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial

Purpose: MPX, a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. Experimental Design: This was a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR PCa, powered to detect a prostate specific antigen doubling time (PSADT) difference of 6 months (low-dose) and 12 months (high-dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500mg MPX (low), 4000mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation and polyphenol pharmacokinetics. Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (p=0.81): control 0.9 months (n=20, range -6.7 to 83.1), low-dose 1.5 months (n=52, range: -10.3 to 87.2), high-dose 0.9 months (n=40, range: -27.3 to 88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms) (6.4 months, p=0.02), but not in control (1.8 months, p=0.25). Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study.

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FDA Approves Second CAR T-cell Therapy [News in Brief]

Axicabtagene ciloleucel OK'd for the treatment of adults with certain non-Hodgkin lymphomas.

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Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma

The incidence of cutaneous melanoma has continued to increase in recent years. For early-stage melanoma, surgical resection is the standard treatment and is associated with an excellent long-term prognosis, with 5-year survival rates of 98% for stage I disease and 90% for stage II disease. However,…

http://ift.tt/2eYhcY8

Delayed Intraventricular Hemorrhage following a Ventriculoperitoneal Shunt Placement: Exploring the Surgical Anatomy of a Rare Complication

Ventriculoperitoneal shunt (VPS) placement is one of the commoner neurosurgical procedures worldwide. The purpose of this article is to report a case of delayed intraventricular hemorrhage (IVH) following a VPS and to review the literature regarding anatomic factors that could potentially explain this rare complication. A 78-year-old man with normal pressure hydrocephalus, who underwent an uneventful right VPS placement, suffered from a catastrophic isolated IVH five days later. The reported cases of delayed intracerebral hemorrhage (ICH) following VPS are rare and those with IVH are even rarer. Potential factors of surgical anatomy that could cause delayed ICH/IVH following a VPS procedure include erosion of vasculature by catheter cannulation, multiple attempts at perforation, puncture of the choroid plexus, improper placement of the tubing within the brain parenchyma, VPS system revision, venous infarction, vascular malformations, head trauma, and brain tumors. Other causes include generalized convulsion, VPS system malfunction, increased intracranial or blood pressure, sudden intracranial hypotension, and bleeding disorders. According to the current literature, our case is the first reported delayed isolated IVH after a VPS placement so far. Neurosurgeons should be aware of the delayed ICH/IVH as a rare, potentially fatal complication of VPS, as well as of its risk factors.

http://ift.tt/2AqpPk5

Targeting de novo lipogenesis as a novel approach in anti-cancer therapy

Targeting de novo lipogenesis as a novel approach in anti-cancer therapy

Targeting <i>de novo</i> lipogenesis as a novel approach in anti-cancer therapy, Published online: 07 November 2017; doi:10.1038/bjc.2017.374

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CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma, Published online: 07 November 2017; doi:10.1038/bjc.2017.364

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Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer, Published online: 07 November 2017; doi:10.1038/bjc.2017.390

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Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response, Published online: 07 November 2017; doi:10.1038/bjc.2017.389

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Targeting de novo lipogenesis as a novel approach in anti-cancer therapy

Targeting de novo lipogenesis as a novel approach in anti-cancer therapy

Targeting <i>de novo</i> lipogenesis as a novel approach in anti-cancer therapy, Published online: 07 November 2017; doi:10.1038/bjc.2017.374

http://ift.tt/2yGpdcX

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma, Published online: 07 November 2017; doi:10.1038/bjc.2017.364

http://ift.tt/2m2rz03

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer, Published online: 07 November 2017; doi:10.1038/bjc.2017.390

http://ift.tt/2yFBeQ5

Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response, Published online: 07 November 2017; doi:10.1038/bjc.2017.389

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Is dose de-escalation possible in sarcoma patients treated with enlarged limb sparing resection?

To evaluate the impact of dose de-escalation in a large series of resected limbs soft tissue sarcomas (STS).

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Targeting de novo lipogenesis as a novel approach in anti-cancer therapy

http://ift.tt/2haLLYd

Targeting de novo lipogenesis as a novel approach in anti-cancer therapy

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Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer

http://ift.tt/2iDRXIB

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer

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CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

http://ift.tt/2iCiZQJ

Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

http://ift.tt/2hPQ8Zx

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

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Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

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Sigmoid volvulus in children: a case report

Sigmoid volvulus is frequently reported in the "volvulus belt" (Middle East, Africa, the Indian subcontinent, Turkey, and South America) and is the third leading cause of large bowel obstruction in North America.

http://ift.tt/2j7wziN

Lingual metastasis as an initial presentation of renal cell carcinoma: a case report

Renal cell carcinoma is the third most common tumor that metastasizes to the head and neck, after breast and lung carcinomas. Tongue metastasis as an initial presentation of renal cell carcinoma is extremely r...

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Curiethérapie prostatique de rattrapage : solution pour les rechutes localisées après irradiation ?

