The prognostic value of neutrophil–lymphocyte ratio is superior to derived neutrophil–lymphocyte ratio in advanced gastric cancer treated with preoperative chemotherapy and sequential R0 resection: a 5-year follow-up

http://ift.tt/2s1oX0n

Bisdemethoxycurcumin in combination with α-PD-L1 antibody boosts immune response against bladder cancer

http://ift.tt/2r3B7ZE

Expression of urinary miRNAs targeting NLRs inflammasomes in bladder cancer

http://ift.tt/2s1wUmb

hrHPV E5 oncoprotein: immune evasion and related immunotherapies

The immune response is a key factor in the fight against HPV infection and related cancers, and thus, HPV is able to promote immune evasion through the expression of oncogenes. In particular, the E5 oncogene i...

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Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath

Chronic migraine headache and acute shortness of breath associated with nausea, vomiting, diaphoresis and increasing retrosternal chest pain..Increased frequency of his migraine headaches associated with vague retrosternal chest pain and epigastric pain...................................................................................................................Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath................................................................................Palpitations, fatigue, vague chest discomfort, and cardiomegaly and pulmonary congestion visible on chest radiograph. He had developed a flu-like illness with low-grade fever, chills, myalgia and headache a week earlier. There had been no preceding cough, hemoptysis, orthopnea, paroxysmal nocturnal dyspnea or ankle edema. .....................................................................................................................................Eosinophilic myocarditis (EM)........................................................................................................Therapeutic effect of anti-IL-5 on eosinophilic myocarditis with large pericardial effusion

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Neoadjuvant chemotherapy with trastuzumab, docetaxel, and carboplatin administered every 3 weeks for Japanese women with HER2-positive primary breast cancer: efficacy and safety

Abstract

Background

This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer.

Methods

Patients with HER2-positive, stage I–III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m², day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease.

Results

Fifty patients were enrolled in this study. Median age was 58 (range 32–75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%).

Conclusion

Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy.

Clinical registration number: http://www.umin.org.auUMIN000013513.

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Neoadjuvant chemotherapy with trastuzumab, docetaxel, and carboplatin administered every 3 weeks for Japanese women with HER2-positive primary breast cancer: efficacy and safety

Abstract

Background

This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer.

Methods

Patients with HER2-positive, stage I–III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m², day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease.

Results

Fifty patients were enrolled in this study. Median age was 58 (range 32–75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%).

Conclusion

Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy.

Clinical registration number: http://www.umin.org.auUMIN000013513.

http://ift.tt/2qUUcfO

Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites

Abstract

Background

The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test.

Methods

We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study.

Results

The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15–9.38 95%C.I.), liver cancer (OR: 4.02; 1.14–14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12–10.39 95%C.I.) independently from Gender and Age.

Conclusions

Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome.

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Long-term use of pegylated liposomal doxorubicin to a cumulative dose of 4600 mg/m2 in recurrent ovarian cancer.

Pegylated liposomal doxorubicin (PLD) is used widely in gynecologic oncology and other oncology disciplines. Native doxorubicin use is associated with the potential for significant toxicity. Cardiac toxicity in particular limits lifetime dose. PLD has not been shown to be associated with clinical cardiac toxicity. We report on the long-term use of PLD in a patient with recurrent high-grade serous ovarian cancer to a lifetime dose of 4600 mg/m2. This therapy was associated with long-term stable disease, good performance status, and minimal adverse effects. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hypoxia as a target for drug combination therapy of liver cancer.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1[alpha] in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivo using an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1[alpha]. Combination treatments were more effective in vivo than either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://ift.tt/1iwynXF Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions.

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug-drug interaction, hepatic dysfunction, population PK, exposure-response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/1hexVwJ Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3'-ethynylcytidine treatment of human cancer cells.

A nucleosidic medicine, 1-(3-C-ethynyl-[beta]-D-ribo-pentofuranosyl)cytosine [3'-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3'-ethyntlcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethyntlcytidine 5'-diphosphate, 3'-ethyntlcytidine 5'-triphosphate). 3'-Ethyntlcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites

Abstract

Background

The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test.

Methods

We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study.

Results

The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15–9.38 95%C.I.), liver cancer (OR: 4.02; 1.14–14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12–10.39 95%C.I.) independently from Gender and Age.

Conclusions

Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome.

http://ift.tt/2rWIDU6

Long-term use of pegylated liposomal doxorubicin to a cumulative dose of 4600 mg/m2 in recurrent ovarian cancer.

Pegylated liposomal doxorubicin (PLD) is used widely in gynecologic oncology and other oncology disciplines. Native doxorubicin use is associated with the potential for significant toxicity. Cardiac toxicity in particular limits lifetime dose. PLD has not been shown to be associated with clinical cardiac toxicity. We report on the long-term use of PLD in a patient with recurrent high-grade serous ovarian cancer to a lifetime dose of 4600 mg/m2. This therapy was associated with long-term stable disease, good performance status, and minimal adverse effects. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2qlSrpi

Hypoxia as a target for drug combination therapy of liver cancer.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1[alpha] in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivo using an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1[alpha]. Combination treatments were more effective in vivo than either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://ift.tt/1iwynXF Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2rFgkfv

A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions.

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug-drug interaction, hepatic dysfunction, population PK, exposure-response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/1hexVwJ Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2qlZluX

Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3'-ethynylcytidine treatment of human cancer cells.

A nucleosidic medicine, 1-(3-C-ethynyl-[beta]-D-ribo-pentofuranosyl)cytosine [3'-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3'-ethyntlcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethyntlcytidine 5'-diphosphate, 3'-ethyntlcytidine 5'-triphosphate). 3'-Ethyntlcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2rFDqTo

Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors

Abstract

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. Median OS was 24 months in Group A (with cumulative dose ≤ 3000 mg) while in Group B (with cumulative dose > 3000 mg), it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

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Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors

Abstract

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. Median OS was 24 months in Group A (with cumulative dose ≤ 3000 mg) while in Group B (with cumulative dose > 3000 mg), it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

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Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials

The primary objective of phase I oncology trials is to find the maximum tolerated dose (MTD). The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared to the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared to the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Freely available, open-source software facilitates the application of the keyboard design.

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Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials

The primary objective of phase I oncology trials is to find the maximum tolerated dose (MTD). The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared to the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared to the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Freely available, open-source software facilitates the application of the keyboard design.

http://ift.tt/2qpEuWN

Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis.

Objective: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. Materials and Methods: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m2) and overweight (BMI, 25 to 29.9 kg/m2) individuals with normal BMI individuals using random-effects model. Results: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. Conclusions: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Impact of the Primary Information Source Used for Decision Making on Treatment Perceptions and Regret in Prostate Cancer.

Objective: To assess the impact of the primary source of information used by prostate cancer patients to select a radiation treatment on their overall treatment experience and on treatment regret. Methods: Patients with low to favorable intermediate-risk prostate cancer treated with stereotactic body radiation therapy, intensity-modulated radiation therapy, or high-dose rate brachytherapy were surveyed. The questionnaire explored the decision-making experience, treatment experience, and treatment regret. Results: In total, 322 consecutive patients were surveyed with an 86% (n=276) response rate. In total, 48% (n=132) selected their radiation oncologist as the primary information source, 23% (n=62) selected their urologist, 16% (n=44) selected the Internet, 6% (n=17) selected other patients, and 8% (n=21) selected other. In total, 39% of patients who selected the Internet as their primary information source reported their actual treatment experience to be worse than expected versus 13% of respondents who selected their urologist, 12% who selected other patients, and 2% who selected their radiation oncologist (P

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Treatment and Outcomes of Primary Urethra Cancer.

