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The elevated risk for physical late effects in childhood cancer survivors (CCS) is well documented, but their risk for mental health problems is less well described.
The authors assembled a cohort of all 5-year CCS who were diagnosed before age 18 years and treated in an Ontario pediatric cancer center between 1987 and 2008. Patients were matched to population controls and linked to health administration databases. The authors calculated rates of mental health care visits (family physician, psychiatrist, emergency department, hospitalization) and the risk for a severe mental health event (emergency department, hospitalization, suicide). Outcomes were compared using recurrent event and survival analyses.
Compared with 20,269 controls, 4117 CCS had a higher rate of mental health visits (adjusted relative rate [RR], 1.34; 95% confidence interval [CI], 1.12-1.52). Higher rates were associated with female gender (RR, 1.39; CI, 1.10-1.75; P = .006) and being diagnosed at ages 15 to 17.9 years (compared with ages 0-4 years: RR, 1.81; 95% CI, 1.17-2.80; P = .008). Cancer type, treatment intensity, and treatments targeting the central nervous system were not significant predictors. Survivors were at increased risk for a severe event compared with controls (adjusted hazard ratio, 1.13; 95% CI, 1.00-1.28; P = .045). CCS who were diagnosed with cancer at age 4 years or younger were at greatest risk: 16.3% (95% CI, 13.2%-19.8%) had experienced a severe event by age 28 years.
CCS experienced higher rates of mental health visits and a greater risk for a severe event than the general population. Survivors of adolescent cancer have a higher rate of mental health visits overall, whereas survivors of cancer before age 4 years have a markedly elevated risk of severe events. Cancer 2018. © 2018 American Cancer Society.
The elevated risk for physical late effects in childhood cancer survivors (CCS) is well documented, but their risk for mental health problems is less well described.
The authors assembled a cohort of all 5-year CCS who were diagnosed before age 18 years and treated in an Ontario pediatric cancer center between 1987 and 2008. Patients were matched to population controls and linked to health administration databases. The authors calculated rates of mental health care visits (family physician, psychiatrist, emergency department, hospitalization) and the risk for a severe mental health event (emergency department, hospitalization, suicide). Outcomes were compared using recurrent event and survival analyses.
Compared with 20,269 controls, 4117 CCS had a higher rate of mental health visits (adjusted relative rate [RR], 1.34; 95% confidence interval [CI], 1.12-1.52). Higher rates were associated with female gender (RR, 1.39; CI, 1.10-1.75; P = .006) and being diagnosed at ages 15 to 17.9 years (compared with ages 0-4 years: RR, 1.81; 95% CI, 1.17-2.80; P = .008). Cancer type, treatment intensity, and treatments targeting the central nervous system were not significant predictors. Survivors were at increased risk for a severe event compared with controls (adjusted hazard ratio, 1.13; 95% CI, 1.00-1.28; P = .045). CCS who were diagnosed with cancer at age 4 years or younger were at greatest risk: 16.3% (95% CI, 13.2%-19.8%) had experienced a severe event by age 28 years.
CCS experienced higher rates of mental health visits and a greater risk for a severe event than the general population. Survivors of adolescent cancer have a higher rate of mental health visits overall, whereas survivors of cancer before age 4 years have a markedly elevated risk of severe events. Cancer 2018. © 2018 American Cancer Society.
Future Oncology, Ahead of Print.
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Both the combination of nivolumab + ipilimumab and single-agent anti-PD-1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD-1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to-lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD-1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD-1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD-1 alone.
The combination of nivolumab and ipilimumab is a highly effective treatment for patients with melanoma, and little is known about the patients who do the best after treatment. For the first time, we report basic clinical laboratory variables which are associated with overall survival following treatment.
Future Oncology, Ahead of Print.
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Both the combination of nivolumab + ipilimumab and single-agent anti-PD-1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD-1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to-lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD-1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD-1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD-1 alone.
The combination of nivolumab and ipilimumab is a highly effective treatment for patients with melanoma, and little is known about the patients who do the best after treatment. For the first time, we report basic clinical laboratory variables which are associated with overall survival following treatment.
Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Brian Marples, Scott M. Welford
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Pervin Hurmuz, Mustafa Cengiz, Faruk Zorlu, Fadil Akyol
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Sue S. Yom, Anthony L. Zietman
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Angélica Pérez-Andújar
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Michael C. Roach, Cliff G. Robinson, Jeffrey D. Bradley
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Sue S. Yom, Paul M. Harari
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Howard M. Sandler
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Matthew Mireles, Ramiro Pino, Bin S. Teh, Andrew Farach, Adrienne Joseph, E. Brian Butler
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Akihiko Ozaki, Masaharu Tsubokura
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Andrew L. Salner
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Laetitia Padovani, Frédérique Chapon, Nicolas André, Mohamed Boucekine, Anne Geoffray, Franck Bourdeau, Julien Masliah-Planchon, Line Claude, Aymeri Huchet, Anne Laprie, Stephane Supiot, Bernard Coche-Dequéant, Christine Kerr, Claire Alapetite, Julie Leseur, Tandat Nguyen, Sophie Chapet, Valerie Bernier, Pierre-Yves Bondiau, Georges Noel, Jean Louis Habrand, Stephanie Bolle, François Doz, Christelle Dufour, Xavier Muracciole, Christian Carrie
PurposeTo identify the incidence of patients with perihippocampal metastases to assess the risk of brain relapse when sparing the hippocampal area. Medulloblastoma (MB) represents 20% of pediatric brain tumors. For high-risk MB patients, the 3- to 5-year event-free survival rate has recently improved from 50% to >76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies of patients receiving whole brain irradiation (WBI) have suggested a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for high-risk MB.Methods and MaterialsFrom 2008 to 2011, 51 patients with high-risk MB were treated according to the French trial primitive neuroectodermal tumor HR+5. Hippocampal contouring was manually generated on 3-dimensional magnetic resonance images according to the Radiation Therapy Oncology Group 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal area and 5 to 15 mm for the rest of the perihippocampal area.ResultsThe median patient age was 8.79 years (33% female). After a follow-up of 2.4 years, 43 patients were alive; 28 had had brain metastasis at diagnosis and 2 at relapse, with 16% in the first perihippocampal area and 43% in the rest of the perihippocampal area. Of the 18 patients without brain metastases at diagnosis, including M1 patients, none developed secondary lesions within the first or the rest of the perihippocampal area, after receiving 36 Gy. No clinical or biological factor was significantly associated with the development of perihippocampal metastases.ConclusionsOur results suggest the HA-WBI strategy should be evaluated for the subgroup of high-risk MB patients without metastatic disease.
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): David J. Brenner, Eric J. Hall
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Beth M. Beadle, Carryn M. Anderson
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Nora Sundahl, Katrien De Wolf, Vibeke Kruse, Annabel Meireson, Dries Reynders, Els Goetghebeur, Mireille Van Gele, Reinhart Speeckaert, Benjamin Hennart, Lieve Brochez, Piet Ost
PurposeTo report the results of a phase 1 trial evaluating the safety of the ipilimumab/radiation therapy combination in patients with metastatic melanoma.Patients and MethodsThirteen patients with metastatic melanoma were enrolled. Trial treatment consisted of 4 cycles of ipilimumab in combination with concurrent dose-escalated high-dose radiation therapy to 1 lesion administered before the third cycle of ipilimumab.ResultsGrade 3 or 4 ipilimumab-related adverse events occurred in 25% of patients. The maximum tolerated radiation therapy dose was not reached. Local control of the irradiated lesions was achieved in 11 of 12 irradiated patients (1 patient had progressive disease before irradiation and dropped out of the trial). Evaluation of the nonirradiated lesions demonstrated that 3 of 13 patients experienced clinical benefit, with 1 patient developing a partial response and 2 patients having confirmed stable disease. Immunomonitoring data showed that in patients without clinical benefit, factors linked to immunotolerance increased early after the initiation of ipilimumab, suggesting that early initiation of radiation therapy might be more effective if combined with ipilimumab.ConclusionsOur findings suggest that the combination of ipilimumab and high-dose radiation therapy is feasible and safe.