Publication date: Available online 6 November 2017
Source:Cancer/Radiothérapie
Author(s): J.-M. Cosset, G. Créhange
La curiethérapie de rattrapage après une première irradiation prostatique est une technique émergente qui vient enrichir l'arsenal thérapeutique dans ces situations difficiles de patients atteints de rechute locale isolée d'un cancer de prostate potentiellement curable. Ces rechutes occultes sont dépistées actuellement de plus en plus précocement à la progression de l'antigène spécifique de la prostate grâce aux avancées des techniques de biopsies, guidées par l'information des nouvelles imageries par résonance magnétique (IRM) et tomographie par émission de positons (TEP). Bénéficiant de la précision balistique propre à la curiethérapie en général (dosimétrie tridimensionnelle), elle permet d'observer des taux de contrôle tumoral supérieur à 50 % à long terme. Ses taux d'incontinence sont constamment inférieurs à ceux observés avec les techniques concurrentes telles que la prostatectomie radicale de rattrapage, les ultrasons focalisés ou la cryothérapie. Un consensus est aujourd'hui établi sur les critères de sélection des patients susceptibles de bénéficier de la curiethérapie de rattrapage. Le consensus est en revanche encore partiel pour ce qui concerne certains détails techniques : bas ou haut débit de dose ? Quelle dose exacte ? Dans quel volume (partiel ou total) ? En attendant les résultats imminents de deux essais de phases II et compte tenu des résultats hétérogènes de la littérature existante, cette technique, d'ores et déjà considérée comme validée dans certaines recommandations américaines (NCCN version 3.2016), doit continuer à être évaluée, préférentiellement dans le cadre d'essais cliniques contrôlés.Salvage brachytherapy after a first prostate radiation therapy is an emerging technique, which has to be considered in the therapeutic armamentarium in the clinically challenging context of patients with isolated local failure from prostate cancer who may still be considered for cure. These occult failures are more and more frequently diagnosed at an early stage, thanks to targeted biopsies and advances in imaging modalities, such as multiparametric MRI and PET-CT. Salvage brachytherapy benefits from the implantation accuracy of brachytherapy procedures using 3D dosimetry and has resulted in more than 50% tumour control rates with long-term. Incontinence rates are always below those of other salvage treatments such as radical prostatectomy, HIFU or cryotherapy. Today, a consensus has been reached to better define good candidates for salvage brachytherapy with respect to disease characteristics at baseline and at failure. No consensus has been clearly defined yet regarding the choice of the technique (low or high dose rate), the total dose to be delivered, or the volume to be implanted (whole gland or focal). While we await robust data from recently completed phase II studies and given the heterogeneous results in the literature, this technique (although already included in the last 2016 NCCN guidelines) remains to be precisely evaluated, optimally within the frame of controlled trials.



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Curiethérapie prostatique de rattrapage : solution pour les rechutes localisées après irradiation ?

Publication date: Available online 6 November 2017
Source:Cancer/Radiothérapie
Author(s): J.-M. Cosset, G. Créhange
La curiethérapie de rattrapage après une première irradiation prostatique est une technique émergente qui vient enrichir l'arsenal thérapeutique dans ces situations difficiles de patients atteints de rechute locale isolée d'un cancer de prostate potentiellement curable. Ces rechutes occultes sont dépistées actuellement de plus en plus précocement à la progression de l'antigène spécifique de la prostate grâce aux avancées des techniques de biopsies, guidées par l'information des nouvelles imageries par résonance magnétique (IRM) et tomographie par émission de positons (TEP). Bénéficiant de la précision balistique propre à la curiethérapie en général (dosimétrie tridimensionnelle), elle permet d'observer des taux de contrôle tumoral supérieur à 50 % à long terme. Ses taux d'incontinence sont constamment inférieurs à ceux observés avec les techniques concurrentes telles que la prostatectomie radicale de rattrapage, les ultrasons focalisés ou la cryothérapie. Un consensus est aujourd'hui établi sur les critères de sélection des patients susceptibles de bénéficier de la curiethérapie de rattrapage. Le consensus est en revanche encore partiel pour ce qui concerne certains détails techniques : bas ou haut débit de dose ? Quelle dose exacte ? Dans quel volume (partiel ou total) ? En attendant les résultats imminents de deux essais de phases II et compte tenu des résultats hétérogènes de la littérature existante, cette technique, d'ores et déjà considérée comme validée dans certaines recommandations américaines (NCCN version 3.2016), doit continuer à être évaluée, préférentiellement dans le cadre d'essais cliniques contrôlés.Salvage brachytherapy after a first prostate radiation therapy is an emerging technique, which has to be considered in the therapeutic armamentarium in the clinically challenging context of patients with isolated local failure from prostate cancer who may still be considered for cure. These occult failures are more and more frequently diagnosed at an early stage, thanks to targeted biopsies and advances in imaging modalities, such as multiparametric MRI and PET-CT. Salvage brachytherapy benefits from the implantation accuracy of brachytherapy procedures using 3D dosimetry and has resulted in more than 50% tumour control rates with long-term. Incontinence rates are always below those of other salvage treatments such as radical prostatectomy, HIFU or cryotherapy. Today, a consensus has been reached to better define good candidates for salvage brachytherapy with respect to disease characteristics at baseline and at failure. No consensus has been clearly defined yet regarding the choice of the technique (low or high dose rate), the total dose to be delivered, or the volume to be implanted (whole gland or focal). While we await robust data from recently completed phase II studies and given the heterogeneous results in the literature, this technique (although already included in the last 2016 NCCN guidelines) remains to be precisely evaluated, optimally within the frame of controlled trials.



http://ift.tt/2zDz9nB

E26 Transformation-Specific Transcription Factor ETS2 as an Oncogene Promotes the Progression of Hypopharyngeal Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2m1q1TJ

Prevalence of anthracycline-related cardiac dysfunction in long-term survivors of adult-onset lymphoma

BACKGROUND

Anthracycline-related heart failure is a leading cause of morbidity in survivors of adult-onset lymphoma. There is a paucity of information on screening for late-occurring preclinical disease, which, in turn, has limited guidelines for early detection and intervention. The objectives of this study were to examine the prevalence and risk of cardiac dysfunction, as measured by echocardiography (abnormal left ventricular systolic/diastolic function or strain), in lymphoma survivors who received treatment with anthracyclines and to evaluate the diagnostic yield of blood biomarkers in the asymptomatic setting.

