Use of the 22C3 anti–programmed death ligand 1 antibody to determine programmed death ligand 1 expression in cytology samples obtained from non–small cell lung cancer patients

BACKGROUND

Pembrolizumab monotherapy is a standard-of-care treatment for the first- and second-line treatment of advanced non–small cell lung cancer with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) values ≥ 50% and ≥ 1%, respectively. PD-L1 testing with the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx companion assay has been validated on tumor tissue with the Dako Autostainer Link 48 (ASL48). 22C3 anti–PD-L1 antibody–based laboratory-developed tests (LDTs) compatible with other autostainers and cytology samples are essential to support pembrolizumab treatment decisions across institutions globally.

METHODS

ASL48 and BenchMark Ultra LDTs were optimized for the evaluation of cytology samples through comparisons with cell lines with known PD-L1 expression levels (strong, moderate, and negative). The PD-L1 TPS was then evaluated for 70 paired biopsy and cytology samples (bronchial washes, n = 40; pleural effusions, n = 30) with these LDTs. Biopsy and cytology LDT TPS values were also compared with a subset of biopsy samples (n = 37) evaluated with the PD-L1 IHC 22C3 pharmDx assay on the ASL48.

RESULTS

Intraclass correlation coefficients of 0.884 to 0.898 were observed for biopsy samples versus cytology samples with the ASL48 and BenchMark Ultra LDTs. Concordance was high, regardless of the TPS cut point (<1% vs ≥ 1% and <50% vs ≥ 50%), sample type (pleural effusion vs bronchial wash), or tumor histology (adenocarcinoma vs squamous cell carcinoma). Concordance was high for each LDT versus the PD-L1 IHC 22C3 pharmDx assay.

CONCLUSIONS

ALS48 and BenchMark Ultra 22C3 antibody concentrate–based LDTs have been validated for PD-L1 testing in cytology samples, and they will support reliable, high-quality PD-L1 testing across regions globally. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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Use of the 22C3 anti–programmed death ligand 1 antibody to determine programmed death ligand 1 expression in cytology samples obtained from non–small cell lung cancer patients

BACKGROUND

Pembrolizumab monotherapy is a standard-of-care treatment for the first- and second-line treatment of advanced non–small cell lung cancer with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) values ≥ 50% and ≥ 1%, respectively. PD-L1 testing with the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx companion assay has been validated on tumor tissue with the Dako Autostainer Link 48 (ASL48). 22C3 anti–PD-L1 antibody–based laboratory-developed tests (LDTs) compatible with other autostainers and cytology samples are essential to support pembrolizumab treatment decisions across institutions globally.

METHODS

ASL48 and BenchMark Ultra LDTs were optimized for the evaluation of cytology samples through comparisons with cell lines with known PD-L1 expression levels (strong, moderate, and negative). The PD-L1 TPS was then evaluated for 70 paired biopsy and cytology samples (bronchial washes, n = 40; pleural effusions, n = 30) with these LDTs. Biopsy and cytology LDT TPS values were also compared with a subset of biopsy samples (n = 37) evaluated with the PD-L1 IHC 22C3 pharmDx assay on the ASL48.

RESULTS

Intraclass correlation coefficients of 0.884 to 0.898 were observed for biopsy samples versus cytology samples with the ASL48 and BenchMark Ultra LDTs. Concordance was high, regardless of the TPS cut point (<1% vs ≥ 1% and <50% vs ≥ 50%), sample type (pleural effusion vs bronchial wash), or tumor histology (adenocarcinoma vs squamous cell carcinoma). Concordance was high for each LDT versus the PD-L1 IHC 22C3 pharmDx assay.

CONCLUSIONS

ALS48 and BenchMark Ultra 22C3 antibody concentrate–based LDTs have been validated for PD-L1 testing in cytology samples, and they will support reliable, high-quality PD-L1 testing across regions globally. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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Physical activity and telomere length in American Indians: the Strong Heart Study

Abstract

Telomere length, a marker of biological aging, has been associated with many chronic diseases, but its relations with physical activity remains unclear. The purpose of this study was to examine the association of objectively measured ambulatory activity with leukocyte telomere length (LTL), a marker of biological aging, among American Indians. This cross-sectional study included 2312 AI participants from the Strong Heart Family Study. Steps per day were measured using Accusplit AE120 pedometers. Quantitative PCR was used to measure LTL. Generalized estimating equations were used to examine the associations of steps per day with LTL. The median steps per day over a 1 week period was 5118 steps (interquartile range = 3163–7576 steps). Compared to participants in the lowest quartile of steps per day, participants in the upper three quartiles of steps per day had longer LTL: beta ± SE = 0.0195 ± 0.0144, 0.0273 ± 0.0139, and 0.0375 ± 0.0143 T/S ratio units longer (p trend = 0.010) after adjustment for potential confounders. These data suggest that ambulatory activity is associated with LTL. Further studies are needed to determine the mechanism by which ambulatory activity influences LTL.

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Modified biweekly cisplatin, docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer

Abstract

Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty-eight patients receiving off-protocol cisplatin (50 mg/m²) in combination with docetaxel (50 mg/m²) plus cetuximab (500 mg/m²) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7–14.2) and 6.3 months (95% CI 5.7–6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted.

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Modified biweekly cisplatin, docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer

Abstract

Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty-eight patients receiving off-protocol cisplatin (50 mg/m²) in combination with docetaxel (50 mg/m²) plus cetuximab (500 mg/m²) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7–14.2) and 6.3 months (95% CI 5.7–6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted.

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Trends of incidence, mortality, and survival of multiple myeloma in Switzerland between 1994 and 2013

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Martin Andres, Anita Feller, Volker Arndt
BackgroundTreatment of multiple myeloma has changed considerably over the last two decades with remarkable reduction in mortality rates in clinical trials and in population-based studies. Since health care systems and patient management differ between countries, population-based data from cancer registries with high coverage may provide further insight into real-life achievements and unmet needs. We report on the first population-based nation-wide study of incidence, mortality and survival of multiple myeloma in Switzerland covering the era of autologous stem cell transplantation and the first proteasome inhibitors and immunomodulatory drugs.MethodsWe performed a retrospective registry study with data from the National Institute for Cancer Epidemiology and Registration (NICER) database in Switzerland from 1994 to 2013.ResultsWe identified 5770 patients with multiple myeloma. Incidence has increased from 419 new cases per year in 1994–1998 to 557 new cases per year in 2009–2013 while the age-adjusted incidence rate remained stable at 4.7–5.0 per 100′000 person-years. Five- and 10-year relative survival increased from 32.6% (95%CI 29.3–36.0) and 17.8% (95%CI 14.9–21.0) in 1994–1998 to 46.4% (95%CI 43.3–49.3) and 25.0% (95%CI 21.9–28.3) in 2009–2013.ConclusionThe increase in incidence can be attributed to demographic changes. There is a trend to longer relative survival in all age groups with substantial increase in myeloma patients aged less than 75 years and only minimal changes in older persons.