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Shang-Jui Wang, Lara Hathout, Usha Malhotra, Nell Maloney-Patel, Sarah Kilic, Elizabeth Poplin, Salma K. Jabbour
Rectal cancer predominantly affects patients older than 70 years, with peak incidence at age 80 to 85 years. However, the standard treatment paradigm for rectal cancer oftentimes cannot be feasibly applied to these patients owing to frailty or comorbid conditions. There are currently little information and no treatment guidelines to help direct therapy for patients who are elderly and/or have significant comorbidities, because most are not included or specifically studied in clinical trials. More recently various alternative treatment options have been brought to light that may potentially be utilized in this group of patients. This critical review examines the available literature on alternative therapies for rectal cancer and proposes a treatment algorithm to help guide clinicians in treatment decision making for elderly and comorbid patients.
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Brian Marples, Scott M. Welford
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Pervin Hurmuz, Mustafa Cengiz, Faruk Zorlu, Fadil Akyol
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Sue S. Yom, Anthony L. Zietman
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Angélica Pérez-Andújar
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Michael C. Roach, Cliff G. Robinson, Jeffrey D. Bradley
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Sue S. Yom, Paul M. Harari
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Beat Bojaxhiu, Frank Ahlhelm, Marc Walser, Lorenzo Placidi, Ulrike Kliebsch, Lorentzos Mikroutsikos, Petra Morach, Alessandra Bolsi, Tony Lomax, Alessia Pica, Damien C. Weber
PurposeTo assess the rate of radiation necrosis (RN) and white matter lesions (WMLs) in pediatric patients with primary brain tumors treated with pencil beam scanning (PBS) proton therapy (PT) with or without concomitant chemotherapy at the PSI.Methods and MaterialsBetween 1999 and 2015, 171 pediatric patients (age <18 years) were treated with PT. Median age at diagnosis was 3.3 years (range, 0.3-17.0 years), and the median delivered dose was 54 Gy (relative biological effectiveness) (range, 40.0–74.1 Gy). Radiation necrosis and WMLs were defined as a new area of abnormal signal intensity on T2-weighted images or increased signal intensity on T2-weighted images, and contrast enhancement on T1 occurring in the brain parenchyma included in the radiation treatment field, which did not demonstrate any abnormality before PT. Radiation necrosis and WMLs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up period for the surviving patients was 49.8 months (range, 5.9-194.7 months).ResultsTwenty-nine patients (17%) developed RN at a median time of 5 months (range, 1-26 months), most of them (n = 17; 59%) being asymptomatic (grade 1). Grade 2, 4, and 5 toxicities occurred in 8, 2, and 2 patients, respectively. Eighteen patients (11%) developed WMLs at a median time of 14.5 months (range, 2-62 months), most of them (n = 13; 72%) being asymptomatic (grade 1). White matter lesion grade 2 and 3 toxicities occurred in 4 and 1 patient(s), respectively. The 5-year RN-free and WML-free survival was 83% and 87%, respectively. In univariate analysis, neoadjuvant (P = .025) or any (P = .03) chemotherapy, hydrocephalus before PT (P = .035), and ependymoma (P = .026) histology were significant predictors of RN.ConclusionsChildren treated with PT demonstrated a low prevalence of symptomatic RN (7%) or WML (3%) compared with similar cohorts treated with either proton or photon radiation therapy. Chemotherapy, ependymomal tumors and hydrocephalus as an initial symptom were significant risk factors for RN.
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Howard M. Sandler
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Matthew Mireles, Ramiro Pino, Bin S. Teh, Andrew Farach, Adrienne Joseph, E. Brian Butler
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Akihiko Ozaki, Masaharu Tsubokura
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Andrew L. Salner
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Laetitia Padovani, Frédérique Chapon, Nicolas André, Mohamed Boucekine, Anne Geoffray, Franck Bourdeau, Julien Masliah-Planchon, Line Claude, Aymeri Huchet, Anne Laprie, Stephane Supiot, Bernard Coche-Dequéant, Christine Kerr, Claire Alapetite, Julie Leseur, Tandat Nguyen, Sophie Chapet, Valerie Bernier, Pierre-Yves Bondiau, Georges Noel, Jean Louis Habrand, Stephanie Bolle, François Doz, Christelle Dufour, Xavier Muracciole, Christian Carrie
PurposeTo identify the incidence of patients with perihippocampal metastases to assess the risk of brain relapse when sparing the hippocampal area. Medulloblastoma (MB) represents 20% of pediatric brain tumors. For high-risk MB patients, the 3- to 5-year event-free survival rate has recently improved from 50% to >76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies of patients receiving whole brain irradiation (WBI) have suggested a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for high-risk MB.Methods and MaterialsFrom 2008 to 2011, 51 patients with high-risk MB were treated according to the French trial primitive neuroectodermal tumor HR+5. Hippocampal contouring was manually generated on 3-dimensional magnetic resonance images according to the Radiation Therapy Oncology Group 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal area and 5 to 15 mm for the rest of the perihippocampal area.ResultsThe median patient age was 8.79 years (33% female). After a follow-up of 2.4 years, 43 patients were alive; 28 had had brain metastasis at diagnosis and 2 at relapse, with 16% in the first perihippocampal area and 43% in the rest of the perihippocampal area. Of the 18 patients without brain metastases at diagnosis, including M1 patients, none developed secondary lesions within the first or the rest of the perihippocampal area, after receiving 36 Gy. No clinical or biological factor was significantly associated with the development of perihippocampal metastases.ConclusionsOur results suggest the HA-WBI strategy should be evaluated for the subgroup of high-risk MB patients without metastatic disease.