METHODS

Lymphoma survivors who underwent hematopoietic cell transplantation (HCT) (n = 78) or received conventional therapy (non-HCT; n = 77) were compared with each other and with a group of matched controls (n = 51); the study was limited to lymphoma survivors who were >5 years from diagnosis.

RESULTS

At a median follow-up of 9.4 years after diagnosis, 1 in 5 (20.6 %) lymphoma survivors had cardiac dysfunction; the odds of having cardiac dysfunction were 6.6-fold greater (odds ratio [OR], 6.6; P = .01) among lymphoma survivors compared with matched controls. There was a dose-dependent risk of cardiac dysfunction according to the cumulative anthracycline dose (controls [referent group], 1-249 mg/m² [OR, 4.7; P = .05], and ≥250 mg/m² [OR, 7.6; P < .01]), but there was no difference in the prevalence of cardiac dysfunction between conventionally treated and HCT survivors. The diagnostic accuracy of cardiac blood biomarkers in the asymptomatic setting was quite poor.

CONCLUSIONS

In these long-term survivors, there was a high rate of cardiac dysfunction that was independent of HCT status. The growing number of lymphoma survivors makes it imperative to identify reliable and cost-effective strategies to decrease the burden of heart failure in this population. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2zkc5Kb

Neuroendocrine tumors and fibrosis: An unsolved mystery?

Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of the digestive and respiratory tract. Although they are relatively rare, their incidence is rising. It has long been observed that they often are associated with the development of fibrosis, both local and distant. Fibrotic complications, such as carcinoid heart disease and mesenteric desmoplasia, may lead to considerable morbidity or even affect prognosis. The elucidation of the pathophysiology of fibrosis would be of critical importance for the development of targeted therapeutic strategies. In this article, the authors review the available evidence regarding the biological basis of fibrosis in neuroendocrine tumors. They explore the role of the tumor microenvironment and the interplay between tumor cells and fibroblasts as a key factor in fibrogenesis and tumor development/progression. They also review the role of serotonin, growth factors, and other peptides in the development of carcinoid-related fibrotic reactions. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2hn1GX3

Prevalence of anthracycline-related cardiac dysfunction in long-term survivors of adult-onset lymphoma

BACKGROUND

Anthracycline-related heart failure is a leading cause of morbidity in survivors of adult-onset lymphoma. There is a paucity of information on screening for late-occurring preclinical disease, which, in turn, has limited guidelines for early detection and intervention. The objectives of this study were to examine the prevalence and risk of cardiac dysfunction, as measured by echocardiography (abnormal left ventricular systolic/diastolic function or strain), in lymphoma survivors who received treatment with anthracyclines and to evaluate the diagnostic yield of blood biomarkers in the asymptomatic setting.

METHODS

Lymphoma survivors who underwent hematopoietic cell transplantation (HCT) (n = 78) or received conventional therapy (non-HCT; n = 77) were compared with each other and with a group of matched controls (n = 51); the study was limited to lymphoma survivors who were >5 years from diagnosis.

RESULTS

At a median follow-up of 9.4 years after diagnosis, 1 in 5 (20.6 %) lymphoma survivors had cardiac dysfunction; the odds of having cardiac dysfunction were 6.6-fold greater (odds ratio [OR], 6.6; P = .01) among lymphoma survivors compared with matched controls. There was a dose-dependent risk of cardiac dysfunction according to the cumulative anthracycline dose (controls [referent group], 1-249 mg/m² [OR, 4.7; P = .05], and ≥250 mg/m² [OR, 7.6; P < .01]), but there was no difference in the prevalence of cardiac dysfunction between conventionally treated and HCT survivors. The diagnostic accuracy of cardiac blood biomarkers in the asymptomatic setting was quite poor.

CONCLUSIONS

In these long-term survivors, there was a high rate of cardiac dysfunction that was independent of HCT status. The growing number of lymphoma survivors makes it imperative to identify reliable and cost-effective strategies to decrease the burden of heart failure in this population. Cancer 2017. © 2017 American Cancer Society.

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Neuroendocrine tumors and fibrosis: An unsolved mystery?

Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of the digestive and respiratory tract. Although they are relatively rare, their incidence is rising. It has long been observed that they often are associated with the development of fibrosis, both local and distant. Fibrotic complications, such as carcinoid heart disease and mesenteric desmoplasia, may lead to considerable morbidity or even affect prognosis. The elucidation of the pathophysiology of fibrosis would be of critical importance for the development of targeted therapeutic strategies. In this article, the authors review the available evidence regarding the biological basis of fibrosis in neuroendocrine tumors. They explore the role of the tumor microenvironment and the interplay between tumor cells and fibroblasts as a key factor in fibrogenesis and tumor development/progression. They also review the role of serotonin, growth factors, and other peptides in the development of carcinoid-related fibrotic reactions. Cancer 2017. © 2017 American Cancer Society.