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Esophageal cancer male to female incidence ratios in Africa: A systematic review and meta-analysis of geographic, time and age trends

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Daniel R.S. Middleton, Liacine Bouaoun, Rachel Hanisch, Freddie Bray, Charles Dzamalala, Steady Chasimpha, Diana Menya, Charles Gombé Mbalawa, Guy N'Da, Mathewos A. Woldegeorgis, Ramou Njie, Moussa Koulibaly, Nathan Buziba, Josefo Ferro, Hassan Nouhou, Femi Ogunbiyi, Henry R. Wabinga, Eric Chokunonga, Margaret Z. Borok, Anne R. Korir, Amos O. Mwasamwaja, Blandina T. Mmbaga, Joachim Schüz, Valerie A. McCormack
Esophageal squamous cell carcinoma (ESCC) remains the predominant histological subtype of esophageal cancer (EC) in many transitioning countries, with an enigmatic and geographically distinct etiology, and consistently elevated incidence rates in many Eastern and Southern African countries. To gain epidemiological insights into ESCC patterns across the continent, we conducted a systematic review and meta-analysis of male-to-female (M:F) sex ratios of EC age-standardised (world) incidence rates in Africa according to geography, time and age at diagnosis. Data from 197 populations in 36 countries were included in the analysis, based on data from cancer registries included in IARC's Cancer Incidence in Five Continents, Cancer in Africa and Cancer in Sub-Saharan Africa reports, alongside a systematic search of peer-reviewed literature. A consistent male excess in incidence rates overall (1.7; 95% CI: 1.4, 2.0), and in the high-risk Eastern (1.6; 95% CI: 1.4, 1.8) and Southern (1.8; 95% CI: 1.5, 2.0) African regions was observed. Within the latter two regions, there was a male excess evident in 30–39 year olds that was not observed in low-risk regions. Despite possible referral biases affecting the interpretability of the M:F ratios in place and time, the high degree of heterogeneity in ESCC incidence implies a large fraction of the disease is preventable, and directs research enquiries to elucidate early-age exposures among young men in Africa.



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Development and validation of a prognostic index for survival in non-small cell lung cancer: Results from a Tunisian cohort study

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Ghassen Soussi, Nissaf Ben Alaya, Nawel Chaouch, Hajer Racil
IntroductionDespite the continuous efforts made with the TNM system, the issue of heterogeneity of prognosis within the stages of non-small cell lung cancer (NSCLC) could not be resolved. Our aim was to identify prognostic factors and develop an index to predict NSCLC survival with greater accuracy.MethodsWe conducted a survival study over 5 years on patients with NSCLC. Kaplan–Meier analysis followed by Cox regression modelling were used. Prognostic indices were derived, using either an additive or a multiplicative pattern, and were compared by their receiver operating characteristics (ROC) curves. We then proceeded to a risk stratification and validation of the index on the derivation cohort.ResultsTwo hundred and sixty-two NSCLC patients were included. Two models were constructed, using the following nine variables as prognostic factors: age, performance status, haemoglobin level, leucocyte count, calcium, lactate dehydrogenase, alkaline phosphatase levels, histological type and TNM stage. Four prognostic indices were derived, and the best one was picked and validated on a population of five risk groups. The higher the risk group, the shorter the survival.ConclusionsThis novel and simple prognostic tool could predict survival more accurately in patients with NSCLC.



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Trends of incidence, mortality, and survival of multiple myeloma in Switzerland between 1994 and 2013

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Martin Andres, Anita Feller, Volker Arndt
BackgroundTreatment of multiple myeloma has changed considerably over the last two decades with remarkable reduction in mortality rates in clinical trials and in population-based studies. Since health care systems and patient management differ between countries, population-based data from cancer registries with high coverage may provide further insight into real-life achievements and unmet needs. We report on the first population-based nation-wide study of incidence, mortality and survival of multiple myeloma in Switzerland covering the era of autologous stem cell transplantation and the first proteasome inhibitors and immunomodulatory drugs.MethodsWe performed a retrospective registry study with data from the National Institute for Cancer Epidemiology and Registration (NICER) database in Switzerland from 1994 to 2013.ResultsWe identified 5770 patients with multiple myeloma. Incidence has increased from 419 new cases per year in 1994–1998 to 557 new cases per year in 2009–2013 while the age-adjusted incidence rate remained stable at 4.7–5.0 per 100′000 person-years. Five- and 10-year relative survival increased from 32.6% (95%CI 29.3–36.0) and 17.8% (95%CI 14.9–21.0) in 1994–1998 to 46.4% (95%CI 43.3–49.3) and 25.0% (95%CI 21.9–28.3) in 2009–2013.ConclusionThe increase in incidence can be attributed to demographic changes. There is a trend to longer relative survival in all age groups with substantial increase in myeloma patients aged less than 75 years and only minimal changes in older persons.



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Esophageal cancer male to female incidence ratios in Africa: A systematic review and meta-analysis of geographic, time and age trends

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Daniel R.S. Middleton, Liacine Bouaoun, Rachel Hanisch, Freddie Bray, Charles Dzamalala, Steady Chasimpha, Diana Menya, Charles Gombé Mbalawa, Guy N'Da, Mathewos A. Woldegeorgis, Ramou Njie, Moussa Koulibaly, Nathan Buziba, Josefo Ferro, Hassan Nouhou, Femi Ogunbiyi, Henry R. Wabinga, Eric Chokunonga, Margaret Z. Borok, Anne R. Korir, Amos O. Mwasamwaja, Blandina T. Mmbaga, Joachim Schüz, Valerie A. McCormack
Esophageal squamous cell carcinoma (ESCC) remains the predominant histological subtype of esophageal cancer (EC) in many transitioning countries, with an enigmatic and geographically distinct etiology, and consistently elevated incidence rates in many Eastern and Southern African countries. To gain epidemiological insights into ESCC patterns across the continent, we conducted a systematic review and meta-analysis of male-to-female (M:F) sex ratios of EC age-standardised (world) incidence rates in Africa according to geography, time and age at diagnosis. Data from 197 populations in 36 countries were included in the analysis, based on data from cancer registries included in IARC's Cancer Incidence in Five Continents, Cancer in Africa and Cancer in Sub-Saharan Africa reports, alongside a systematic search of peer-reviewed literature. A consistent male excess in incidence rates overall (1.7; 95% CI: 1.4, 2.0), and in the high-risk Eastern (1.6; 95% CI: 1.4, 1.8) and Southern (1.8; 95% CI: 1.5, 2.0) African regions was observed. Within the latter two regions, there was a male excess evident in 30–39 year olds that was not observed in low-risk regions. Despite possible referral biases affecting the interpretability of the M:F ratios in place and time, the high degree of heterogeneity in ESCC incidence implies a large fraction of the disease is preventable, and directs research enquiries to elucidate early-age exposures among young men in Africa.



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Development and validation of a prognostic index for survival in non-small cell lung cancer: Results from a Tunisian cohort study

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Ghassen Soussi, Nissaf Ben Alaya, Nawel Chaouch, Hajer Racil
IntroductionDespite the continuous efforts made with the TNM system, the issue of heterogeneity of prognosis within the stages of non-small cell lung cancer (NSCLC) could not be resolved. Our aim was to identify prognostic factors and develop an index to predict NSCLC survival with greater accuracy.MethodsWe conducted a survival study over 5 years on patients with NSCLC. Kaplan–Meier analysis followed by Cox regression modelling were used. Prognostic indices were derived, using either an additive or a multiplicative pattern, and were compared by their receiver operating characteristics (ROC) curves. We then proceeded to a risk stratification and validation of the index on the derivation cohort.ResultsTwo hundred and sixty-two NSCLC patients were included. Two models were constructed, using the following nine variables as prognostic factors: age, performance status, haemoglobin level, leucocyte count, calcium, lactate dehydrogenase, alkaline phosphatase levels, histological type and TNM stage. Four prognostic indices were derived, and the best one was picked and validated on a population of five risk groups. The higher the risk group, the shorter the survival.ConclusionsThis novel and simple prognostic tool could predict survival more accurately in patients with NSCLC.



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Brainstem Injury in Pediatric Patients With Posterior Fossa Tumors Treated With Proton Beam Therapy and Associated Dosimetric Factors

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Michelle S. Gentile, Beow Y. Yeap, Harald Paganetti, Claire P. Goebel, Dillon E. Gaudet, Sara L. Gallotto, Elizabeth A. Weyman, Michael L. Morgan, Shannon M. MacDonald, Drosoula Giantsoudi, Judith Adams, Nancy J. Tarbell, Hanne Kooy, Torunn I. Yock
PurposeProton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2%-8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution.Methods and MaterialsThe study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.ResultsThe histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (Dmax), 55.2 Gy RBE (range, 48.4-60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); Dmax, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving ≥55 Gy RBE (V55), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem Dmax in the highest quartile (≥55.8 Gy RBE, P = .016) and a V55 in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection.ConclusionsThe incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when Dmax and V55 are kept <55.8 Gy RBE and ≤6.0%, respectively, the 5-year rate of radiation brainstem injury would be <2%.