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): David J. Brenner, Eric J. Hall
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Beth M. Beadle, Carryn M. Anderson
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Nora Sundahl, Katrien De Wolf, Vibeke Kruse, Annabel Meireson, Dries Reynders, Els Goetghebeur, Mireille Van Gele, Reinhart Speeckaert, Benjamin Hennart, Lieve Brochez, Piet Ost
PurposeTo report the results of a phase 1 trial evaluating the safety of the ipilimumab/radiation therapy combination in patients with metastatic melanoma.Patients and MethodsThirteen patients with metastatic melanoma were enrolled. Trial treatment consisted of 4 cycles of ipilimumab in combination with concurrent dose-escalated high-dose radiation therapy to 1 lesion administered before the third cycle of ipilimumab.ResultsGrade 3 or 4 ipilimumab-related adverse events occurred in 25% of patients. The maximum tolerated radiation therapy dose was not reached. Local control of the irradiated lesions was achieved in 11 of 12 irradiated patients (1 patient had progressive disease before irradiation and dropped out of the trial). Evaluation of the nonirradiated lesions demonstrated that 3 of 13 patients experienced clinical benefit, with 1 patient developing a partial response and 2 patients having confirmed stable disease. Immunomonitoring data showed that in patients without clinical benefit, factors linked to immunotolerance increased early after the initiation of ipilimumab, suggesting that early initiation of radiation therapy might be more effective if combined with ipilimumab.ConclusionsOur findings suggest that the combination of ipilimumab and high-dose radiation therapy is feasible and safe.
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Publication date: 15 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 4
Author(s): Shang-Jui Wang, Lara Hathout, Usha Malhotra, Nell Maloney-Patel, Sarah Kilic, Elizabeth Poplin, Salma K. Jabbour
Rectal cancer predominantly affects patients older than 70 years, with peak incidence at age 80 to 85 years. However, the standard treatment paradigm for rectal cancer oftentimes cannot be feasibly applied to these patients owing to frailty or comorbid conditions. There are currently little information and no treatment guidelines to help direct therapy for patients who are elderly and/or have significant comorbidities, because most are not included or specifically studied in clinical trials. More recently various alternative treatment options have been brought to light that may potentially be utilized in this group of patients. This critical review examines the available literature on alternative therapies for rectal cancer and proposes a treatment algorithm to help guide clinicians in treatment decision making for elderly and comorbid patients.
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TASIN-1 (Truncated APC Selective INhibitor-1) is a recently identified small molecule that selectively kills colorectal cancer cells that express truncated APC by reducing cellular cholesterol levels. However, the downstream mechanism responsible for its cytotoxicity is not well understood. In this study, we show that TASIN-1 leads to apoptotic cell death via inducing ER stress-dependent JNK activation in human truncated APC colon cancer cells, accompanied by production of reactive oxygen species (ROS). In addition, TASIN-1 inhibits Akt activity through a cholesterol-dependent manner. Human colon tumor xenografts in immunodeficient mice also show the same TASIN-1 induced molecular mechanisms of tumor cell death as observed in vitro. Taken together, cholesterol depletion by TASIN-1 treatment induces apoptotic cell death through activating ER stress/ROS/JNK axis and inhibiting Akt pro-survival signaling in colon cancer cells with truncated APC both in vitro and in vivo.