Background: Urethral cancer is a rare malignancy, representing

http://ift.tt/2rWrx8P

Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or [beta]-blockers in Older Adults With Breast Cancer.

Purpose: Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or [beta]-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. Materials and Methods: A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. Results: The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs=6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P

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Immune Atlases Created for Kidney, Lung Cancers [News in Brief]

In-depth analyses reveal dysregulated, immunosuppressive landscape in both tumor types.

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Three Drugs Approved for Urothelial Carcinoma by FDA [News in Brief]

Checkpoint inhibitors pembrolizumab, avelumab, and durvalumab add to the list of similar drugs approved for treating bladder cancer.

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Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis.

Objective: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. Materials and Methods: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m2) and overweight (BMI, 25 to 29.9 kg/m2) individuals with normal BMI individuals using random-effects model. Results: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. Conclusions: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Impact of the Primary Information Source Used for Decision Making on Treatment Perceptions and Regret in Prostate Cancer.

Objective: To assess the impact of the primary source of information used by prostate cancer patients to select a radiation treatment on their overall treatment experience and on treatment regret. Methods: Patients with low to favorable intermediate-risk prostate cancer treated with stereotactic body radiation therapy, intensity-modulated radiation therapy, or high-dose rate brachytherapy were surveyed. The questionnaire explored the decision-making experience, treatment experience, and treatment regret. Results: In total, 322 consecutive patients were surveyed with an 86% (n=276) response rate. In total, 48% (n=132) selected their radiation oncologist as the primary information source, 23% (n=62) selected their urologist, 16% (n=44) selected the Internet, 6% (n=17) selected other patients, and 8% (n=21) selected other. In total, 39% of patients who selected the Internet as their primary information source reported their actual treatment experience to be worse than expected versus 13% of respondents who selected their urologist, 12% who selected other patients, and 2% who selected their radiation oncologist (P

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Treatment and Outcomes of Primary Urethra Cancer.

Background: Urethral cancer is a rare malignancy, representing

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Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or [beta]-blockers in Older Adults With Breast Cancer.

Purpose: Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or [beta]-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. Materials and Methods: A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. Results: The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs=6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P

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PTK7 is a novel oncogenic target for esophageal squamous cell carcinoma

Abstract

Background

Overexpression of PTK7 has been found in multiple cancers and has been proposed to serve as a prognostic marker for intrahepatic cholangiocarcinoma. Its role in esophageal cancer, however, remains to be clarified. We hypothesize that PTK7 positively regulates tumorigenesis of esophageal cancer.

Methods

We examined PTK7 expression pattern in human esophageal squamous carcinoma by Oncomine expression analysis and by immunohistochemistry (IHC) staining. We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells. Expressions of major apoptotic regulators and effectors were also determined by quantitative real-time PCR in PTK7-defective cells. We further overexpressed PTK7 in the cell to evaluate its effects on cell proliferation, apoptosis, and migration.

Results

Both Oncomine expression and IHC analyses showed that PTK7 is overexpressed in clinical esophageal squamous cell carcinoma tumors. PTK7 siRNA suppressed cell growth and promoted apoptosis of TE-5 and TE-9. PTK7-defective cells further displayed reduced cellular migration that was concomitant with upregulation of E-cadherin. Conversely, overexpression of PTK7 promotes cell proliferation and invasion, while apoptosis of the PTK7-overexpressing cells is repressed. Notably, major apoptotic regulators, such as p53 and caspases, are significantly upregulated in siPTK7 cells.

Conclusions

PTK7 plays an oncogenic role in tumorigenesis and metastasis of esophageal squamous carcinoma. PTK7 achieves its oncogenic function in esophageal squamous cell carcinoma partially through the negative regulation of apoptosis.

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Combining serum miRNAs, CEA, and CYFRA21-1 with imaging and clinical features to distinguish benign and malignant pulmonary nodules: a pilot study

Abstract

Background

Our study was designed to improve the accuracy of determining whether pulmonary nodules are benign or malignant.

Methods

We evaluated the clinical and imaging features and serum markers: neuron specific enolase (NSE), carcino-embryonic antigen (CEA), cytokeratin fragment antigen 21–1 (CYFRA 21–1), miRNA-21-5p, and miR-574-5pof in 39 patients with pathology information. Factors that differed significantly between those with benign versus malignant pulmonary nodules were used to establish a prediction model for identifying malignant nodules.

Results

The studied nodules were 51.3% malignant and 48.7% benign. Age, smoking status, nodule diameter, history of emphysema, vascular sign, burr sign, CYFRA21-1, CEA, miRNA-21-5p, and miRNA-574-5p differed significantly between the benign and malignant nodule groups. Serum levels of CYRFA21-1 and CEA could be used to distinguish between malignant and benign nodules with a positive predictive value (PPV) of 80.0%, a negative predictive value (NPV) of 84.2%, and an area under the receiver operating characteristics curve (AUC) of 0.863. Using the serum levels of miRNA-21-5p and miRNA-574-5p, the PPV was 55%, the NPV was 84.2%, and the AUC was 0.797. When all four serum markers were combined, the PPV was 80%, the NPV was 89.5%, and the AUC was 0.921. We established a prediction model for malignant nodules, including clinical features, imaging features, and serum markers. In cross-validation, the ratio of discriminant conformance was 95%.

Conclusions

Serum levels of miRNA-21-5p and miRNA-574-5p are significantly higher in patients with malignant nodules than in patients with benign nodules and are potential serum biomarkers. Our prediction model could improve malignant nodule diagnosis.

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Efficacy of prophylactic splenectomy for proximal advanced gastric cancer invading greater curvature

Abstract

Background

For proximal gastric cancer invading the greater curvature, concomitant splenectomy is frequently performed to secure the clearance of lymph node metastases. However, prognostic impact of prophylactic splenectomy remains unclear. The aim of this study was to clarify the oncological significance of prophylactic splenectomy for advanced proximal gastric cancer invading the greater curvature.

Methods

Retrospective review of 108 patients who underwent total or subtotal gastrectomy for advanced proximal gastric cancer involving the greater curvature was performed. Short-term and long-term outcomes were compared between the patients who underwent splenectomy (n = 63) and those who did not (n = 45).

Results

Patients who underwent splenectomy showed higher amount of blood loss (538 vs. 450 mL, p = 0.016) and morbidity rate (30.2 vs. 13.3, p = 0.041) compared with those who did not undergo splenectomy. In particular, pancreas-related complications were frequently observed among patients who received splenectomy (17.4 vs. 0%, p = 0.003). However, no significant improvement of long-term outcomes were confirmed in the cases with splenectomy (5-year recurrence-free rate, 60.2 vs. 67.3%; p = 0.609 and 5-year overall survival rates, 63.7 vs. 73.6%; p = 0.769). On the other hand, splenectomy was correlated with marginally better survival in patients with Borrmann type 1 or 2 gastric cancer (p = 0.072).

Conclusions

For advanced proximal gastric cancer involving the greater curvature, prophylactic splenectomy may have no significant prognostic impact despite the increased morbidity rate after surgery. Such surgical procedure should be avoided as long as lymph node involvement is not evident.

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PTK7 is a novel oncogenic target for esophageal squamous cell carcinoma

Abstract

Background

Overexpression of PTK7 has been found in multiple cancers and has been proposed to serve as a prognostic marker for intrahepatic cholangiocarcinoma. Its role in esophageal cancer, however, remains to be clarified. We hypothesize that PTK7 positively regulates tumorigenesis of esophageal cancer.