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E26 Transformation-Specific Transcription Factor ETS2 as an Oncogene Promotes the Progression of Hypopharyngeal Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Cultural Competence in Global Health

By Nathan Douthit

[I]n the…aim to produce cultural competence, one dimension to be avoided is… narrowly defining competence… in its traditional sense: an easily demonstrable mastery of a finite body of knowledge. Rather, cultural competence…is best described… as a commitment and active engagement in a lifelong process that individuals enter into on an ongoing basis with patients, communities, colleagues, and with themselves.^[1]

            Dunton et al describe the importance of cultural competence in taking care of patients in minority communities in "Navigating care for Bedouin patients with diabetes." They describe the case of a patient with a 30 year history of diabetes. Despite his best efforts, the doctor's success when, "encouraging the patient to make lifestyle changes… proved virtually impossible." He developed End Stage Renal Disease as a result, and then suddenly passed away, likely secondary to "a heart attack due to complications from chronic diabetes."

            In light of the rise of chronic disease, specifically as demonstrated in a "minority culture within a larger Western society," the training of culturally competent physicians is essential. In this case, fatalism plays a key role. The eldest son writes,

            "During my father's disease, his socioeconomic situation was good…. He could go to the experts…. [But] he didn't consider diabetes a major threat. He was shocked when he was told he needed dialysis. He initially refused treatment for a few weeks before we convinced him with the help of his doctor…. We were sorry that he died. But in our society, we believe in God and see this as the will of God. We can't do anything about it."

            Addressing fatalism, a "main obstacle in educating and motivating patients," requires a culturally sensitive dialogue. The authors recommend focusing on quality of life rather than threat of death. Having patients "consider how changes in lifestyle will help in remaining strong and active until the prewritten day of death," may help in addressing this issue.

            According to the authors, "the link between trust and the adherence to treatment regimens is found within many communities." Training culturally competent physicians must focus on having knowledge, skills, and respect and being able to implement these effectively in cross cultural situations.^[2] "Culturally appropriate intervention channels" are key to reducing stigma and raising patient awareness of available resources.

            Cultural competence has been shown to improve many health behaviors, specifically related to nutrition, exercise and substance use habits.^[3] Culturally competent physicians must be willing to partner with local leaders. As the authors write, "if community and leaders could establish the importance of diet as something on par with the importance of vaccinations, it would contribute to changing the culture positively."

BMJ Case Reports invites authors to publish cases regarding cultural competence and humility in training global health practitioners. Global health case reports can emphasize:

            -The effects of culturally appropriate health interventions

            -Training methods for culturally competent global health practitioners

            -Disease spread or exacerbation as a result of cultural incompetence

            -Innovation in culturally appropriate interventions

Manuscripts may be submitted by students, physicians, nurses or other medical professionals to BMJ Case Reports. For more information, review the blog on how to write a global health case report.

Read more about cultural competence and humility in the interaction of clinicians with patients at BMJ Case Reports

            –A Rohingya refugee's journey in Australia and the barriers to accessing healthcare

            –Ethiopian-Israeli community

            –Analysis of the psychosocial impact of caretaking on the parents of an infant with severe congenital heart defect.

Read more about cultural competence and humility from other sources

            -Tervalon M, Murray-Garcia J. Cultural humility versus cultural competence: a critical distinction in defining physician training outcomes in multicultural education. Journal of health care for the poor and underserved. 1998;9(2):117-25.

            -Brach C, Fraserirector I. Can cultural competency reduce racial and ethnic health disparities? A review and conceptual model. Medical Care Research and Review. 2000 Nov;57(1_suppl):181-217

            -Goode TD, Dunne MC, Bronheim S. The evidence base for cultural and linguistic competency in health care. New York^ eNY NY: Commonwealth Fund; 2006 Oct.

^[1] Tervalon M, Murray-Garcia J. Cultural humility versus cultural competence: a critical distinction in defining physician training outcomes in multicultural education. Journal of health care for the poor and underserved. 1998;9(2):117-25.

^[2] Brach C, Fraserirector I. Can cultural competency reduce racial and ethnic health disparities? A review and conceptual model. Medical Care Research and Review. 2000 Nov;57(1_suppl):181-217.

^[3] Goode TD, Dunne MC, Bronheim S. The evidence base for cultural and linguistic competency in health care. New York^ eNY NY: Commonwealth Fund; 2006 Oct.

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European guidelines on perioperative venous thromboembolism prophylaxis: Neurosurgery

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Surgery during pregnancy and the immediate postpartum period

No abstract available

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European Guidelines on perioperative venous thromboembolism prophylaxis: Executive summary

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Day surgery and fast-track surgery

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Intensive care

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the obese patient

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Cardiovascular and thoracic surgery

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Chronic treatments with antiplatelet agents

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Aspirin

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Patients with preexisting coagulation disorders and after severe perioperative bleeding

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Mechanical prophylaxis

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis: Inferior vena cava filters

No abstract available

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European guidelines on perioperative venous thromboembolism prophylaxis

No abstract available

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E26 Transformation-Specific Transcription Factor ETS2 as an Oncogene Promotes the Progression of Hypopharyngeal Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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E26 Transformation-Specific Transcription Factor ETS2 as an Oncogene Promotes the Progression of Hypopharyngeal Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Response