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In Reply to Daisne et al

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Jean-Emmanuel Bibault, Philippe Giraud, Magali Morelle, Lionel Perrier, Marius Huguet




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Stereotactic Radiosurgery for Resected Brain Metastases: New Evidence Supports a Practice Shift, but Questions Remain

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Giuseppe Minniti, Scott G. Soltys, Lia M. Halasz, John C. Breneman, Michael Chan, Nadia N. Laack, John P. Kirkpatrick




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Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Suk W. Yoon, Vadim Tsvankin, Zachary Shrock, Boyu Meng, Xiaofeng Zhang, Mark Dewhirst, Peter Fecci, Justus Adamson, Mark Oldham
PurposeThis work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions.Methods and MaterialsIn vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation.ResultsLuminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P << .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present.ConclusionThis work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam.



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Radiation Oncology in Egypt: A Model for Africa

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Mohamed S. Zaghloul, Mai K. Bishr




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Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Nina N. Sanford, Allison M. Martin, Andrew M. Brunner, Gregory M. Cote, Edwin Choy, Thomas F. DeLaney, Ayal A. Aizer, Yen-Lin Chen
PurposeTo compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia.Methods and MaterialsPatients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population.ResultsA total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02).ConclusionsPatients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small.



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Seymour H. Levitt, MD, 1928-2017

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Luther W. Brady




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In Reply to McClelland et al

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Nina N. Sanford, Helen A. Shih




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Involved-Site Radiation to Maximize Control

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Parag Sanghvi




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Issue Highlights

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3





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Watch and Wait, Salvage Later

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Avyakta Kallam, James O. Armitage




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Curative Radiation Therapy at Time of Progression Under Active Surveillance Compared With Up-front Radical Radiation Therapy for Prostate Cancer

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Alejandro Berlin, Ardalan E. Ahmad, Melvin L.K. Chua, Fabio Y. Moraes, Haiyan Jiang, Maria Komisarenko, Narhari Trimilshina, Hamid Raziee, Ali Hosni, Jure Murgic, Peter Chung, Robert G. Bristow, Antonio Finelli
PurposeTo describe and compare outcomes in men with initially presumed indolent prostate cancer receiving definitive radiation therapy after active surveillance (AS) versus those in a risk-matched cohort undergoing up-front radiation therapy.Methods and MaterialsMen prospectively enrolled in an AS program between 1992 and 2014 and subsequently undergoing curative radiation therapy (ie, image guided radiation therapy [IGRT] or low-dose-rate brachytherapy [LDR-BT]) were identified. Biochemical relapse–free rate (bRFR), metastasis-free rate (mFR), and overall survival (OS) were compared against a cohort of men treated up front, matched by age, clinical prognostic indices (risk group, prostate-specific antigen, cT category, Gleason score, percentage of involved biopsy cores), and radiation therapy modality.ResultsOf 1070 patients in the AS registry, 200 underwent definitive radiation therapy (143 IGRT and 57 LDR-BT) after a median of 32.9 (interquartile range [IQR] 20.6-59.8) months on surveillance. Main reasons for treatment were grade and volume upgrading (57.5% and 26%, respectively). Median follow-up after radiation therapy was 4.9 (IQR 3.1-7.5) years. At 5 years the bRFR, mFR, and OS were, respectively, 97%, 99%, and 98.5%. No patient died of prostate cancer. Adequate risk-matching was confirmed in an independent cohort comprising 359 patients receiving up-front IGRT (71%) or LDR-BT (29%) and followed for a median of 9 (IQR 3.1-7.5) years. There was no difference in the disease-specific outcomes (bRFR, mFR) between the 2 cohorts (Gray's P value of .257 and .934, respectively). In multivariate analyses, timing of radical radiation therapy (deferred vs up-front) was not correlated to biochemical relapse or metastases occurrence.ConclusionsCurative-intent radiation therapy (ie, dose-escalated IGRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Deferring radical therapy after a period of AS does not seem to result in inferior oncologic outcomes compared with patients with similar risk characteristics undergoing up-front treatment.



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Observe, and Keep Chemotherapy Up the Sleeve

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Carol Marquez




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Normal Tissue Complication Probability Modeling of Pulmonary Toxicity After Stereotactic and Hypofractionated Radiation Therapy for Central Lung Tumors

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): H. Tekatli, M. Duijm, E. Oomen-de Hoop, W. Verbakel, W. Schillemans, B.J. Slotman, J.J. Nuyttens, S. Senan
PurposeTo evaluate clinical pulmonary and radiographic bronchial toxicity after stereotactic ablative radiation therapy and hypofractionated radiation therapy for central lung tumors, and perform normal tissue complication probability modeling and multivariable analyses to identify predictors for toxicity.Methods and MaterialsA pooled analysis was performed of patients with a central lung tumor treated using ≤12 fractions at 2 centers between 2006 and 2015. Airways were manually contoured on planning computed tomography scans, and doses were recalculated to an equivalent dose of 2 Gy per fraction with an α/β ratio of 3. Grade ≥3 (≥G3) clinical pulmonary toxicity was evaluated by 2 or more physicians. Radiographic toxicity was defined as a stenosis or an occlusion with or without atelectasis using follow-up computed tomography scans. Logistic regression analyses were used for statistical analyses.ResultsA total of 585 bronchial structures were studied in 195 patients who were mainly treated using 5 or 8 fractions (60%). Median patient survival was 27.9 months (95% confidence interval 22.3-33.6 months). Clinical ≥G3 toxicity was observed in 24 patients (12%) and radiographic bronchial toxicity in 55 patients (28%), both mainly manifesting ≤12 months after treatment. All analyzed dosimetric parameters correlated with clinical and lobar bronchial radiographic toxicity, with V130Gy,EQD having the highest odds ratio. Normal tissue complication probability modeling showed a volume dependency for the development of both clinical and radiographic toxicity. On multivariate analyses, significant predictors for ≥G3 toxicity were a planning target volume overlapping the trachea or main stem bronchus (P = .005), chronic obstructive pulmonary disease (P = .034), and the total V130Gy,EQD (P = .012). Radiographic bronchial toxicity did not significantly correlate with clinical toxicity (P = .663).ConclusionsWe identified patient and dosimetric factors associated with clinical and radiographic toxicity after high-dose radiation therapy for central lung tumors. Additional data from prospective studies are needed to validate these findings.



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Development of a Radiation Oncology Resident Continuity Clinic to Improve Clinical Competency and Patient Compliance

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Stella K. Yoo, Shelly X. Bian, Eugene Lin, Sukhjeet S. Batth, Lydia W. Ng, Jacob Andrade, Patrick A. Williams, Anthony H. Pham, Omar M. Ragab, Naomi R. Schechter, Eric L. Chang, Richard L.S. Jennelle




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Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Rachel J. Carter, Catherine M. Nickson, James M. Thompson, Andrzej Kacperek, Mark A. Hill, Jason L. Parsons
PurposeTo investigate the precise mechanism of recognition and processing of ionizing radiation (IR)-induced complex DNA damage (CDD), where two or more DNA lesions are in close proximity, in cellular DNA which is packaged with histones to form chromatin.Methods and MaterialsHeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells were irradiated with high linear energy transfer (LET) α-particles or protons, versus low-LET protons and X rays. At various time points after irradiation, site-specific histone post-translational modifications were analyzed by quantitative Western blotting; DNA damage and repair were measured by different versions of the comet assay; and cell survival was determined using clonogenic assays.ResultsSite-specific histone post-translational modifications after low- and high-LET radiation, particularly proton irradiation, were screened, aiming to identify those responsive to CDD. We demonstrate that histone H2B ubiquitylated on lysine 120 (H2Bub) is specifically induced several hours after irradiation in response to high-LET α-particles and protons but not by low-LET protons or X rays/γ-radiation. This is associated with increased levels of CDD, which contributes to decreased cell survival. We further discovered that modulation of H2Bub is under the control of two E3 ubiquitin ligases, MSL2 and RNF20/RNF40 complex, whose depletion leads to defective processing and further persistence of CDD, and to additional decreased cell survival after irradiation.ConclusionThis study demonstrates that the signaling and repair of CDD, particularly induced by high-LET IR is co-ordinated through the specific induction of H2Bub catalyzed by MSL2 and RNF20/40, a mechanism that contributes significantly to cell survival after irradiation.