Methods

We examined PTK7 expression pattern in human esophageal squamous carcinoma by Oncomine expression analysis and by immunohistochemistry (IHC) staining. We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells. Expressions of major apoptotic regulators and effectors were also determined by quantitative real-time PCR in PTK7-defective cells. We further overexpressed PTK7 in the cell to evaluate its effects on cell proliferation, apoptosis, and migration.

Results

Both Oncomine expression and IHC analyses showed that PTK7 is overexpressed in clinical esophageal squamous cell carcinoma tumors. PTK7 siRNA suppressed cell growth and promoted apoptosis of TE-5 and TE-9. PTK7-defective cells further displayed reduced cellular migration that was concomitant with upregulation of E-cadherin. Conversely, overexpression of PTK7 promotes cell proliferation and invasion, while apoptosis of the PTK7-overexpressing cells is repressed. Notably, major apoptotic regulators, such as p53 and caspases, are significantly upregulated in siPTK7 cells.

Conclusions

PTK7 plays an oncogenic role in tumorigenesis and metastasis of esophageal squamous carcinoma. PTK7 achieves its oncogenic function in esophageal squamous cell carcinoma partially through the negative regulation of apoptosis.

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Combining serum miRNAs, CEA, and CYFRA21-1 with imaging and clinical features to distinguish benign and malignant pulmonary nodules: a pilot study

Abstract

Background

Our study was designed to improve the accuracy of determining whether pulmonary nodules are benign or malignant.

Methods

We evaluated the clinical and imaging features and serum markers: neuron specific enolase (NSE), carcino-embryonic antigen (CEA), cytokeratin fragment antigen 21–1 (CYFRA 21–1), miRNA-21-5p, and miR-574-5pof in 39 patients with pathology information. Factors that differed significantly between those with benign versus malignant pulmonary nodules were used to establish a prediction model for identifying malignant nodules.

Results

The studied nodules were 51.3% malignant and 48.7% benign. Age, smoking status, nodule diameter, history of emphysema, vascular sign, burr sign, CYFRA21-1, CEA, miRNA-21-5p, and miRNA-574-5p differed significantly between the benign and malignant nodule groups. Serum levels of CYRFA21-1 and CEA could be used to distinguish between malignant and benign nodules with a positive predictive value (PPV) of 80.0%, a negative predictive value (NPV) of 84.2%, and an area under the receiver operating characteristics curve (AUC) of 0.863. Using the serum levels of miRNA-21-5p and miRNA-574-5p, the PPV was 55%, the NPV was 84.2%, and the AUC was 0.797. When all four serum markers were combined, the PPV was 80%, the NPV was 89.5%, and the AUC was 0.921. We established a prediction model for malignant nodules, including clinical features, imaging features, and serum markers. In cross-validation, the ratio of discriminant conformance was 95%.

Conclusions

Serum levels of miRNA-21-5p and miRNA-574-5p are significantly higher in patients with malignant nodules than in patients with benign nodules and are potential serum biomarkers. Our prediction model could improve malignant nodule diagnosis.

http://ift.tt/2r362F6

Efficacy of prophylactic splenectomy for proximal advanced gastric cancer invading greater curvature

Abstract

Background

For proximal gastric cancer invading the greater curvature, concomitant splenectomy is frequently performed to secure the clearance of lymph node metastases. However, prognostic impact of prophylactic splenectomy remains unclear. The aim of this study was to clarify the oncological significance of prophylactic splenectomy for advanced proximal gastric cancer invading the greater curvature.

Methods

Retrospective review of 108 patients who underwent total or subtotal gastrectomy for advanced proximal gastric cancer involving the greater curvature was performed. Short-term and long-term outcomes were compared between the patients who underwent splenectomy (n = 63) and those who did not (n = 45).

Results

Patients who underwent splenectomy showed higher amount of blood loss (538 vs. 450 mL, p = 0.016) and morbidity rate (30.2 vs. 13.3, p = 0.041) compared with those who did not undergo splenectomy. In particular, pancreas-related complications were frequently observed among patients who received splenectomy (17.4 vs. 0%, p = 0.003). However, no significant improvement of long-term outcomes were confirmed in the cases with splenectomy (5-year recurrence-free rate, 60.2 vs. 67.3%; p = 0.609 and 5-year overall survival rates, 63.7 vs. 73.6%; p = 0.769). On the other hand, splenectomy was correlated with marginally better survival in patients with Borrmann type 1 or 2 gastric cancer (p = 0.072).

Conclusions

For advanced proximal gastric cancer involving the greater curvature, prophylactic splenectomy may have no significant prognostic impact despite the increased morbidity rate after surgery. Such surgical procedure should be avoided as long as lymph node involvement is not evident.

http://ift.tt/2s1ovPW

Early-stage non-small cell lung cancer in the USA: patterns of care and survival among elderly patients at least 80 years old

Abstract

Background

The purpose of this study was to analyze the patterns of care of local therapies and their impact on overall survival (OS) among elderly patients with early-stage non-small cell lung cancer (NSCLC) in the USA.

Methods

The National Cancer Database was queried for patients at least age 80 years with NSCLC diagnosed in 2004–2013 with clinical stage T1–3N0M0. Local therapy was analyzed over time and by age. Multivariable (MVA) models were performed to investigate the impact of prognostic factors on OS.

Results

Among 40,561 patients meeting inclusion criteria, 17,418 (43%), 13,008 (32%), and 10,135 (25%) of patients underwent surgical resection, radiotherapy, and observation, respectively, as their initial mode of local therapy. Overtime, while the utilization of surgical managements generally remained stable, the utilization of conventionally fractionated radiotherapy and observation decreased in favor of stereotactic body radiotherapy (SBRT, p < 0.001). Among operable patients (n = 16,377), after MVA several factors were associated with OS including the choice of local therapy favoring resection over conventionally fractionated radiotherapy and observation (HR compared to lobectomy 1.362, and 2.656, respectively, each p < 0.001). In contrast, there was no statistical difference in OS between resection and SBRT among operable patients (HR for SBRT 1.128, p = 0.156).

Conclusions

The utilization of SBRT as the definitive local therapy in elderly patients with early-stage NSCLC is increasing in the USA. Given its generally favorable toxicity profile, SBRT should be considered in the substantial proportion of elderly patients still not receiving any definitive local therapy. Among medically operable elderly patients, OS was similar between resection and SBRT.

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Clinical outcomes following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic adenocarcinoma

Abstract

Objectives

The purpose of this study was to report on progression-free survival (PFS), overall survival (OS), and related toxicities following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic cancer (PCa).

Methods

The RSSearch® Patient Registry was screened for PCa patients treated with SBRT. The relationship between PFS, OS, and potential prognostic factors were evaluated using the Kaplan-Meier method and continuous log-rank analysis, and the correlation between treatment planning and toxicity incidence was examined by logistic regression.

Results

Sixty patients met inclusion criteria. Twenty-three patients (38.33%) had received adjuvant gemcitabine. Following SBRT, median PFS was 6.07 months (range: 2.33 - 34.4 months) and median OS was 8.55 months (range: 2.66 - 78.53 months). Single-fraction SBRT trended towards poorer median PFS (5.13 vs. 6.76 months; p = 0.0122) with no significant difference in median OS (10.3 vs. 7.17 months; p = 0.8896). PCas located in the head had a significantly higher median OS (9.58 months) as compared to those in the body (5.66 months; p = 0.0376). Adjuvant gemcitabine did not result in superior PFS (5.12 vs. 6.35 months; p = 0.52) or OS (8.67 vs. 7.07 months; p = 0.6010). Eight (13.3%) and six (10%) patients reported acute and late toxicities, respectively, that were all Grade 1 or 2. Single-fraction SBRT was associated with an increased risk of toxicity incidence (5/9 patients vs. 3/51 patients; p = 0.001).