Lung cancer is the leading cause of cancer deaths worldwide. Approximately 85% of all lung cancers are non-small-cell histology (NSCLC). Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than fifteen percent of patients survive beyond five years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide. We demonstrate that constitutive interferon-stimulated gene expression, including an Interferon-Related DNA Damage Resistance Signature (IRDS), predicts for sensitivity to SAR. Importantly, tumor cell-intrinsic expression of PD-L1 is interferon-inducible and abrogated by SAR. Taken together, these findings suggest potential dual roles for JAK2 inhibitors, both as a novel monotherapy in NSCLCs resistant to genotoxic therapies, and in tandem with immune checkpoint inhibition.
Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant EGFR mutations, including L858R, exon 19 deletion, L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and several exon 20 insertion mutations. Using structural analyses, we also elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in EGFR exon 20 insertion mutations. The efficacy of naquotinib in cells with L858R, exon 19 deletion, and exon 19 deletion+T790M was comparable to that of osimertinib. Interestingly, naquotinib was more potent than osimertinib for L858R+T790M. Additionally, naquotinib and osimertinib had comparable efficacy and a wide therapeutic window for cells with EGFR exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses, and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations, and help clarify the biology of EGFR exon 20 insertion mutations.
TASIN-1 (Truncated APC Selective INhibitor-1) is a recently identified small molecule that selectively kills colorectal cancer cells that express truncated APC by reducing cellular cholesterol levels. However, the downstream mechanism responsible for its cytotoxicity is not well understood. In this study, we show that TASIN-1 leads to apoptotic cell death via inducing ER stress-dependent JNK activation in human truncated APC colon cancer cells, accompanied by production of reactive oxygen species (ROS). In addition, TASIN-1 inhibits Akt activity through a cholesterol-dependent manner. Human colon tumor xenografts in immunodeficient mice also show the same TASIN-1 induced molecular mechanisms of tumor cell death as observed in vitro. Taken together, cholesterol depletion by TASIN-1 treatment induces apoptotic cell death through activating ER stress/ROS/JNK axis and inhibiting Akt pro-survival signaling in colon cancer cells with truncated APC both in vitro and in vivo.
Lung cancer is the leading cause of cancer deaths worldwide. Approximately 85% of all lung cancers are non-small-cell histology (NSCLC). Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than fifteen percent of patients survive beyond five years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide. We demonstrate that constitutive interferon-stimulated gene expression, including an Interferon-Related DNA Damage Resistance Signature (IRDS), predicts for sensitivity to SAR. Importantly, tumor cell-intrinsic expression of PD-L1 is interferon-inducible and abrogated by SAR. Taken together, these findings suggest potential dual roles for JAK2 inhibitors, both as a novel monotherapy in NSCLCs resistant to genotoxic therapies, and in tandem with immune checkpoint inhibition.
Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant EGFR mutations, including L858R, exon 19 deletion, L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and several exon 20 insertion mutations. Using structural analyses, we also elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in EGFR exon 20 insertion mutations. The efficacy of naquotinib in cells with L858R, exon 19 deletion, and exon 19 deletion+T790M was comparable to that of osimertinib. Interestingly, naquotinib was more potent than osimertinib for L858R+T790M. Additionally, naquotinib and osimertinib had comparable efficacy and a wide therapeutic window for cells with EGFR exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses, and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations, and help clarify the biology of EGFR exon 20 insertion mutations.
The treatment of newly diagnosed multiple myeloma has changed dramatically over the past 20 years, from near uniform application of chemotherapy to a patient performance status- and risk-based approach. Furthermore, initiation of treatment criteria have evolved from a pure end-organ damage-based definition to include risk factors of transformation to frank myeloma. Besides, the mainly cytogenetically defined Multiple Myeloma (MM) risk status, transplant eligibility of patients still serves primarily to allocate patients within a rational treatment algorithm.