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Utilizing 10-Year Results From the American Board of Radiology Clinical Examination to Identify Areas for Programmatic Improvement

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Robert B. Den, Marlene Folino, Adam P. Dicker




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In Reply to Leddy

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Nishant K. Shah, Brad Zehr, Ankit Agarwal, Apar Gupta, Ariel E. Hirsch




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In Reply to Overgaard et al

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): William A. Stokes, Sana D. Karam




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Radiation Safety for Pregnant Workers at a Proton Facility

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Genevieve Maquilan, Marc R. Bussière, Joseph McCormack, Tara Medich, Andrzej Niemierko, Helen A. Shih
PurposeTo quantify radiation exposure of radiation therapy technologists (RTTs) in a proton treatment facility in comparison with a photon therapy facility, to inform and establish these specialized occupational safety guidelines.Methods and MaterialsTwo groups of RTTs, consisting of 12 full-time passive scattering proton RTTs and 18 full-time conventional photon RTTs, wore an additional dosimetry badge at the waist for a period of 14 weeks. The 2 groups of RTTs were given identical instructions on the proper use of the badges. To compare exposures between passive scatter and scanning beam systems, exposure rates from activated equipment in both systems were measured.ResultsOver the 14-week period, the mean and standard deviation background-corrected dose for the passively scattered proton RTTs was 39.9 ± 5.4 mrem. The mean and standard deviation background-corrected dose for the conventional photon RTTs was similar at 39.9 ± 9.0 mrem (P = .6). Exposure rates were lower in equipment activated in a scanning beam system in comparison with those from a passive scatter system.ConclusionsRadiation dose to passively scattered proton and photon radiation therapy technologists was similar when measured with a dosimeter worn at the waist over a period of 14 weeks. On the basis of these data, the departmental policy permits pregnant radiation workers to work in proton treatment areas, and the policy for pregnant workers does not differ between proton and photon radiation workers or between passive scatter and scanning beam systems. All employees are encouraged to limit time near and proximity to activated equipment.



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Brainstem Injury in Pediatric Patients With Posterior Fossa Tumors Treated With Proton Beam Therapy and Associated Dosimetric Factors

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Michelle S. Gentile, Beow Y. Yeap, Harald Paganetti, Claire P. Goebel, Dillon E. Gaudet, Sara L. Gallotto, Elizabeth A. Weyman, Michael L. Morgan, Shannon M. MacDonald, Drosoula Giantsoudi, Judith Adams, Nancy J. Tarbell, Hanne Kooy, Torunn I. Yock
PurposeProton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2%-8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution.Methods and MaterialsThe study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.ResultsThe histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (Dmax), 55.2 Gy RBE (range, 48.4-60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); Dmax, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving ≥55 Gy RBE (V55), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem Dmax in the highest quartile (≥55.8 Gy RBE, P = .016) and a V55 in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection.ConclusionsThe incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when Dmax and V55 are kept <55.8 Gy RBE and ≤6.0%, respectively, the 5-year rate of radiation brainstem injury would be <2%.



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In Reply to Daisne et al

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Jean-Emmanuel Bibault, Philippe Giraud, Magali Morelle, Lionel Perrier, Marius Huguet




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Stereotactic Radiosurgery for Resected Brain Metastases: New Evidence Supports a Practice Shift, but Questions Remain

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Giuseppe Minniti, Scott G. Soltys, Lia M. Halasz, John C. Breneman, Michael Chan, Nadia N. Laack, John P. Kirkpatrick




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Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Suk W. Yoon, Vadim Tsvankin, Zachary Shrock, Boyu Meng, Xiaofeng Zhang, Mark Dewhirst, Peter Fecci, Justus Adamson, Mark Oldham
PurposeThis work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions.Methods and MaterialsIn vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation.ResultsLuminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P << .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present.ConclusionThis work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam.



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Radiation Oncology in Egypt: A Model for Africa

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Mohamed S. Zaghloul, Mai K. Bishr




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Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Nina N. Sanford, Allison M. Martin, Andrew M. Brunner, Gregory M. Cote, Edwin Choy, Thomas F. DeLaney, Ayal A. Aizer, Yen-Lin Chen
PurposeTo compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia.Methods and MaterialsPatients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population.ResultsA total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02).ConclusionsPatients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small.



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Seymour H. Levitt, MD, 1928-2017

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Luther W. Brady




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In Reply to McClelland et al

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Nina N. Sanford, Helen A. Shih




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Involved-Site Radiation to Maximize Control

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Parag Sanghvi




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Issue Highlights

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3





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Watch and Wait, Salvage Later

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Avyakta Kallam, James O. Armitage




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Curative Radiation Therapy at Time of Progression Under Active Surveillance Compared With Up-front Radical Radiation Therapy for Prostate Cancer

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Alejandro Berlin, Ardalan E. Ahmad, Melvin L.K. Chua, Fabio Y. Moraes, Haiyan Jiang, Maria Komisarenko, Narhari Trimilshina, Hamid Raziee, Ali Hosni, Jure Murgic, Peter Chung, Robert G. Bristow, Antonio Finelli
PurposeTo describe and compare outcomes in men with initially presumed indolent prostate cancer receiving definitive radiation therapy after active surveillance (AS) versus those in a risk-matched cohort undergoing up-front radiation therapy.Methods and MaterialsMen prospectively enrolled in an AS program between 1992 and 2014 and subsequently undergoing curative radiation therapy (ie, image guided radiation therapy [IGRT] or low-dose-rate brachytherapy [LDR-BT]) were identified. Biochemical relapse–free rate (bRFR), metastasis-free rate (mFR), and overall survival (OS) were compared against a cohort of men treated up front, matched by age, clinical prognostic indices (risk group, prostate-specific antigen, cT category, Gleason score, percentage of involved biopsy cores), and radiation therapy modality.ResultsOf 1070 patients in the AS registry, 200 underwent definitive radiation therapy (143 IGRT and 57 LDR-BT) after a median of 32.9 (interquartile range [IQR] 20.6-59.8) months on surveillance. Main reasons for treatment were grade and volume upgrading (57.5% and 26%, respectively). Median follow-up after radiation therapy was 4.9 (IQR 3.1-7.5) years. At 5 years the bRFR, mFR, and OS were, respectively, 97%, 99%, and 98.5%. No patient died of prostate cancer. Adequate risk-matching was confirmed in an independent cohort comprising 359 patients receiving up-front IGRT (71%) or LDR-BT (29%) and followed for a median of 9 (IQR 3.1-7.5) years. There was no difference in the disease-specific outcomes (bRFR, mFR) between the 2 cohorts (Gray's P value of .257 and .934, respectively). In multivariate analyses, timing of radical radiation therapy (deferred vs up-front) was not correlated to biochemical relapse or metastases occurrence.ConclusionsCurative-intent radiation therapy (ie, dose-escalated IGRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Deferring radical therapy after a period of AS does not seem to result in inferior oncologic outcomes compared with patients with similar risk characteristics undergoing up-front treatment.