Conclusion

SBRT was well-tolerated by PCa patients with fractionated SBRT trending towards superior PFS and less toxicity as compared to single-fraction SBRT.

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Current practices in the management of stage IB, grade 3 endometrial cancer in the United States

Abstract

Objectives

Endometrial cancer is the most common gynecologic malignancy in the United States (US). Most patients are diagnosed with early stage disease and those with stage IB, grade 3 disease have inferior outcomes. Due to the heterogeneity among these patients, existing data has failed to yield cohesive recommendations to guide management decisions. The present study sought to analyze current practices regarding the use of adjuvant radiation for these patients.

Methods

The Surveillance, Epidemiology, and End Results Program was used to find all cases of endometrial cancer diagnosed between 2009 and 2013 in patients aged 18 or older. Data regarding the age (<60 versus ≥60), race (white versus non-white), tumor size (less than or equal to 4 cm versus >4 cm), type of surgery performed (less than the total hysterectomy and bilateral salpingo-oophrectomy, TH/BSO, versus greater than or equal to TH/BSO), number of nodes examined (<10 versus ≥10), radiation sequence with surgery (none versus adjuvant radiation), and type of radiation (brachytherapy versus external beam radiation versus both) was extracted from the database. We compared type of treatment administered based on the presence of risk factors. We also analyzed survival outcomes based on these clinic-pathologic factors.

Results

There were no differences between patients receiving surgery alone versus adjuvant radiation based on any parameter. Among those who received radiation, we found no differences between the type of radiation administered, except with respect to tumor size. Patients with small tumors (<4 cm) were more likely to be offered VBT alone (p = 0.03). The overall survival (OS) estimate for the group as a whole was 89% at 59 months. The OS for VBT alone and EBRT alone was 89%, while for the combination, it was 91%. Large tumor size and sub-optimal surgery were associated with inferior survival.

Conclusion

The current study highlights the fact that there is tremendous variation in the management of patients with stage IB, grade 3 endometrial cancer. Forty percent of patients in the US are not offered adjuvant radiation, despite inferior outcomes among these patients when treated with surgery alone. Clearly defined, uniform guidelines are needed to standardize management decisions for this group of patients. Uniform practice is especially important to cut costs in medicine and standardize treatment across health networks.

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Early-stage non-small cell lung cancer in the USA: patterns of care and survival among elderly patients at least 80 years old

Abstract

Background

The purpose of this study was to analyze the patterns of care of local therapies and their impact on overall survival (OS) among elderly patients with early-stage non-small cell lung cancer (NSCLC) in the USA.

Methods

The National Cancer Database was queried for patients at least age 80 years with NSCLC diagnosed in 2004–2013 with clinical stage T1–3N0M0. Local therapy was analyzed over time and by age. Multivariable (MVA) models were performed to investigate the impact of prognostic factors on OS.

Results

Among 40,561 patients meeting inclusion criteria, 17,418 (43%), 13,008 (32%), and 10,135 (25%) of patients underwent surgical resection, radiotherapy, and observation, respectively, as their initial mode of local therapy. Overtime, while the utilization of surgical managements generally remained stable, the utilization of conventionally fractionated radiotherapy and observation decreased in favor of stereotactic body radiotherapy (SBRT, p < 0.001). Among operable patients (n = 16,377), after MVA several factors were associated with OS including the choice of local therapy favoring resection over conventionally fractionated radiotherapy and observation (HR compared to lobectomy 1.362, and 2.656, respectively, each p < 0.001). In contrast, there was no statistical difference in OS between resection and SBRT among operable patients (HR for SBRT 1.128, p = 0.156).

Conclusions

The utilization of SBRT as the definitive local therapy in elderly patients with early-stage NSCLC is increasing in the USA. Given its generally favorable toxicity profile, SBRT should be considered in the substantial proportion of elderly patients still not receiving any definitive local therapy. Among medically operable elderly patients, OS was similar between resection and SBRT.

http://ift.tt/2s1f7vv

Clinical outcomes following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic adenocarcinoma

Abstract

Objectives

The purpose of this study was to report on progression-free survival (PFS), overall survival (OS), and related toxicities following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic cancer (PCa).

Methods

The RSSearch® Patient Registry was screened for PCa patients treated with SBRT. The relationship between PFS, OS, and potential prognostic factors were evaluated using the Kaplan-Meier method and continuous log-rank analysis, and the correlation between treatment planning and toxicity incidence was examined by logistic regression.

Results

Sixty patients met inclusion criteria. Twenty-three patients (38.33%) had received adjuvant gemcitabine. Following SBRT, median PFS was 6.07 months (range: 2.33 - 34.4 months) and median OS was 8.55 months (range: 2.66 - 78.53 months). Single-fraction SBRT trended towards poorer median PFS (5.13 vs. 6.76 months; p = 0.0122) with no significant difference in median OS (10.3 vs. 7.17 months; p = 0.8896). PCas located in the head had a significantly higher median OS (9.58 months) as compared to those in the body (5.66 months; p = 0.0376). Adjuvant gemcitabine did not result in superior PFS (5.12 vs. 6.35 months; p = 0.52) or OS (8.67 vs. 7.07 months; p = 0.6010). Eight (13.3%) and six (10%) patients reported acute and late toxicities, respectively, that were all Grade 1 or 2. Single-fraction SBRT was associated with an increased risk of toxicity incidence (5/9 patients vs. 3/51 patients; p = 0.001).

Conclusion

SBRT was well-tolerated by PCa patients with fractionated SBRT trending towards superior PFS and less toxicity as compared to single-fraction SBRT.

http://ift.tt/2r3bFDh

Current practices in the management of stage IB, grade 3 endometrial cancer in the United States

Abstract

Objectives

Endometrial cancer is the most common gynecologic malignancy in the United States (US). Most patients are diagnosed with early stage disease and those with stage IB, grade 3 disease have inferior outcomes. Due to the heterogeneity among these patients, existing data has failed to yield cohesive recommendations to guide management decisions. The present study sought to analyze current practices regarding the use of adjuvant radiation for these patients.

Methods

The Surveillance, Epidemiology, and End Results Program was used to find all cases of endometrial cancer diagnosed between 2009 and 2013 in patients aged 18 or older. Data regarding the age (<60 versus ≥60), race (white versus non-white), tumor size (less than or equal to 4 cm versus >4 cm), type of surgery performed (less than the total hysterectomy and bilateral salpingo-oophrectomy, TH/BSO, versus greater than or equal to TH/BSO), number of nodes examined (<10 versus ≥10), radiation sequence with surgery (none versus adjuvant radiation), and type of radiation (brachytherapy versus external beam radiation versus both) was extracted from the database. We compared type of treatment administered based on the presence of risk factors. We also analyzed survival outcomes based on these clinic-pathologic factors.

Results

There were no differences between patients receiving surgery alone versus adjuvant radiation based on any parameter. Among those who received radiation, we found no differences between the type of radiation administered, except with respect to tumor size. Patients with small tumors (<4 cm) were more likely to be offered VBT alone (p = 0.03). The overall survival (OS) estimate for the group as a whole was 89% at 59 months. The OS for VBT alone and EBRT alone was 89%, while for the combination, it was 91%. Large tumor size and sub-optimal surgery were associated with inferior survival.