Because of its increased convenience and decreased cost, once-daily hypofractionated radiotherapy (HFX; 2.25 Gy/fraction) has been adopted over other altered-fractionation schedules in the United States for the management of early-stage glottic cancer. In our patterns-of-care analysis, we found that over 80% of patients were treated with either hypofractionation (2.25 Gy/fraction) or conventional fractionation (CFX; 2.0 Gy/fraction); utilization rates of other altered-fractionation regimens were 2.6% or less. Given the low utilization rates of fractionation schedules not recommended by the National Comprehensive Cancer Network guidelines, we did not compare other altered-fractionation schedules to CFX. Therefore, we were not able to make conclusions regarding the optimal radiotherapy treatment schedule; we could only conclude that our findings suggest that HFX is superior to CFX.

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RE: Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival

An article in the Journal by Bledsoe et al. recently reported on patterns of care and survival in patients treated with radiotherapy for early-stage glottic carcinoma (1). A similar study by Stokes et al. was also published in the International Journal of Radiation Oncology * Biology * Physics (2). Both evaluated the role of hypofractionated radiotherapy using the National Cancer Database and identified almost the same patients. The results and conclusions, not surprisingly, were the same: that hypofractionated radiotherapy yielded a small overall survival benefit.

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Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers

Abstract

Purpose

Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.

Methods

Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan–Meier analyses were performed.

Results

2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30–39 years. Kaplan–Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002).

Conclusions

The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

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Vitamin D supplementation decreases serum 27-hydroxycholesterol in a pilot breast cancer trial

Abstract

Purpose

27-hydroxycholesterol (27HC), an endogenous selective estrogen receptor modulator (SERM), drives the growth of estrogen receptor-positive (ER+) breast cancer. 1,25-dihydroxyvitamin D (1,25(OH)₂D), the active metabolite of vitamin D, is known to inhibit expression of CYP27B1, which is very similar in structure and function to CYP27A1, the synthesizing enzyme of 27HC. Therefore, we hypothesized that 1,25(OH)₂D may also inhibit expression of CYP27A1, thereby reducing 27HC concentrations in the blood and tissues that express CYP27A1, including breast cancer tissue.

Methods

27HC, 25-hydroxyvitamin D (25OHD), and 1,25(OH)₂D were measured in sera from 29 breast cancer patients before and after supplementation with low-dose (400 IU/day) or high-dose (10,000 IU/day) vitamin D in the interval between biopsy and surgery.

Results

A significant increase (p = 4.3E−5) in 25OHD and a decrease (p = 1.7E−1) in 27HC was observed in high-dose versus low-dose vitamin D subjects. Excluding two statistical outliers, 25OHD and 27HC levels were inversely correlated (p = 7.0E−3).

Conclusions

Vitamin D supplementation can decrease circulating 27HC of breast cancer patients, likely by CYP27A1 inhibition. This suggests a new and additional modality by which vitamin D can inhibit ER+ breast cancer growth, though a larger study is needed for verification.

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32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Part One

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32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Part Two

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Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain

Abstract

Background

Everolimus with exemestane has shown promising activity in patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant advanced breast cancer. It is necessary, therefore, to characterize the safety profile of this new combination in the real-world clinical setting and in the broadest possible population.

Patients and methods

Post-menopausal women with HR-positive HER2-negative advanced breast cancer progressing after prior non-steroidal aromatase inhibitors (NSAIs) were included. The objectives of this analysis were to evaluate the safety profile of this combination in a subset of Spanish patients in the BALLET trial and to characterize grade 3 and 4 adverse events (AEs) in routine clinical practice in Spain.

Results

Between September 2012 and July 2013, 429 patients (20% of the overall study population) were included in the BALLET study in 52 hospitals in Spain, of whom 100 (23%) were ≥ 70 years. The median treatment duration was 3.14 and 3.03 months for exemestane and everolimus, respectively. The most common reasons for discontinuation of treatment were local reimbursement of everolimus (43%), followed by disease progression (31%) and the incidence of AEs (15%). The most frequent AEs causing permanent discontinuation were pneumonitis (4%), asthenia (2%) and stomatitis (2%). Overall, 87% of patients experienced at least one AE of any grade, 30% of patients at least one grade 3 AE and 2% of patients a grade 4 AE.

Conclusion

The safety profile in Spanish patients of the BALLET trial is consistent with the results obtained in the overall population of the trial, as well as in previous clinical trials.

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SEOM clinical guideline for the management of malignant melanoma (2017)

Abstract

All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams.

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Older cancer patients in cancer clinical trials are underrepresented. Systematic literature review of almost 5000 meta- and pooled analyses of phase III randomized trials of survival from breast, prostate and lung cancer

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Cita Dunn, Andrew Wilson, Freddy Sitas
BackgroundOlder people represent increasing proportions of the population with cancer. To understand the representivity of cancer treatments in older people, we performed a systematic literature review using PRISMA guidelines of the age distribution of clinical trial participants for three leading cancer types, namely breast, prostate, and lung.MethodsWe used PubMed to identify articles detailing meta or pooled-analyses of phase III, randomised controlled trials (RCTs) of survival for breast, prostate and lung cancer, published ≤5 years from 2016. We compared the age distribution of participants to that of these cancers for "More developed regions".Results4993 potential papers were identified, but only three papers on breast cancer, three on lung cancer, and none on prostate cancer presented the age distribution of their participants. Except for one paper of breast cancer, participants ≥70 years in all other papers were underrepresented.ConclusionsWe recommend the age distribution of patients be clearly reported in all clinical trials, as per guidelines. Clinical trials ought to be more representative of the populations most affected by the disease for which treatments are being tested. This should lead to better knowledge of effectiveness of treatments and better translation of trial results to optimal care of older cancer patients.