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Observe, and Keep Chemotherapy Up the Sleeve

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Carol Marquez




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Normal Tissue Complication Probability Modeling of Pulmonary Toxicity After Stereotactic and Hypofractionated Radiation Therapy for Central Lung Tumors

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): H. Tekatli, M. Duijm, E. Oomen-de Hoop, W. Verbakel, W. Schillemans, B.J. Slotman, J.J. Nuyttens, S. Senan
PurposeTo evaluate clinical pulmonary and radiographic bronchial toxicity after stereotactic ablative radiation therapy and hypofractionated radiation therapy for central lung tumors, and perform normal tissue complication probability modeling and multivariable analyses to identify predictors for toxicity.Methods and MaterialsA pooled analysis was performed of patients with a central lung tumor treated using ≤12 fractions at 2 centers between 2006 and 2015. Airways were manually contoured on planning computed tomography scans, and doses were recalculated to an equivalent dose of 2 Gy per fraction with an α/β ratio of 3. Grade ≥3 (≥G3) clinical pulmonary toxicity was evaluated by 2 or more physicians. Radiographic toxicity was defined as a stenosis or an occlusion with or without atelectasis using follow-up computed tomography scans. Logistic regression analyses were used for statistical analyses.ResultsA total of 585 bronchial structures were studied in 195 patients who were mainly treated using 5 or 8 fractions (60%). Median patient survival was 27.9 months (95% confidence interval 22.3-33.6 months). Clinical ≥G3 toxicity was observed in 24 patients (12%) and radiographic bronchial toxicity in 55 patients (28%), both mainly manifesting ≤12 months after treatment. All analyzed dosimetric parameters correlated with clinical and lobar bronchial radiographic toxicity, with V130Gy,EQD having the highest odds ratio. Normal tissue complication probability modeling showed a volume dependency for the development of both clinical and radiographic toxicity. On multivariate analyses, significant predictors for ≥G3 toxicity were a planning target volume overlapping the trachea or main stem bronchus (P = .005), chronic obstructive pulmonary disease (P = .034), and the total V130Gy,EQD (P = .012). Radiographic bronchial toxicity did not significantly correlate with clinical toxicity (P = .663).ConclusionsWe identified patient and dosimetric factors associated with clinical and radiographic toxicity after high-dose radiation therapy for central lung tumors. Additional data from prospective studies are needed to validate these findings.



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Development of a Radiation Oncology Resident Continuity Clinic to Improve Clinical Competency and Patient Compliance

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Stella K. Yoo, Shelly X. Bian, Eugene Lin, Sukhjeet S. Batth, Lydia W. Ng, Jacob Andrade, Patrick A. Williams, Anthony H. Pham, Omar M. Ragab, Naomi R. Schechter, Eric L. Chang, Richard L.S. Jennelle




http://ift.tt/2EmTnE5

Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Rachel J. Carter, Catherine M. Nickson, James M. Thompson, Andrzej Kacperek, Mark A. Hill, Jason L. Parsons
PurposeTo investigate the precise mechanism of recognition and processing of ionizing radiation (IR)-induced complex DNA damage (CDD), where two or more DNA lesions are in close proximity, in cellular DNA which is packaged with histones to form chromatin.Methods and MaterialsHeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells were irradiated with high linear energy transfer (LET) α-particles or protons, versus low-LET protons and X rays. At various time points after irradiation, site-specific histone post-translational modifications were analyzed by quantitative Western blotting; DNA damage and repair were measured by different versions of the comet assay; and cell survival was determined using clonogenic assays.ResultsSite-specific histone post-translational modifications after low- and high-LET radiation, particularly proton irradiation, were screened, aiming to identify those responsive to CDD. We demonstrate that histone H2B ubiquitylated on lysine 120 (H2Bub) is specifically induced several hours after irradiation in response to high-LET α-particles and protons but not by low-LET protons or X rays/γ-radiation. This is associated with increased levels of CDD, which contributes to decreased cell survival. We further discovered that modulation of H2Bub is under the control of two E3 ubiquitin ligases, MSL2 and RNF20/RNF40 complex, whose depletion leads to defective processing and further persistence of CDD, and to additional decreased cell survival after irradiation.ConclusionThis study demonstrates that the signaling and repair of CDD, particularly induced by high-LET IR is co-ordinated through the specific induction of H2Bub catalyzed by MSL2 and RNF20/40, a mechanism that contributes significantly to cell survival after irradiation.



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Utilizing 10-Year Results From the American Board of Radiology Clinical Examination to Identify Areas for Programmatic Improvement

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Robert B. Den, Marlene Folino, Adam P. Dicker




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In Reply to Leddy

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Nishant K. Shah, Brad Zehr, Ankit Agarwal, Apar Gupta, Ariel E. Hirsch




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In Reply to Overgaard et al

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): William A. Stokes, Sana D. Karam




http://ift.tt/2EnZloh

Radiation Safety for Pregnant Workers at a Proton Facility

Publication date: 1 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 100, Issue 3
Author(s): Genevieve Maquilan, Marc R. Bussière, Joseph McCormack, Tara Medich, Andrzej Niemierko, Helen A. Shih
PurposeTo quantify radiation exposure of radiation therapy technologists (RTTs) in a proton treatment facility in comparison with a photon therapy facility, to inform and establish these specialized occupational safety guidelines.Methods and MaterialsTwo groups of RTTs, consisting of 12 full-time passive scattering proton RTTs and 18 full-time conventional photon RTTs, wore an additional dosimetry badge at the waist for a period of 14 weeks. The 2 groups of RTTs were given identical instructions on the proper use of the badges. To compare exposures between passive scatter and scanning beam systems, exposure rates from activated equipment in both systems were measured.ResultsOver the 14-week period, the mean and standard deviation background-corrected dose for the passively scattered proton RTTs was 39.9 ± 5.4 mrem. The mean and standard deviation background-corrected dose for the conventional photon RTTs was similar at 39.9 ± 9.0 mrem (P = .6). Exposure rates were lower in equipment activated in a scanning beam system in comparison with those from a passive scatter system.ConclusionsRadiation dose to passively scattered proton and photon radiation therapy technologists was similar when measured with a dosimeter worn at the waist over a period of 14 weeks. On the basis of these data, the departmental policy permits pregnant radiation workers to work in proton treatment areas, and the policy for pregnant workers does not differ between proton and photon radiation workers or between passive scatter and scanning beam systems. All employees are encouraged to limit time near and proximity to activated equipment.



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Mentoring: Giving Forward While Giving Back

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Mentoring: Giving Forward While Giving Back

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Renal function and urological complications after radical hysterectomy with postoperative radiotherapy and platinum-based chemotherapy for cervical cancer

Abstract

Background

We aimed to clarify renal functional changes long term and serious urological complications in women with cervical cancer who undergo radical hysterectomy followed by pelvic radiotherapy and/or platinum-based chemotherapy to treat the initial disease.

Methods

Data on 380 women who underwent radical hysterectomy at the National Kyushu Cancer Center from January 1997 to December 2013 were reviewed. Main outcome measures were the estimated glomerular filtration rate (eGFR) and monitored abnormal urological findings.

Results

Postoperative eGFR was significantly lower than preoperative eGFR in 179 women with surgery alone and in 201 women with additional pelvic radiotherapy and/or chemotherapy (both P < 0.01). Two types of univariate analyses for eGFR reduction in women after treatment showed that older age, advanced stage, pelvic radiotherapy, and platinum-based chemotherapy were significant variables on both analyses. Two types of multivariate analyses showed that platinum-based chemotherapy or pelvic radiotherapy were associated with impaired renal function (odds ratio 1.96, 95% confidence interval 1.08–3.54 and odds ratio 2.85, 95% confidence interval 1.12–7.24, for the respective analyses). There was a higher rate of bladder wall thickening in women with pelvic radiotherapy had than those without it (17.4% vs. 2.7%, P < 0.01). One serious urological complication (intraperitoneal rupture of the bladder) occurred among women who underwent pelvic radiotherapy (0.6% vs. 0%).

Conclusions

Surgeons should be aware that eGFR is reduced after platinum-based chemotherapy and/or postoperative pelvic radiotherapy. Serious and life-threatening urological complications are rare, but surgeons should be aware of the possibility during the long follow-up.