Conclusion

The current study highlights the fact that there is tremendous variation in the management of patients with stage IB, grade 3 endometrial cancer. Forty percent of patients in the US are not offered adjuvant radiation, despite inferior outcomes among these patients when treated with surgery alone. Clearly defined, uniform guidelines are needed to standardize management decisions for this group of patients. Uniform practice is especially important to cut costs in medicine and standardize treatment across health networks.

http://ift.tt/2s1fGFH

Highly recurrent H3F3A mutations with additional epigenetic regulator alterations in giant cell tumor of bone

Abstract

Recurrent H3F3A and IDH2 mutations have been reported in giant cell tumor of bone (GCTB). However, the reported incidences have varied, and other molecular genetic alterations have not been identified due to the small number of cases analyzed with comprehensive methods. Moreover, the relative sensitivities of Sanger sequencing and next-generation sequencing (NGS) for the detection of H3F3A mutations in DNA extracted from archival formalin-fixed paraffin-embedded (FFPE) for clinical diagnosis have not been assessed. To address these issues, we conducted whole-exome sequencing of 7 GCTBs and integrated the previously published genomic sequencing data of 6 GCTBs. We subsequently performed targeted sequencing of an additional 39 GCTBs, including 2 atypical cases and an extremely rare case of primary malignant transformation of GCTB. We also evaluated the sensitivity of Sanger sequencing for detecting H3F3A mutations in FFPE samples that are usually utilized for clinical diagnosis. H3F3A glycine hotspot mutations were the most frequently detected mutations (96%) in the 52 GCTBs by NGS. Of the 50 hotspot mutations, p.G34W was observed in 48 cases and p.G34L/G34R was detected in one. One of two atypical GCTB cases with wild-type H3F3A had a H3F3B mutation (p.G34V). Other mutated genes were not recurrent. Sanger sequencing did not detect H3F3A mutations in 10 of 15 H3F3A NGS mutation-positive FFPE samples. In conclusion, we confirmed that H3F3A is the most frequently mutated GCTB driver gene, and that H3F3A mutations are not present in atypical GCTBs. Sanger sequencing was much less sensitive than targeted NGS for detecting H3F3A mutations in FFPE samples. This article is protected by copyright. All rights reserved.

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Highly recurrent H3F3A mutations with additional epigenetic regulator alterations in giant cell tumor of bone

Abstract

Recurrent H3F3A and IDH2 mutations have been reported in giant cell tumor of bone (GCTB). However, the reported incidences have varied, and other molecular genetic alterations have not been identified due to the small number of cases analyzed with comprehensive methods. Moreover, the relative sensitivities of Sanger sequencing and next-generation sequencing (NGS) for the detection of H3F3A mutations in DNA extracted from archival formalin-fixed paraffin-embedded (FFPE) for clinical diagnosis have not been assessed. To address these issues, we conducted whole-exome sequencing of 7 GCTBs and integrated the previously published genomic sequencing data of 6 GCTBs. We subsequently performed targeted sequencing of an additional 39 GCTBs, including 2 atypical cases and an extremely rare case of primary malignant transformation of GCTB. We also evaluated the sensitivity of Sanger sequencing for detecting H3F3A mutations in FFPE samples that are usually utilized for clinical diagnosis. H3F3A glycine hotspot mutations were the most frequently detected mutations (96%) in the 52 GCTBs by NGS. Of the 50 hotspot mutations, p.G34W was observed in 48 cases and p.G34L/G34R was detected in one. One of two atypical GCTB cases with wild-type H3F3A had a H3F3B mutation (p.G34V). Other mutated genes were not recurrent. Sanger sequencing did not detect H3F3A mutations in 10 of 15 H3F3A NGS mutation-positive FFPE samples. In conclusion, we confirmed that H3F3A is the most frequently mutated GCTB driver gene, and that H3F3A mutations are not present in atypical GCTBs. Sanger sequencing was much less sensitive than targeted NGS for detecting H3F3A mutations in FFPE samples. This article is protected by copyright. All rights reserved.

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The Expression of MCM7 is a Useful Biomarker in the Early Diagnostic of Gastric Cancer

Abstract

The aim of this study was to investigate the expression of minichromosome maintenance complex component 7 (MCM7) in gastric mucosal lesions, further to find its potential effect as a biomarker to distinguish intraepithelial neoplasia from gastric mucosal lesions. MCM7 and Ki67 were detected in 93 cases of gastric mucosal lesions by immunohistochemistry. MCM7 and Ki67 expression in GT were lowest compared with other groups (P<0.001), meanwhile there were significant differences compared with Group IM and other groups in MCM7 and Ki67 expression (P<0.001). MCM7 and Ki67 expression in GSC were highest (P<0.05). Groups of LGN, HGN and GIC had no significant differences in MCM7 expression (P>0.05), but there was significant difference compared with Group LGN and Group GIC in Ki67 expression (P<0.05). MCM7 expression elevated with tumor grade increasing and had positive correlation with Ki67 significantly (r=0.940, P<0.001). Furthermore, in some cases, some tumor cells were immunoreactive to MCM7 but negative to Ki67. So we concluded that MCM7 is helpful for us to make differential diagnosis in pathological grade, MCM7 combination of Ki67 may serve as more sensitive proliferation markers for evaluation of gastric carcinoma and precancerous lesions.

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The Expression of MCM7 is a Useful Biomarker in the Early Diagnostic of Gastric Cancer

Abstract

The aim of this study was to investigate the expression of minichromosome maintenance complex component 7 (MCM7) in gastric mucosal lesions, further to find its potential effect as a biomarker to distinguish intraepithelial neoplasia from gastric mucosal lesions. MCM7 and Ki67 were detected in 93 cases of gastric mucosal lesions by immunohistochemistry. MCM7 and Ki67 expression in GT were lowest compared with other groups (P<0.001), meanwhile there were significant differences compared with Group IM and other groups in MCM7 and Ki67 expression (P<0.001). MCM7 and Ki67 expression in GSC were highest (P<0.05). Groups of LGN, HGN and GIC had no significant differences in MCM7 expression (P>0.05), but there was significant difference compared with Group LGN and Group GIC in Ki67 expression (P<0.05). MCM7 expression elevated with tumor grade increasing and had positive correlation with Ki67 significantly (r=0.940, P<0.001). Furthermore, in some cases, some tumor cells were immunoreactive to MCM7 but negative to Ki67. So we concluded that MCM7 is helpful for us to make differential diagnosis in pathological grade, MCM7 combination of Ki67 may serve as more sensitive proliferation markers for evaluation of gastric carcinoma and precancerous lesions.

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Histone H3 K27M mutations in adult cerebellar high-grade gliomas

Abstract

Adult cerebellar high-grade gliomas (HGG) are rare and their molecular basis has not been fully elucidated. Although a diffuse midline glioma H3 K27M-mutant, a recently characterized variant of HGG, was reported to occasionally occur in the cerebellum, adult cases were rarely tested for this mutation; only five mutant cases have been reported to date. It currently remains unknown whether H3 K27M-mutant cerebellar gliomas share common histological features or have a uniformly dismal prognosis. In the present study, we assessed the prevalence of histone H3 K27M mutations in ten adult cerebellar HGG, identifying two H3F3A-mutant cases. One case was a 70-year-old female with a cystic lesion. Histologically, the tumor was considered to be glioblastoma; however, a part of the tumor exhibiting low proliferative activity appeared to be consistent with long-standing H3 K27M-mutant tumors in the literature. Another case was a 69-year-old male. The tumor showed a distinct circumscribed histology with minimal astrocytic differentiation, suggesting a nosological issue in the diagnosis of diffuse midline glioma. More cerebellar tumors need to be tested for H3 K27M mutations to clarify the clinical and histopathological spectra of this tumor.