Graphical abstract

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32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Part One

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32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Part Two

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Older cancer patients in cancer clinical trials are underrepresented. Systematic literature review of almost 5000 meta- and pooled analyses of phase III randomized trials of survival from breast, prostate and lung cancer

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Cita Dunn, Andrew Wilson, Freddy Sitas
BackgroundOlder people represent increasing proportions of the population with cancer. To understand the representivity of cancer treatments in older people, we performed a systematic literature review using PRISMA guidelines of the age distribution of clinical trial participants for three leading cancer types, namely breast, prostate, and lung.MethodsWe used PubMed to identify articles detailing meta or pooled-analyses of phase III, randomised controlled trials (RCTs) of survival for breast, prostate and lung cancer, published ≤5 years from 2016. We compared the age distribution of participants to that of these cancers for "More developed regions".Results4993 potential papers were identified, but only three papers on breast cancer, three on lung cancer, and none on prostate cancer presented the age distribution of their participants. Except for one paper of breast cancer, participants ≥70 years in all other papers were underrepresented.ConclusionsWe recommend the age distribution of patients be clearly reported in all clinical trials, as per guidelines. Clinical trials ought to be more representative of the populations most affected by the disease for which treatments are being tested. This should lead to better knowledge of effectiveness of treatments and better translation of trial results to optimal care of older cancer patients.

Graphical abstract

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Biobehavioral modulation of the exosome transcriptome in ovarian carcinoma

BACKGROUND

Social factors in the patient macroenvironment have been shown to influence molecular events in the tumor microenvironment and thereby influence cancer progression. However, biomarkers providing a window into the longitudinal effects of biobehavioral factors on tumor biology over time are lacking. Exosome analysis is a novel strategy for in vivo monitoring of dynamic changes in tumor cells. This study examined exosomal profiles from patients with low or high levels of social support for epithelial-mesenchymal transition (EMT) polarization and gene expression related to inflammation and β-adrenergic signaling.

METHODS

Exosomes were isolated from plasma sampled from a series of 40 women before primary surgical resection of advanced-stage, high-grade ovarian carcinoma. Samples were selected for analysis on the basis of extremes of low and high levels of social support. After exosomal isolation and RNA extraction, a microarray analysis of the transcriptome was performed.

RESULTS

Primary analyses identified significant upregulation of 67 mesenchymal-characteristic gene transcripts and downregulation of 63 epithelial-characteristic transcripts in patients with low social support; this demonstrated increased EMT polarization (P = .0002). Secondary analyses using promoter sequence bioinformatics supported a priori hypotheses linking low social support to 1) increased activity of cyclic adenosine monophosphate response element binding protein (CREB)/activating transcription factor (ATF) family transcription factors that mediate the β-adrenergic response to catecholamines via the cyclic adenosine monophosphate/protein kinase A signaling pathway (mean fold change for CREB: 2.24 ± 0.65; P = .0019; mean fold change for ATF: 2.00 ± 0.55; P = .0049) and 2) increased activity of the proinflammatory nuclear factor κB/Rel family of transcription factors (mean fold change: 2.10 ± 0.70; P = .0109).

CONCLUSIONS

These findings suggest the possibility of leveraging exosomes as a noninvasive assessment of biobehavioral factors to help to direct personalized treatment approaches. Cancer 2017. © 2017 American Cancer Society.

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Individualized outcome prognostication for patients with laryngeal cancer

BACKGROUND

Accurate prognostication is essential to the optimal management of laryngeal cancer. Predictive models have been developed to calculate the risk of oncologic outcomes, but extensive external validation of accuracy and reliability is necessary before implementing them into clinical practice.

METHOD

Four published prognostic calculators that predict 5-year overall survival for patients with laryngeal cancer were evaluated using patient information from a prospective epidemiology study cohort (n = 246; median follow-up, 60 months) with previously untreated, stage I through IVb laryngeal squamous cell carcinoma.

RESULTS

Different calculators yielded substantially different predictions for individual patients. The observed 5-year overall survival was significantly higher than the averaged predicted 5-year overall survival of the 4 calculators (71.9%; 95% confidence interval [CI], 65%-78%] vs 47.7%). Statistical analyses demonstrated the calculators' limited capacity to discriminate outcomes for risk-stratified patients. The area under the receiver operating characteristic curve ranged from 0.68 to 0.72. C-index values were similar for each of the 4 models (range, 0.66-0.68). There was a lower than expected hazard of death for patients who received induction (bioselective) chemotherapy (hazard ratio, 0.46; 95% CI, 0.24-0.88; P = .024) or primary surgical intervention (hazard ratio, 0.43; 95 % CI, 0.21-0.90; P = .024) compared with those who received concurrent chemoradiation.