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Significance of preoperative butyrylcholinesterase level as an independent predictor of survival in patients with upper urinary tract urothelial carcinoma treated with nephroureterectomy

Abstract

Objectives

Butyrylcholinesterase (BChE) is an alpha-glycoprotein synthesized in the liver. Its serum levels are reportedly correlated with disease activity in patients with cancer. The aim of this study was to estimate the potential prognostic significance of preoperative serum BChE levels in patients with upper urinary tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU).

Methods

Of the 220 patients with UTUC who underwent RNU between 1995 and 2016 at Hirosaki University Hospital, 149 patients with available laboratory data were included for analysis. Covariates included age, sex, preoperative laboratory data, clinical T and N grades, tumor grade, tumor location and preoperative chemotherapy. Univariate and multivariate analyses were performed to identify clinical factors associated with overall survival (OS) and disease-free survival (DFS). Univariate analysis was performed using the Kaplan–Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model.

Results

The median BChE level was 276 U/l and the optimal cut-off point for the serum BChE level was determined to be 218 IU/ml. The 5-year OS and DFS rates were 81.0% and 73.7%, respectively. The 5-year OS and DFS rates were significantly greater in the BChE ≥ 218 than <218 U/l groups (86.6% vs. 53.7%, P < 0.001 and 76.4% vs. 58.3%, P = 0.049, respectively). In multivariate analysis, BChE levels were most significantly associated with OS, whereas BChE level and tumor grade were significantly associated with DFS.

Conclusions

This study validated preoperative serum BChE levels as an independent prognostic factor for UTUC after RNU.

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Promises and challenges of immuno-oncology from a clinical perspective

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Cancer incidence rates in the world from the Cancer Incidence in Five Continents XI

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Promises and challenges of immuno-oncology from a clinical perspective

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Preclinical [18F]tetrafluoroborate-PET/CT imaging of pituitary gland hyperplasia

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Wide-spread ignorance on the treatment of subcutaneous malignant tumors; a questionnaire-based study

Abstract

Background

Subcutaneous malignant tumors are often treated by non-specialized clinicians in musculoskeletal oncology. While the resection of subcutaneous tumors appears technically feasible, unplanned resection of malignant tumors can result in a devastating clinical outcome. The aim of this study was to evaluate the potential estrangement in the awareness of and the treatment strategy for the patients with subcutaneous soft tissue tumors between musculoskeletal oncologists and non-specialized clinicians.

Methods

A questionnaire probing the clinical assessment of subcutaneous tumors was sent to orthopedic surgeons, dermatologists, plastic surgeons, and general surgeons. Results of the questionnaire were statistically analyzed.

Results

One hundred sixteen clinicians out of 150 responded to the questionnaire; the response rate was 77.3%. Among those, 46 clinicians had treated subcutaneous tumors. Thirty-nine of these 46 clinicians (27 musculoskeletal oncologists and 12 non-specialized clinicians) preoperatively performed enhanced MRI for diagnostic evaluation. Preoperative incisional biopsy to confirm the pathological diagnosis was performed by 36 of the 46 clinicians (29 musculoskeletal oncologists and seven non-specialized clinicians). These results indicate that musculoskeletal oncologists perform preoperative enhanced MRI (P = 0.08) and biopsy (P < 0.01) more frequently than non-specialized clinicians. The recognition rate of 'myxofibrosarcoma' was 60.8% among clinicians with an experience with sarcoma treatment (25 musculoskeletal oncologists and three non-specialized clinicians). The recognition rate of 'myxofibrosarcoma' between musculoskeletal oncologists and non-specialized clinicians was statistically significant (P < 0.01).

Conclusions

Preoperative evaluations for subcutaneous tumors are more often inappropriate in non-specialized clinicians than those who are. Therefore, it will be mandatory to raise the awareness of this condition to improve the clinical outcome of patients with subcutaneous tumors.

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Repression of the expression of PPP3CC by ZEB1 confers activation of NF-κB and contributes to invasion and growth in glioma cells

Abstract

Background

Gliomas are highly malignant brain tumors. Aberrant activation of NF-κB plays a crucial role in tumor progression.

Method

ELISA assay was used to detect NF-κB activity in glimoas cells with different treatments. PPP3CC expression was evaluated by qRT-PCR and western blot assay. Kaplan–Meier analysis estimated the overall survival rates according to the protein level of PPP3CC. Transwell and MTS assay were performed to determine cell invasion and growth. Chromatin immunoprecipitation combined with luciferase reporter assays illustrated the transcriptional regulation of PPP3CC.

Results

We showed that PPP3CC decrease was responsible for constitutive activation of NF-κB in gliomas. Restored PPP3CC expression inhibited activation of NF-κB. PPP3CC was frequently decreased in gliomas and that repression of the expression of PPP3CC correlated glioma progression. The ectopic expression of PPP3CC inhibited the invasive potential of glioma cells, and inhibited glioma cells proliferation in vitro and growth in vivo. Additionally, the expression of Zinc finger E-box-binding homeobox 1(ZEB1) was increased in gliomas and was negatively correlated with clinical outcomes of glioma patients. ZEB1 inversely correlated with the expression of PPP3CC. ZEB1 was also confirmed to physically bind to the PPP3CC promoter. ZEB1 knockdown resulted in an increase in the expression of PPP3CC and elevation of PPP3CC promoter activity in glioma cells.

Conclusion

These findings indicated that the down-regulation of PPP3CC by ZEB1 resulted in activation of NF-κB is a critical oncogenic event in gliomas.

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Prediction of acute gastrointestinal and genitourinary radiation toxicity in prostate cancer patients using lymphocyte microRNA

Abstract

Background

To search for novel biomarkers that can predict acute radiation toxicity, we conducted microRNA expression analysis of peripheral blood lymphocytes (PBLs).

Methods

The discovery cohort was 69 patients with localized adenocarcinoma of the prostate who received intensity-modulated radiation therapy between October 2007 and October 2010. The validation cohort was 72 patients treated with low-dose-rate brachytherapy between May 2008 and March 2014. After13 microRNAs were selected by TaqMan® Array analysis in a preliminary experiment, expression of these microRNAs in all samples was analyzed by RT-PCR.

Results

In the discovery cohort, the average prostate volume, the rectal volume receiving 70 Gy, and expression of miR-410 and miR-221 were significant risk factors for Grade 1–2 gastrointestinal toxicity. Receiver operating characteristic analysis showed that the area under the curve (AUC) was 0.807. The maximum dose to the urinary bladder, prostate volume, pretreatment urinary function score, and miR-99a and miR-221 expression were risk factors for Grade 2 genitourinary toxicity. The corresponding AUC was 0.796.In the validation cohort, reproducibility of these markers was confirmed for gastrointestinal toxicity, but not for genitourinary toxicity.

Conclusion

Combining radiation dose parameters with microRNA expression in PBLs may be useful for predicting acute gastrointestinal toxicity of radiation therapy, thus contributing to personalized treatment of prostate cancer.

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Nomograms for predicting disease progression in patients of Stage I non-small cell lung cancer treated with stereotactic body radiotherapy

Abstract

Objective

Non-local progression is a major concern in non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Herein we aimed to create a pre-treatment prognostic nomogram for patients with Stage I NSCLC receiving SBRT.

Methods

We retrospectively studied 182 eligible patients. Patients were randomly divided into a model (70%) group and a validation (30%) group. In the model group, thirteen parameters consisting of patient, treatment, and tumor factors were studied and multivariate Cox proportional hazards regression was performed to identify independent predictors for survival outcome, based on which we developed clinical nomogram. The nomogram was externally validated in the validation group.

Results

Multivariate analysis showed that tumor size (P = 0.011) was the only factor correlated with 2-year overall survival, whereas 2-year locoregional control (LRC) was significantly related to tumor size (P = 0.024) and the maximum standardized uptake value (SUV_max) (P = 0.044), so does 2-year progression-free survival (PFS) (tumor size: P = 0.026; SUV_max: P = 0.038). Nomogram for 2-year LRC and 2-year PFS were created based on aforementioned results. The C-indexes for the nomograms to predict 2-year LRC and PFS were 0.816 and 0.804, respectively, in model group, and were 0.729 and 0.731, respectively, in the validation group. Calibration plots also showed that the model performed well.