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Patient compliance for postoperative radiotherapy and survival outcome of women with stage I endometrioid endometrial cancer

Background and Objectives

To examine characteristics and survival outcome of women with endometrial cancer who declined postoperative radiotherapy.

Methods

A retrospective study was conducted to examine surgically-treated grade 1-2 stage IB and grade 3 stage IA-IB endometrioid endometrial cancer in the Surveillance, Epidemiology, and End Results Program between 1983 and 2013 (n = 10 613). Associations of patient declination for guideline-based postoperative radiotherapy and clinico-pathological demographics or survival outcome were examined on multivariable analysis.

Results

There were 323 (3.0%) women who declined adjuvant radiotherapy. Women who declined postoperative radiotherapy were more likely to be older, White, Western U.S. residents, and register in recent years (all, adjusted-P < 0.05). On multivariable analysis, patient declination for guideline-based postoperative radiotherapy remained an independent prognostic factor for decreased endometrial cancer-specific survival in unstaged grade 1-2 stage IB or staged/unstated grade 3 stage IA-IB diseases (adjusted-hazard ratio 1.84, 95% confidence interval 1.34-2.51, P = 0.001). Association of patient declination for guideline-based postoperative radiotherapy and decreased overall survival remained independent in the entire cohort on multivariable analysis (adjuvant-hazard ratio 1.71, 95% confidence interval 1.44-2.02, P < 0.001).

Conclusions

Our study suggested that patient compliance to guideline-based postoperative radiotherapy is a prognostic factor for women with stage I endometrioid endometrial cancer.

http://ift.tt/2rVgQ6l

The prognostic utility of the “Tumor Burden Score” based on preoperative radiographic features of colorectal liver metastases

Background

Recently, a tumor-burden "metro ticket" score (TBS) based on final pathology was proposed to predict outcome following resection of colorectal liver metastasis (CRLM). We sought to validate the TBS prognostic tool using preoperative radiologic cross-sectional imaging.

Methods

Imaging TBS was defined on a Cartesian plane that incorporated both maximum tumor size (x-axis) and lesion number (y-axis) assessed by pre-operative imaging. The discriminatory power (area under the curve [AUC]) and goodness-of-fit (Harrel's C statistic and Somer's D statistics) of the imaging TBS model was assessed.

Results

Imaging and pathologic TBS correlated strongly (r = 0.76, P < 0.01). Among patients treated with neoadjuvant therapy, the correlation was strongest among patients with progressive disease/stable disease (PD/SD) (r = 0.81). Discriminatory power of the imaging-based versus pathology-based TBS models were comparable (AUC 0.64 vs. 0.67, respectively P > 0.05). An incremental worsening of long-term survival was noted as the imaging TBS increased (5-year OS: Zone1, Zone2, and Zone3—61.3%, 46.7%, and 38.5%, respectively; P = 0.03). The imaging-based TBS model outperformed the "classic" pathology-based Fong score (Harrel's C-index: imaging TBS-0.56 vs. Fong score-0.53; Somers'D-index: imaging TBS-012 vs. Fong score-0.06).

Conclusions

Imaging-based TBS was superior to traditional tumor size and number and was comparable to pathology-based TBS. Imaging-based TBS may have the potential to facilitate improved preoperative risk stratification of patients with CRLM.

http://ift.tt/2rmgKHJ

Sterilization of tumor-positive lymph nodes of esophageal cancer by neo-adjuvant treatment is associated with worse survival compared to tumor-negative lymph nodes treated with surgery first

Background and Objectives

Lymph node (LN) involvement by esophageal cancer is associated with compromised long-term prognosis. This study assessed whether LN downstaging by neoadjuvant treatment (NAT) might offer a survival benefit compared to patients with a priori negative LN.

Methods

Patients undergoing esophagectomy for cancer between 2005 and 2014 were screened for inclusion. Group 1 included cN0 patients confirmed as pN0 who were treated with surgery first, whereas group 2 included patients initially cN+ and down-staged to ypN0 after NAT. Survival analysis was performed with the Kaplan-Meier and Cox regression methods.

Results

Fifty-seven patients were included in our study, 24 in group 1 and 33 in group 2. Group 2 patients had more locally advanced lesions compared to a priori negative patients, and despite complete LN sterilization by NAT they still had worse long-term survival. Overall 3-year survival was 86.8% for a priori LN negative versus 63.3% for downstaged patients (P = 0.013), while disease-free survival was 79.6% and 57.9%, respectively (P = 0.021). Tumor recurrence was also earlier and more disseminated for the down-staged group.

Conclusions

Downstaged LN, despite the systemic effect of NAT, still inherit an increased risk for early tumor recurrence and worse long-term survival compared to a priori negative LN.

http://ift.tt/2rVl2Dh

The vascularized groin lymph node flap (VGLN): Anatomical study and flap planning using multi-detector CT scanner. The golden triangle for flap harvesting

Introduction: A growing number of surgeons perform lymph node transfers for the treatment of lymphedema. When harvesting a vascularized lymph node groin flap (VGLNF) one of the major concerns is the potential risk of iatrogenic lymphedema of the donor-site. This article helps understanding of the lymph node distribution of the groin in order to minimize this risk.

Materials and Methods: Fifty consecutive patients undergoing abdominal mapping by multi-detector CT scanner were included and 100 groins analyzed. The groin was divided in three zones (of which zone II is the safe zone) and lymph nodes were counted and mapped with their distances to anatomic landmarks. Further node units were plotted and counted.

Results: The average age was 48 years. A mean number of nodes of 6.5/groin was found. In zone II, which is our zone of interest a mean of 3.1 nodes were counted with a mean size of 7.8 mm. In three patients no nodes were found in zone II. In five patients nodes were seen in zone II but were not sufficient in size or number to be considered a lymph node unit. On average the lymph node unit in zone II was found to be 48.3 mm from the pubic tubercle when projected on a line from the pubic tubercle to the anterior superior iliac spine, 16.0 mm caudal to this line, and 20.4 mm above the groin crease. On average the lymph node unit was a mean of 41.7 mm lateral to the SCIV-SIEV confluence.

Conclusion: This study provides increased understanding of the lymphatic anatomy in zone II of the groin flap and suggests a refined technique for designing the VGLNF. As with any flap there is a degree of individual patient variability. However, having information on the most common anatomy and flap design is of great value.

http://ift.tt/2rmjs0b

PARP Inhibitors in Prostate Cancer

Opinion Statement

The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.

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Finer leaf resolution and steeper beam edges using a virtual isocentre in concurrence to PTV-shaped collimators in standard distance – a planning study

Abstract

Purpose

Investigation of a reduced source to target distance to improve organ at risk sparing during stereotactic irradiation (STX).

Methods

The authors present a planning study with perfectly target-volume adapted collimator compared with multi-leaf collimator (MLC) at reduced source to virtual isocentre distance (SVID) in contrast to normal source to isocentre distance (SID) for stereotactic applications. The role of MLC leaf width and 20–80% penumbra was examined concerning the healthy tissue sparing. Several prescription schemes and target diameters are considered.

Results

Paddick's gradient index (GI) as well as comparison of the mean doses to spherical shells at several distances to the target is evaluated. Both emphasize the same results: the healthy tissue sparing in the high dose area around the planning target volume (PTV) is improved at reduced SVID ≤ 70 cm. The effect can be attributed more to steeper penumbra than to finer leaf resolution. Comparing circular collimators at different SVID just as MLC-shaped collimators, always the GI was reduced. Even MLC-shaped collimator at SVID 70 cm had better healthy tissue sparing than an optimal shaped circular collimator at SID 100 cm.

Regarding penumbra changes due to varying SVID, the results of the planning study are underlined by film dosimetry measurements with Agility™ MLC.