CONCLUSIONS

Suboptimal reliability and accuracy limit the integration of existing individualized prediction tools into routine clinical decision making. The calculators predicted significantly worse than observed survival among patients who received induction chemotherapy and primary surgery, suggesting a need for updated consideration of modern treatment modalities. Further development of individualized prognostic calculators may improve risk prediction, treatment planning, and counseling for patients with laryngeal cancer. Cancer 2017. © 2017 American Cancer Society.

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A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis

BACKGROUND

In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen-identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP-) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP.

METHODS

In the current study, the authors performed a long-term follow-up to discover possible late effects of the intensified GVHD prophylaxis.

RESULTS

The median follow-up for surviving patients was 24.5 years. In the MP+ group, the overall survival and recurrence-free survival were higher (P = .021 and P = .028, respectively) and the nonrecurrence mortality was lower (P = .003) than in the MP- group. There was a trend toward a lower cumulative incidence and a significantly lower prevalence (P = .031) of chronic GVHD in the MP+ group. There was no difference noted with regard to the rate of disease recurrence or in the incidence of secondary malignancies. Eleven patients in the MP- group but none in the MP+ group died >15 years after transplantation. At the end of follow-up, the overall survival rates in the MP+ and MP- groups were 55% and 20%, respectively, and the recurrence-free survival rates were 49% and 15%, respectively.

CONCLUSIONS

Long-term survival was found to be higher among the patients given MP in addition to cyclosporine and methotrexate. There was marked late nonrecurrence mortality observed in the group not given MP. No adverse late effects caused by the addition of corticosteroid were observed. Cancer 2017. © 2017 American Cancer Society.

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Longitudinal analysis of quality of life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children's Oncology Group AALL0932 trial

BACKGROUND

Children with average-risk acute lymphoblastic leukemia (AR-ALL) face many challenges that can adversely affect their quality of life (QOL). However, to the authors' knowledge, patterns and predictors of QOL impairment during therapy have not been well characterized to date.

METHODS

Patients with AR-ALL who were enrolled on the Children's Oncology Group AALL0932 trial were offered participation in this prospective cohort study if they were aged ≥4 years at the time of diagnosis and had an English-speaking parent. At approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis, parents completed the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0) and McMaster Family Assessment Device instruments for QOL (physical, emotional, and social functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (2 standard deviations below the population mean) were calculated at each time point. Longitudinal impairment patterns and predictors were examined.

RESULTS

A total of 594 participants with AR-ALL were diagnosed at a mean age of 6.0 years (standard deviation, 1.6 years). At 2 months, a substantial proportion of participants had impaired scores for physical (36.5%; 95% confidence interval [95% CI], 32.3%-40.8%) and emotional (26.2%; 95% CI, 22.5%-30.2%) functioning compared with population norms of 2.3%. These elevations persisted at 26 months. Emotional impairment at 2 months (odds ratio, 3.4; 95% CI, 1.5-7.7) was found to significantly predict emotional impairment at 26 months. In repeated measures analysis with multivariate modeling, unhealthy family functioning (odds ratio, 1.5; 95% CI, 1.1-2.1) significantly predicted emotional impairment controlling for age and sex. QOL outcomes were similar between sexes at the end of therapy (26 months for girls and 38 months for boys).

CONCLUSIONS

Many children with AR-ALL experience physical and emotional functioning impairment that begins early in treatment and persists. Early screening may identify high-risk patients who might benefit from family-based interventions. Cancer 2017. © 2017 American Cancer Society.

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Trends and variations in postmastectomy radiation therapy for breast cancer in patients with 1 to 3 positive lymph nodes: A National Cancer Data Base analysis

BACKGROUND

High-level evidence is lacking to guide treatment decisions about postmastectomy radiation therapy (PMRT) in patients who have breast cancer with 1 to 3 positive lymph nodes who receive contemporary systemic therapies, leading to potential variations in PMRT delivery. The objective of this study was to examine nationwide trends in PMRT use in this group.

METHODS

The National Cancer Data Base (NCDB) was used to identify 93,372 women who had T1-T2N1 breast cancer diagnosed between 2003 and 2012. Patients who received neoadjuvant chemotherapy or radiation therapy (RT) and those who had bilateral breast cancers were excluded. Time trends were evaluated using the Cochrane-Armitage test and correlated the receipt of PMRT with various patient demographic, facility, clinicopathologic, and treatment variables using multivariable logistic regression. A second analysis was performed for patients who were diagnosed during 2010 and included radiation oncologist density as an additional covariate. P values < .0001 were considered statistically significant.

RESULTS

Overall, 22.5% of the study population received PMRT, representing an increase from 19.1% in 2003 to 30.3% in 2012. Factors associated with greater PMRT use included younger age, lower Charlson-Deyo comorbidity scores, shorter distance to the treating facility, treatment at a comprehensive cancer program, facility location in the New England Census division, and higher density of radiation oncologists. Increased PMRT use was associated with later year of diagnosis, receipt of chemotherapy, receipt of hormone therapy, higher grade disease, larger tumor size, greater numbers of positive lymph nodes, positive margins, and absence of immediate breast reconstruction (all P < .0001).

CONCLUSIONS

The receipt of PMRT by patients with breast cancer who have 1 to 3 positive lymph nodes has increased over time, with wide variability in practice patterns in the United States. Cancer 2017. © 2017 American Cancer Society.