Conclusions

Tumor of larger size and higher SUV_max predisposed patients to early onset of locoregional and distant progression. The nomogram developed in our study would be helpful in clinical decision-making and selection of patients who may benefit from more rigorous follow-up and aggressive systemic treatment plan.

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Chemotherapy for hepatocellular carcinoma: current status and future perspectives

Abstract

Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase III placebo-controlled studies, sorafenib is currently acknowledged worldwide as the standard therapeutic agent for advanced HCC. Following the introduction of sorafenib for the treatment of HCC, Phase III trials of numerous other agents as first-line or second-line chemotherapy have been conducted to determine if any of these agents might offer superior survival benefit to sorafenib. In 2016, a clear survival benefit of regorafenib over placebo was demonstrated in HCC patients showing disease progression after sorafenib treatment. A year later, in 2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the overall survival, in chemo-naïve patients with advanced HCC. More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib. At present, various novel combination regimens including these agents are currently under development. Hepatic arterial infusion chemotherapy (HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, based on reports of high response rates and favorable long-term outcomes. Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib alone as first-line therapy have been conducted in patients with advanced HCC, no firm evidence of the superiority of one over the other has been established yet. In the future, demonstration of the survival advantage of HAIC and the recognition of HAIC as one of the standard treatments for patients with advanced HCC are expected.

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Risk and prognostic factors for multiple primary carcinomas in patients with head and neck cancer

Abstract

Background

Unexpected multiple primary carcinomas (MPCs) that develop in patients with head and neck carcinomas complicate approaches to their management. We therefore investigated the clinical factors associated with survival outcomes after the treatment of MPCs.

Methods

We performed a retrospective review of records of 1104 patients who underwent treatment for primary head and neck carcinoma at Hamamatsu University Hospital. We evaluated clinical staging, age, sex, smoking, alcohol consumption, the primary tumor site (particularly the involvement of the mucosal epithelial lining of the aerodigestive tract), and overall survival (OS) as determined by Kaplan–Meier analysis. Information on patients' survival status was obtained after a mean follow-up period of 43.8 months (range, 1–144 months).

Results

Among 566 patients with mucosa-associated carcinoma arising in the epithelial lining, the 5- and 10-year OS rates (68.49% and 58.96%, respectively) were significantly shorter than those of patients with mucosa non-associated carcinoma (74.22%, and 66.76%, respectively) (log-rank P = 0.0219). Older age (P = 0.016) and male sex (P < 0.001) were likely independent risk factors for developing MPCs; smoking (P < 0.001) and alcohol consumption (P < 0.001) were also significant risk factors.

Conclusion

Mucosa-associated carcinomas arising in the epithelial lining of the aerodigestive tract in the head and neck are a significant risk factor for developing MPC and are a poor prognostic factor. Careful follow-up and more frequent examinations of the aerodigestive tracts of these patients are recommended.

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The distress and benefit to bereaved family members of participating in a post-bereavement survey

Abstract

Background

Few studies have simultaneously collected quantitative data regarding the positive and negative effects of participating in post-bereavement surveys.

Methods

We conducted a cross-sectional postal questionnaire survey in October 2013. Potential participants were caregivers for family members who had died in four inpatient palliative care units, two home hospices, and a general hospital. We collected opinions regarding the distress and benefit of completing a post-bereavement survey. After collecting data, we provided feedback to participating institutions in the form of study results and de-identified open-ended comments.

Results

Of 692 potential participants, 596 were sent questionnaires; 393 returned questionnaires were valid and analyzed. Of the respondents, 62% reported being distressed by completing the questionnaire. Female participants and those who were mentally ill during the caregiving period reported more distress. However, 86% of respondents reported they found the questionnaire beneficial. Better quality of end-of-life care and respondent depression were associated with more benefit. Major benefits were: contributing to the development of end-of-life care as a family (63%); expressing gratitude to the hospital and medical staff (60%); and looking back and reflecting on the end-of-life period (40%). Feeling benefit was not correlated with feeling distressed (P = −0.02).

Conclusion

In this large-scale study on the effects of post-bereavement surveys in Japan, many bereaved family members reported that completing the survey was beneficial. In addition to possibly having feelings of distress, post-bereavement surveys might also be beneficial to end-of-life care facilities.

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External validation of two web-based postoperative nomograms predicting the probability of early biochemical recurrence after radical prostatectomy: a retrospective cohort study

Abstract

The present study aimed to validate and compare the predictive accuracies of the Memorial Sloan Kettering Cancer Center (MSKCC) and Johns Hopkins University (JHU) web-based postoperative nomograms for predicting early biochemical recurrence (BCR) after radical prostatectomy (RP) and to analyze clinicopathological factors to predict early BCR after RP using our dataset. The c-index was 0.72 (95% confidence (CI): 0.61–0.83) for the MSKCC nomogram and 0.71 (95% CI: 0.61–0.81) for the and JHU nomogram, demonstrating fair performance in the Japanese population. Furthermore, we statistically analyzed our 174 patients to elucidate prognostic factors for early BCR within 2 years. Lymphovascular invasion (LVI) including lymphatic vessel invasion (ly) was a significant predictor of early BCR in addition to common variables (pT stage, extraprostatic extension, positive surgical margin and seminal vesicle invasion). LVI, particularly ly, may provide a good predictor of early BCR after RP and improve the accuracy of the nomograms.

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Correlation of biologically effective dose and the tumor control in Stage I (<5 cm) non-small cell lung cancer with stereotactic ablative radiotherapy: a single institutional cohort study

Abstract

Backgrounds

Stereotactic ablative radiotherapy (SABR) is one of the newly developed innovative radiotherapy and of which optimal dose prescription needs to be standardized. We aimed to investigate the dose–response relationship for patients with SABR.

Methods

Fifty-three patients with Stage I non-small cell lung cancer patients, who underwent SABR between November 2006 and January 2015, were evaluated retrospectively. Thirteen patients (24.5%), who refused the surgery were included and 40 patients (75.5%) were medically inoperable at diagnosis. The median age was 74 years. The median SABR dose was 50 Gy in 3–8 fractions and the median biologically effective dose (BED;α/β = 10) was 105.6 Gy (range: 60–160.53 Gy).

Results

The median follow-up was 37.1 months. The 1 and 3 year local control rates were 91.7% and 85.1%. The 3 year overall and progression-free survival rate were 63.3% and 47.5%, respectively, and freedom from progression was 62.2%. Local control rate and 3-year overall survival according to tumor size was 100% and 79.4% in T1 tumors in a while 61.8% and 45% in T2a tumors. The 3-year local and regional control by BED₁₀ was 79.4% and 69.4% in ≤100 Gy vs. 89.1% and 100% in >100 Gy (P = 0.526, 0.004). Dyspnea more than Grade 3 was reported in six (11.3%) patients and Grade 1 chest pain was shown in five (9.4%) patients.

Conclusions

The excellent regional control was conferred with a prescription of more than BED₁₀ of 100 Gy, which also might be needed to achieve better local tumor control in T2a patients with tolerable lung function.

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A randomized Phase III trial of lobe-specific vs. systematic nodal dissection for clinical Stage I–II non-small cell lung cancer (JCOG1413)

Abstract

In January 2017, the Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group commenced a randomized Phase III trial to confirm the clinical benefit of lobe-specific nodal dissection for clinical Stage I–II non-small cell lung cancer. The primary endpoint is overall survival, and the main objective is to confirm the non-inferiority of lobe-specific in comparison to systematic nodal dissection with regard to lobectomy. The secondary endpoints are relapse-free survival, %local recurrence, %regional lymph node recurrence, operation time, blood loss, length of hospitalization, duration of chest tube placement and adverse events. A total of 1700 patients will be accrued from 44 Japanese institutions within 5 years. This study is the first and large prospective trial to evaluate whether the difference in the area of nodal dissection affects the overall survival of patients with relatively early-stage non-small cell lung cancer. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000025530.