While all transplant-eligible MM patients should receive a triplet induction therapy followed by autologous transplantation and, in most cases, lenalidomide maintenance, other therapeutic elements (e. g., other maintenance strategies, consolidation, tandem transplantation,..) have to be decided on an individualized appraisal of risk and toxicities. Standard-risk patients should never be undertreated, as they derive the highest relative benefit from using the best available registered therapies. However, high-risk patients should be preferentially treated inside clinical trials testing additive innovative treatments, as the improvement in the prognosis of this group of patients by standard therapies has been underwhelming. Furthermore, the evaluation process of non-transplant-eligible patients should always comprise an evaluation of performance status, frailty, and comorbidities (e. g., a comprehensive geriatric assessment) to facilitate the allocation of individualized therapies.
Correction to:
memo 2017
http://ift.tt/2EYYUBd
Unfortunately, the title of this article was published incorrect.
The correct title is: Report from the WCLC 2017 Congress, Yokohama, 15th–18th October, 2017.
The original article has been …
Survival after childhood cancer has improved substantially; therefore, the number of childhood cancer survivors is increasing. This growing population of childhood cancer survivors, however, is at risk of a spectrum of adverse health outcomes. Unfortunately, until now, there was a lack of comprehensive follow-up recommendations. The purpose of this article is to provide information on recently developed harmonized evidence-based guidelines on surveillance investigations to screen for the early detection of breast cancer, cardiomyopathy, male gonadotoxicity, and premature ovarian failure in childhood cancer survivors. We point out the need for a multidisciplinary pediatric and adult specialist team, who together develop multidisciplinary long-term follow-up clinics.
Primary malignant pleural effusion has been reported in about 134 cases of multiple myeloma (MM). Associated pleural effusions in cases of MM portend a poor prognosis and identifying them is highly relevant. Reported is the case of a man diagnosed with MM who developed primary myelomatous pleural effusion in the setting of multiple relapses and subsequent mortality within 2 months of the pleural effusion diagnosis.
A 61-year-old African American man was diagnosed with MM in 2011. He received induction therapy of lenalidomide and dexamethasone and an autologous stem cell transplant in 2012. Over the next 5 years, the patient went through alternating periods of remission and relapse that were treated with two rounds of thoracic spine radiation therapy and chemotherapeutic agents. In September 2017, the patient presented with worsening dyspnea and was found to have pleural effusion. Fluid analysis showed plasma cell dyscrasia. Fluid drainage was performed, then the patient was discharged after 1 week which was followed by rapid re-accumulation of fluid and rehospitalization about 10 days after discharge. The patient passed away a few weeks after the second admission.
Pleural effusion carries a differential diagnosis which may include malignancy but is commonly thought to be less specific to multiple myeloma but should still remain in the differential diagnosis. To our knowledge, this is the first case of myelomatous pleural effusion (MPE) that was reported after multiple relapses of MM. MPE is a very rare complication of MM, and its presence is a strong indicator of imminent mortality and need for comfort care in case of multiple relapses. End-stage pleural effusion in MM in the setting of proteasome inhibitor adds more therapeutic and diagnostic challenges.
The STAMPEDE and CHAARTED trials brought about practice-changing innovation in the management of patients with metastatic, castration-naive prostate cancer (CNPC). These trials reported a clinically meaningful overall survival benefit of chemohormonal therapy consisting of the addition of six cycles of docetaxel to androgen deprivation therapy (ADT) in high-volume metastatic CNPC. Moreover, the STAMPEDE study also transformed our thinking about conducting clinical trials through its adaptive, multigroup, multistage trial design. With the recent results of the LATITUDE trial and publication of another STAMPEDE cohort, the combination of ADT and abiraterone/prednisone became a viable alternative to chemohormonal therapy. Results of these trials have been exhaustively scrutinized and finally incorporated in recent guidelines, although the appropriate selection of patients who will benefit from either therapeutic option remains to be discussed individually. As both combinations lead to an almost identical survival benefit, the decision is often based on patient-related factors and/or personal preferences. This short review provides evidence to support decision-making between chemohormonal therapy and the combination of ADT plus abiraterone/prednisone as well as an outlook on current therapeutic developments in advanced prostate cancer.
The treatment of newly diagnosed multiple myeloma has changed dramatically over the past 20 years, from near uniform application of chemotherapy to a patient performance status- and risk-based approach. Furthermore, initiation of treatment criteria have evolved from a pure end-organ damage-based definition to include risk factors of transformation to frank myeloma. Besides, the mainly cytogenetically defined Multiple Myeloma (MM) risk status, transplant eligibility of patients still serves primarily to allocate patients within a rational treatment algorithm.