Conclusion

Penumbra requires more attention in comparing studies, especially studies using different planning systems. Reduced SVID probably allows usage of conventional MLC for STX-like irradiations.

http://ift.tt/2r1ZmY4

Patterns of local-regional recurrence after conformal and intensity-modulated radiotherapy for head and neck cancer

Abstract

Aim

To evaluate the patterns of loco-regional recurrences in head and neck cancer patients

Methods

Twenty-six out of 112 patients treated with primary or postoperative 3D CRT or IMRT for their primary and recurrent disease between 2007 and 2013 were included. The CT images of recurrent disease were rigidly registered with the primary CT images for each patient. To assess overlaps and overlap localization, the recurrence volume overlapping with the primary target volume was identified. For relapses occurring in the regional lymph nodes, the epicenter distance in recurrences and primary volumes and dose in recurrences were also identified. The recurrences were defined as in-field, marginal or out-of-field.

Results

The majority of the failures occurred within 1 year after completed primary treatment. The dose differences in recurrence volume were not statistically significant when patients were treated with IMRT or 3D CRT. Recurrence in 15/26 of the included patients occurred in the regional lymph nodes located fully or partly inside the primary target volume or the elective lymph node region. The majority of recurrences were recognized as in-field, independent of the primary treatment.

Conclusion

Recurrence in the majority of the patients occurred in the regional lymph nodes located in high dose area. The cause of recurrence may be due to inadequate total dose in the primary treatment and/or lack of optimal primary diagnosis leading to inadequate primary target delineation.

http://ift.tt/2qoLOBJ

C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy

Abstract

Background

Neuroblastoma is the most common solid tumor in childhood and develops from undifferentiated progenitor cells of the sympathetic nervous system. In neuronal tumor cells DNA-damaging chemotherapeutic agents activate the transcription factor FOXO3 which regulates the formation of reactive oxygen species (ROS) and cell death as well as a longevity program associated with therapy resistance.

We demonstrated before that C10ORF10/DEPP, a transcriptional target of FOXO3, localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification. In the present study, we investigated the impact of FOXO3 and DEPP on the regulation of autophagy. Autophagy serves to reduce oxidative damage as it triggers a self-degradative process for the removal of aggregated or misfolded proteins and damaged organelles.

Methods

The effect of FOXO3 and DEPP on autophagy induction was analyzed using live cell fluorescence microscopy and immunoblot analyses of SH-EP cells transfected with a plasmid for EYFP-LC3 and with siRNAs specific for LC3, respectively. ROS steady-state levels were measured with reduced MitoTrackerRed CM-H2XROS. Cellular apoptosis was analyzed by flow cytometry and the caspase 3/7 assay.

Results

We report for the first time that DEPP induces ROS accumulation and thereby mediates the formation of autophagosomes as inhibition of ROS formation by N-acetyl-cysteine completely blocks autophagy. We further demonstrate that H₂O₂-treatment triggers autophagy-induction by FOXO3-mediated DEPP expression. Importantly, knockdown of DEPP was sufficient to efficiently inhibit autophagy-induction under different stress conditions such as serum starvation and genotoxic stress, suggesting that DEPP expression is critical for the initiation of autophagy in neuroblastoma. FOXO3-triggered autophagy partially protects neuroblastoma cells from cell death. Consistent with this concept, we demonstrate that inhibition of autophagy by LC3-knockdown significantly increased etoposide- and doxorubicin-induced apoptosis. These results were also confirmed by the use of the autophagy-inhibitor chloroquine that significantly enhanced the chemotherapeutic effect of etoposide and doxorubicin in neuronal tumor cells.

Conclusion

Targeting FOXO3/DEPP-triggered autophagy is a promising strategy to sensitize neuroblastoma cells to chemotherapy.

http://ift.tt/2ql0Zwx

Finer leaf resolution and steeper beam edges using a virtual isocentre in concurrence to PTV-shaped collimators in standard distance – a planning study

Abstract

Purpose

Investigation of a reduced source to target distance to improve organ at risk sparing during stereotactic irradiation (STX).

Methods

The authors present a planning study with perfectly target-volume adapted collimator compared with multi-leaf collimator (MLC) at reduced source to virtual isocentre distance (SVID) in contrast to normal source to isocentre distance (SID) for stereotactic applications. The role of MLC leaf width and 20–80% penumbra was examined concerning the healthy tissue sparing. Several prescription schemes and target diameters are considered.

Results

Paddick's gradient index (GI) as well as comparison of the mean doses to spherical shells at several distances to the target is evaluated. Both emphasize the same results: the healthy tissue sparing in the high dose area around the planning target volume (PTV) is improved at reduced SVID ≤ 70 cm. The effect can be attributed more to steeper penumbra than to finer leaf resolution. Comparing circular collimators at different SVID just as MLC-shaped collimators, always the GI was reduced. Even MLC-shaped collimator at SVID 70 cm had better healthy tissue sparing than an optimal shaped circular collimator at SID 100 cm.

Regarding penumbra changes due to varying SVID, the results of the planning study are underlined by film dosimetry measurements with Agility™ MLC.

Conclusion

Penumbra requires more attention in comparing studies, especially studies using different planning systems. Reduced SVID probably allows usage of conventional MLC for STX-like irradiations.

from Cancer via ola Kala on Inoreader http://ift.tt/2r1ZmY4
via IFTTT

Patterns of local-regional recurrence after conformal and intensity-modulated radiotherapy for head and neck cancer

Abstract

Aim

To evaluate the patterns of loco-regional recurrences in head and neck cancer patients

Methods

Twenty-six out of 112 patients treated with primary or postoperative 3D CRT or IMRT for their primary and recurrent disease between 2007 and 2013 were included. The CT images of recurrent disease were rigidly registered with the primary CT images for each patient. To assess overlaps and overlap localization, the recurrence volume overlapping with the primary target volume was identified. For relapses occurring in the regional lymph nodes, the epicenter distance in recurrences and primary volumes and dose in recurrences were also identified. The recurrences were defined as in-field, marginal or out-of-field.

Results

The majority of the failures occurred within 1 year after completed primary treatment. The dose differences in recurrence volume were not statistically significant when patients were treated with IMRT or 3D CRT. Recurrence in 15/26 of the included patients occurred in the regional lymph nodes located fully or partly inside the primary target volume or the elective lymph node region. The majority of recurrences were recognized as in-field, independent of the primary treatment.

Conclusion

Recurrence in the majority of the patients occurred in the regional lymph nodes located in high dose area. The cause of recurrence may be due to inadequate total dose in the primary treatment and/or lack of optimal primary diagnosis leading to inadequate primary target delineation.

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

C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy

Abstract

Background

Neuroblastoma is the most common solid tumor in childhood and develops from undifferentiated progenitor cells of the sympathetic nervous system. In neuronal tumor cells DNA-damaging chemotherapeutic agents activate the transcription factor FOXO3 which regulates the formation of reactive oxygen species (ROS) and cell death as well as a longevity program associated with therapy resistance.

We demonstrated before that C10ORF10/DEPP, a transcriptional target of FOXO3, localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification. In the present study, we investigated the impact of FOXO3 and DEPP on the regulation of autophagy. Autophagy serves to reduce oxidative damage as it triggers a self-degradative process for the removal of aggregated or misfolded proteins and damaged organelles.

Methods

The effect of FOXO3 and DEPP on autophagy induction was analyzed using live cell fluorescence microscopy and immunoblot analyses of SH-EP cells transfected with a plasmid for EYFP-LC3 and with siRNAs specific for LC3, respectively. ROS steady-state levels were measured with reduced MitoTrackerRed CM-H2XROS. Cellular apoptosis was analyzed by flow cytometry and the caspase 3/7 assay.