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Impact of the insurance type of head and neck cancer patients on their hospitalization utilization patterns

BACKGROUND

Head and neck cancer (HNC) patients with Medicaid, Medicare, or no insurance show poor outcomes in comparison with privately insured patients. It was hypothesized that nonprivate insurance coverage biases the selection of the treatment site to favor hospitals that are not associated with optimum treatment outcomes. This study assessed the relation between the insurance type of HNC patients and the hospital type for inpatient care.

METHODS

Adult HNC patients were identified from the Nationwide Inpatient Sample (2012 and 2013). The primary exposure was the insurance provider type. The outcome was the hospital type, which was classified by the hospital's ownership and its location and teaching status. Multivariate multinomial logistic regression models were constructed to control for the patient's age, sex, race, income, mortality risk, and geographic location. The analysis was weighted and was adjusted for multiple comparisons.

RESULTS

In all, 37,466 HNC patients representing 187,330 patients nationally were identified. After adjustments for age, sex, race, income, and mortality risk, in comparison with privately insured patients, Medicaid, Medicare, and uninsured patients demonstrated 1.14 to 2.29 increased odds of undergoing treatment at rural, urban nonteaching, private investor–owned, or government (nonfederal) hospitals (P < .05). This trend remained apparent even after adjustments for the geographic location.

CONCLUSIONS

Uninsured patients or patients insured by government programs predominantly underwent care for HNC at hospital types most often associated with inferior survival outcomes. This finding could explain some proportion of insurance-related disparities in HNC outcomes. Further studies are warranted to determine whether interventions to promote equitable access to optimal hospital settings for patients, regardless of their insurance type, might improve outcomes among nonprivate insurance holders. Cancer 2017. © 2017 American Cancer Society.

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Estimating global treatment toxicity burden from adverse-event data

BACKGROUND

A summary measure that reflects the global toxicity burden of a treatment is essential for comparing therapies. Current toxicity summaries are ad hoc and do not distinguish among the severities and types of toxicities. Here a clinically feasible method for estimating the toxicity burden, based on a prospective evaluation of the toxicity profile of a randomized clinical trial of 746 prostate cancer patients conducted by SWOG, is proposed.

METHODS

For 308 patients who experienced severe toxicities, 2 physicians randomly selected from 14 physicians evaluated each toxicity profile and assigned a visual analogue scale score (0-10) based on their impression of the global burden of toxicities. With mixed-effects models, severity scores and a 10-point toxicity burden score (TBS) were derived from 27 predictors accounting for severe (grade 3) and life-threatening (grade 4) toxicities for each organ class of the Common Terminology Criteria for Adverse Events.

RESULTS

For most organ classes, grade 3 toxicities had a TBS of 4.14 (95% confidence interval [CI], 3.65-4.63), but infections, cardiovascular events, and pulmonary events had a higher TBS with differences of 0.87 (95% CI, 0.53-1.21), 0.88 (95% CI, 0.51-1.25), and 0.73 (95% CI, 0.22-1.24), respectively. Moreover, most grade 4 events had a higher TBS than grade 3 events, except for hemorrhaging, pain, metabolic events, and musculoskeletal events. The intrarater and interrater correlations were 0.91 and 0.59, respectively.

CONCLUSIONS

The burden of toxicity grades differs with toxicity types. A TBS provides a toxicity burden summary that incorporates physicians' perspectives and differentiates between severe and life-threatening toxicities and organ classes. Cancer 2017. © 2017 American Cancer Society.

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Global and targeted circulating microRNA profiling of colorectal adenoma and colorectal cancer

BACKGROUND

Circulating microRNAs (miRNAs) are emerging as promising biomarkers for cancer. The objective of the current study was to investigate the potential of circulating cell-free miRNAs as biomarkers for colorectal cancer (CRC) and its precursor lesion, colorectal adenoma.

METHODS

The serum levels of 800 miRNAs were assessed in a discovery set of 21 patients with CRC, 19 patients with adenoma, and 21 healthy controls using the NanoString miRNA analysis platform. Significantly differentially expressed miRNAs were examined further in a validation cohort of 34 patients with CRC, 33 patients with adenoma, and 35 healthy controls using Fluidigm quantitative polymerase chain reaction assays.

RESULTS

The ratios between the expression values of the differentially expressed miRNAs were computed. Three miRNA ratios (miR-17-5p/miR-135b, miR-92a-3p/miR135b, and miR-451a/miR-491-5p) were validated for discriminating patients with adenoma and those with CRC from the healthy control group, and 5 miRNA ratios (let-7b/miR-367-3p, miR-130a-3p/miR-409-3p, miR-148-3p/miR-27b, miR-148a-3p/miR-409-3p, and miR-21-5p/miR-367-3p) were validated for discriminating patients with CRC from those with adenoma and healthy controls. The area under the receiver operating characteristic curve values for the 3 miRNA ratios in discriminating patients with adenoma from healthy controls were 0.831 and 0.735, respectively, in the discovery and validation sets. The area under the receiver operating characteristic curve values for the 5 miRNA ratios in discriminating patients with CRC from those with adenoma were 0.797 and 0.732, respectively, in the discovery and validation sets. Pathway analysis revealed that target genes regulated by the miRNAs from the miRNA ratios were enriched mainly in metabolism-related and inflammation-related pathways.

CONCLUSIONS

The data from the current study suggest that circulating miRNAs can distinguish patients with CRC and those with adenoma and may represent novel biomarkers for the early, noninvasive detection of CRC. Cancer 2017. © 2017 American Cancer Society.

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