While all transplant-eligible MM patients should receive a triplet induction therapy followed by autologous transplantation and, in most cases, lenalidomide maintenance, other therapeutic elements (e. g., other maintenance strategies, consolidation, tandem transplantation,..) have to be decided on an individualized appraisal of risk and toxicities. Standard-risk patients should never be undertreated, as they derive the highest relative benefit from using the best available registered therapies. However, high-risk patients should be preferentially treated inside clinical trials testing additive innovative treatments, as the improvement in the prognosis of this group of patients by standard therapies has been underwhelming. Furthermore, the evaluation process of non-transplant-eligible patients should always comprise an evaluation of performance status, frailty, and comorbidities (e. g., a comprehensive geriatric assessment) to facilitate the allocation of individualized therapies.
Correction to:
memo 2017
http://ift.tt/2EYYUBd
Unfortunately, the title of this article was published incorrect.
The correct title is: Report from the WCLC 2017 Congress, Yokohama, 15th–18th October, 2017.
The original article has been …
Survival after childhood cancer has improved substantially; therefore, the number of childhood cancer survivors is increasing. This growing population of childhood cancer survivors, however, is at risk of a spectrum of adverse health outcomes. Unfortunately, until now, there was a lack of comprehensive follow-up recommendations. The purpose of this article is to provide information on recently developed harmonized evidence-based guidelines on surveillance investigations to screen for the early detection of breast cancer, cardiomyopathy, male gonadotoxicity, and premature ovarian failure in childhood cancer survivors. We point out the need for a multidisciplinary pediatric and adult specialist team, who together develop multidisciplinary long-term follow-up clinics.
Primary malignant pleural effusion has been reported in about 134 cases of multiple myeloma (MM). Associated pleural effusions in cases of MM portend a poor prognosis and identifying them is highly relevant. Reported is the case of a man diagnosed with MM who developed primary myelomatous pleural effusion in the setting of multiple relapses and subsequent mortality within 2 months of the pleural effusion diagnosis.
A 61-year-old African American man was diagnosed with MM in 2011. He received induction therapy of lenalidomide and dexamethasone and an autologous stem cell transplant in 2012. Over the next 5 years, the patient went through alternating periods of remission and relapse that were treated with two rounds of thoracic spine radiation therapy and chemotherapeutic agents. In September 2017, the patient presented with worsening dyspnea and was found to have pleural effusion. Fluid analysis showed plasma cell dyscrasia. Fluid drainage was performed, then the patient was discharged after 1 week which was followed by rapid re-accumulation of fluid and rehospitalization about 10 days after discharge. The patient passed away a few weeks after the second admission.
Pleural effusion carries a differential diagnosis which may include malignancy but is commonly thought to be less specific to multiple myeloma but should still remain in the differential diagnosis. To our knowledge, this is the first case of myelomatous pleural effusion (MPE) that was reported after multiple relapses of MM. MPE is a very rare complication of MM, and its presence is a strong indicator of imminent mortality and need for comfort care in case of multiple relapses. End-stage pleural effusion in MM in the setting of proteasome inhibitor adds more therapeutic and diagnostic challenges.
The STAMPEDE and CHAARTED trials brought about practice-changing innovation in the management of patients with metastatic, castration-naive prostate cancer (CNPC). These trials reported a clinically meaningful overall survival benefit of chemohormonal therapy consisting of the addition of six cycles of docetaxel to androgen deprivation therapy (ADT) in high-volume metastatic CNPC. Moreover, the STAMPEDE study also transformed our thinking about conducting clinical trials through its adaptive, multigroup, multistage trial design. With the recent results of the LATITUDE trial and publication of another STAMPEDE cohort, the combination of ADT and abiraterone/prednisone became a viable alternative to chemohormonal therapy. Results of these trials have been exhaustively scrutinized and finally incorporated in recent guidelines, although the appropriate selection of patients who will benefit from either therapeutic option remains to be discussed individually. As both combinations lead to an almost identical survival benefit, the decision is often based on patient-related factors and/or personal preferences. This short review provides evidence to support decision-making between chemohormonal therapy and the combination of ADT plus abiraterone/prednisone as well as an outlook on current therapeutic developments in advanced prostate cancer.