Results

We report for the first time that DEPP induces ROS accumulation and thereby mediates the formation of autophagosomes as inhibition of ROS formation by N-acetyl-cysteine completely blocks autophagy. We further demonstrate that H₂O₂-treatment triggers autophagy-induction by FOXO3-mediated DEPP expression. Importantly, knockdown of DEPP was sufficient to efficiently inhibit autophagy-induction under different stress conditions such as serum starvation and genotoxic stress, suggesting that DEPP expression is critical for the initiation of autophagy in neuroblastoma. FOXO3-triggered autophagy partially protects neuroblastoma cells from cell death. Consistent with this concept, we demonstrate that inhibition of autophagy by LC3-knockdown significantly increased etoposide- and doxorubicin-induced apoptosis. These results were also confirmed by the use of the autophagy-inhibitor chloroquine that significantly enhanced the chemotherapeutic effect of etoposide and doxorubicin in neuronal tumor cells.

Conclusion

Targeting FOXO3/DEPP-triggered autophagy is a promising strategy to sensitize neuroblastoma cells to chemotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2ql0Zwx
via IFTTT

Patient compliance for postoperative radiotherapy and survival outcome of women with stage I endometrioid endometrial cancer

Background and Objectives

To examine characteristics and survival outcome of women with endometrial cancer who declined postoperative radiotherapy.

Methods

A retrospective study was conducted to examine surgically-treated grade 1-2 stage IB and grade 3 stage IA-IB endometrioid endometrial cancer in the Surveillance, Epidemiology, and End Results Program between 1983 and 2013 (n = 10 613). Associations of patient declination for guideline-based postoperative radiotherapy and clinico-pathological demographics or survival outcome were examined on multivariable analysis.

Results

There were 323 (3.0%) women who declined adjuvant radiotherapy. Women who declined postoperative radiotherapy were more likely to be older, White, Western U.S. residents, and register in recent years (all, adjusted-P < 0.05). On multivariable analysis, patient declination for guideline-based postoperative radiotherapy remained an independent prognostic factor for decreased endometrial cancer-specific survival in unstaged grade 1-2 stage IB or staged/unstated grade 3 stage IA-IB diseases (adjusted-hazard ratio 1.84, 95% confidence interval 1.34-2.51, P = 0.001). Association of patient declination for guideline-based postoperative radiotherapy and decreased overall survival remained independent in the entire cohort on multivariable analysis (adjuvant-hazard ratio 1.71, 95% confidence interval 1.44-2.02, P < 0.001).

Conclusions

Our study suggested that patient compliance to guideline-based postoperative radiotherapy is a prognostic factor for women with stage I endometrioid endometrial cancer.

http://ift.tt/2rVgQ6l

The prognostic utility of the “Tumor Burden Score” based on preoperative radiographic features of colorectal liver metastases

Background

Recently, a tumor-burden "metro ticket" score (TBS) based on final pathology was proposed to predict outcome following resection of colorectal liver metastasis (CRLM). We sought to validate the TBS prognostic tool using preoperative radiologic cross-sectional imaging.

Methods

Imaging TBS was defined on a Cartesian plane that incorporated both maximum tumor size (x-axis) and lesion number (y-axis) assessed by pre-operative imaging. The discriminatory power (area under the curve [AUC]) and goodness-of-fit (Harrel's C statistic and Somer's D statistics) of the imaging TBS model was assessed.

Results

Imaging and pathologic TBS correlated strongly (r = 0.76, P < 0.01). Among patients treated with neoadjuvant therapy, the correlation was strongest among patients with progressive disease/stable disease (PD/SD) (r = 0.81). Discriminatory power of the imaging-based versus pathology-based TBS models were comparable (AUC 0.64 vs. 0.67, respectively P > 0.05). An incremental worsening of long-term survival was noted as the imaging TBS increased (5-year OS: Zone1, Zone2, and Zone3—61.3%, 46.7%, and 38.5%, respectively; P = 0.03). The imaging-based TBS model outperformed the "classic" pathology-based Fong score (Harrel's C-index: imaging TBS-0.56 vs. Fong score-0.53; Somers'D-index: imaging TBS-012 vs. Fong score-0.06).

Conclusions

Imaging-based TBS was superior to traditional tumor size and number and was comparable to pathology-based TBS. Imaging-based TBS may have the potential to facilitate improved preoperative risk stratification of patients with CRLM.

http://ift.tt/2rmgKHJ

Sterilization of tumor-positive lymph nodes of esophageal cancer by neo-adjuvant treatment is associated with worse survival compared to tumor-negative lymph nodes treated with surgery first

Background and Objectives

Lymph node (LN) involvement by esophageal cancer is associated with compromised long-term prognosis. This study assessed whether LN downstaging by neoadjuvant treatment (NAT) might offer a survival benefit compared to patients with a priori negative LN.

Methods

Patients undergoing esophagectomy for cancer between 2005 and 2014 were screened for inclusion. Group 1 included cN0 patients confirmed as pN0 who were treated with surgery first, whereas group 2 included patients initially cN+ and down-staged to ypN0 after NAT. Survival analysis was performed with the Kaplan-Meier and Cox regression methods.

Results

Fifty-seven patients were included in our study, 24 in group 1 and 33 in group 2. Group 2 patients had more locally advanced lesions compared to a priori negative patients, and despite complete LN sterilization by NAT they still had worse long-term survival. Overall 3-year survival was 86.8% for a priori LN negative versus 63.3% for downstaged patients (P = 0.013), while disease-free survival was 79.6% and 57.9%, respectively (P = 0.021). Tumor recurrence was also earlier and more disseminated for the down-staged group.

Conclusions

Downstaged LN, despite the systemic effect of NAT, still inherit an increased risk for early tumor recurrence and worse long-term survival compared to a priori negative LN.

http://ift.tt/2rVl2Dh

The vascularized groin lymph node flap (VGLN): Anatomical study and flap planning using multi-detector CT scanner. The golden triangle for flap harvesting

Introduction: A growing number of surgeons perform lymph node transfers for the treatment of lymphedema. When harvesting a vascularized lymph node groin flap (VGLNF) one of the major concerns is the potential risk of iatrogenic lymphedema of the donor-site. This article helps understanding of the lymph node distribution of the groin in order to minimize this risk.

Materials and Methods: Fifty consecutive patients undergoing abdominal mapping by multi-detector CT scanner were included and 100 groins analyzed. The groin was divided in three zones (of which zone II is the safe zone) and lymph nodes were counted and mapped with their distances to anatomic landmarks. Further node units were plotted and counted.

Results: The average age was 48 years. A mean number of nodes of 6.5/groin was found. In zone II, which is our zone of interest a mean of 3.1 nodes were counted with a mean size of 7.8 mm. In three patients no nodes were found in zone II. In five patients nodes were seen in zone II but were not sufficient in size or number to be considered a lymph node unit. On average the lymph node unit in zone II was found to be 48.3 mm from the pubic tubercle when projected on a line from the pubic tubercle to the anterior superior iliac spine, 16.0 mm caudal to this line, and 20.4 mm above the groin crease. On average the lymph node unit was a mean of 41.7 mm lateral to the SCIV-SIEV confluence.

Conclusion: This study provides increased understanding of the lymphatic anatomy in zone II of the groin flap and suggests a refined technique for designing the VGLNF. As with any flap there is a degree of individual patient variability. However, having information on the most common anatomy and flap design is of great value.

http://ift.tt/2rmjs0b