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Cancer incidence rates in the world from the Cancer Incidence in Five Continents XI

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Does fluid collection impact radiotherapy outcomes after wide excision of lower extremity soft tissue sarcoma?

Abstract

Background

Fluid collection (FC) of lymph or blood may accumulate at the site of excision after surgery for soft tissue sarcoma, with reported incidence rates from 10% to 36%. The purpose of this study is to analyze the impact of FC on local recurrence (LR) and wound complication rates after adjuvant postoperative radiotherapy (PORT) in lower extremity soft tissue sarcoma (LE-STS).

Methods

Eighty-eight patients diagnosed with LE-STS were curatively treated with wide excision and PORT. FC developed in 51.1% of patients. Full FC volumes were included in the irradiation field throughout the full course of PORT for 36 patients (80.0%). A median of 61.2 and 63 Gy was prescribed for patients with and without FC, respectively.

Results

After a median follow-up of 4.3 years, patients with and without FC had 5-year local control rates of 77.7% and 90.8% (P = 0.105). Eight patients with FC had LR, of which six patients had recurrent tumors at or within 4 cm of the FC wall and three of these patients had out-of-field LR. Wound complication occurred after RT in 3 (6.7%) of 45 patients with FC and 1 (2.3%) of 43 patients without FC.

Conclusions

FC presents a potential risk for increased LR, particularly near the FC wall. Based on reasonable wound complication rates, we suggest the need and feasibility of fully including FC volumes in the irradiation field.

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Preclinical [18F]tetrafluoroborate-PET/CT imaging of pituitary gland hyperplasia

http://ift.tt/2nOnKsY

Wide-spread ignorance on the treatment of subcutaneous malignant tumors; a questionnaire-based study

Abstract

Background

Subcutaneous malignant tumors are often treated by non-specialized clinicians in musculoskeletal oncology. While the resection of subcutaneous tumors appears technically feasible, unplanned resection of malignant tumors can result in a devastating clinical outcome. The aim of this study was to evaluate the potential estrangement in the awareness of and the treatment strategy for the patients with subcutaneous soft tissue tumors between musculoskeletal oncologists and non-specialized clinicians.

Methods

A questionnaire probing the clinical assessment of subcutaneous tumors was sent to orthopedic surgeons, dermatologists, plastic surgeons, and general surgeons. Results of the questionnaire were statistically analyzed.

Results

One hundred sixteen clinicians out of 150 responded to the questionnaire; the response rate was 77.3%. Among those, 46 clinicians had treated subcutaneous tumors. Thirty-nine of these 46 clinicians (27 musculoskeletal oncologists and 12 non-specialized clinicians) preoperatively performed enhanced MRI for diagnostic evaluation. Preoperative incisional biopsy to confirm the pathological diagnosis was performed by 36 of the 46 clinicians (29 musculoskeletal oncologists and seven non-specialized clinicians). These results indicate that musculoskeletal oncologists perform preoperative enhanced MRI (P = 0.08) and biopsy (P < 0.01) more frequently than non-specialized clinicians. The recognition rate of 'myxofibrosarcoma' was 60.8% among clinicians with an experience with sarcoma treatment (25 musculoskeletal oncologists and three non-specialized clinicians). The recognition rate of 'myxofibrosarcoma' between musculoskeletal oncologists and non-specialized clinicians was statistically significant (P < 0.01).

Conclusions

Preoperative evaluations for subcutaneous tumors are more often inappropriate in non-specialized clinicians than those who are. Therefore, it will be mandatory to raise the awareness of this condition to improve the clinical outcome of patients with subcutaneous tumors.

http://ift.tt/2nEjgG8

Repression of the expression of PPP3CC by ZEB1 confers activation of NF-κB and contributes to invasion and growth in glioma cells

Abstract

Background

Gliomas are highly malignant brain tumors. Aberrant activation of NF-κB plays a crucial role in tumor progression.

Method

ELISA assay was used to detect NF-κB activity in glimoas cells with different treatments. PPP3CC expression was evaluated by qRT-PCR and western blot assay. Kaplan–Meier analysis estimated the overall survival rates according to the protein level of PPP3CC. Transwell and MTS assay were performed to determine cell invasion and growth. Chromatin immunoprecipitation combined with luciferase reporter assays illustrated the transcriptional regulation of PPP3CC.

Results

We showed that PPP3CC decrease was responsible for constitutive activation of NF-κB in gliomas. Restored PPP3CC expression inhibited activation of NF-κB. PPP3CC was frequently decreased in gliomas and that repression of the expression of PPP3CC correlated glioma progression. The ectopic expression of PPP3CC inhibited the invasive potential of glioma cells, and inhibited glioma cells proliferation in vitro and growth in vivo. Additionally, the expression of Zinc finger E-box-binding homeobox 1(ZEB1) was increased in gliomas and was negatively correlated with clinical outcomes of glioma patients. ZEB1 inversely correlated with the expression of PPP3CC. ZEB1 was also confirmed to physically bind to the PPP3CC promoter. ZEB1 knockdown resulted in an increase in the expression of PPP3CC and elevation of PPP3CC promoter activity in glioma cells.

Conclusion

These findings indicated that the down-regulation of PPP3CC by ZEB1 resulted in activation of NF-κB is a critical oncogenic event in gliomas.

http://ift.tt/2nOmciI

Prediction of acute gastrointestinal and genitourinary radiation toxicity in prostate cancer patients using lymphocyte microRNA

Abstract

Background

To search for novel biomarkers that can predict acute radiation toxicity, we conducted microRNA expression analysis of peripheral blood lymphocytes (PBLs).

Methods

The discovery cohort was 69 patients with localized adenocarcinoma of the prostate who received intensity-modulated radiation therapy between October 2007 and October 2010. The validation cohort was 72 patients treated with low-dose-rate brachytherapy between May 2008 and March 2014. After13 microRNAs were selected by TaqMan® Array analysis in a preliminary experiment, expression of these microRNAs in all samples was analyzed by RT-PCR.

Results

In the discovery cohort, the average prostate volume, the rectal volume receiving 70 Gy, and expression of miR-410 and miR-221 were significant risk factors for Grade 1–2 gastrointestinal toxicity. Receiver operating characteristic analysis showed that the area under the curve (AUC) was 0.807. The maximum dose to the urinary bladder, prostate volume, pretreatment urinary function score, and miR-99a and miR-221 expression were risk factors for Grade 2 genitourinary toxicity. The corresponding AUC was 0.796.In the validation cohort, reproducibility of these markers was confirmed for gastrointestinal toxicity, but not for genitourinary toxicity.

Conclusion

Combining radiation dose parameters with microRNA expression in PBLs may be useful for predicting acute gastrointestinal toxicity of radiation therapy, thus contributing to personalized treatment of prostate cancer.

http://ift.tt/2nHrlcZ

Nomograms for predicting disease progression in patients of Stage I non-small cell lung cancer treated with stereotactic body radiotherapy

Abstract

Objective

Non-local progression is a major concern in non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Herein we aimed to create a pre-treatment prognostic nomogram for patients with Stage I NSCLC receiving SBRT.

Methods

We retrospectively studied 182 eligible patients. Patients were randomly divided into a model (70%) group and a validation (30%) group. In the model group, thirteen parameters consisting of patient, treatment, and tumor factors were studied and multivariate Cox proportional hazards regression was performed to identify independent predictors for survival outcome, based on which we developed clinical nomogram. The nomogram was externally validated in the validation group.

Results

Multivariate analysis showed that tumor size (P = 0.011) was the only factor correlated with 2-year overall survival, whereas 2-year locoregional control (LRC) was significantly related to tumor size (P = 0.024) and the maximum standardized uptake value (SUV_max) (P = 0.044), so does 2-year progression-free survival (PFS) (tumor size: P = 0.026; SUV_max: P = 0.038). Nomogram for 2-year LRC and 2-year PFS were created based on aforementioned results. The C-indexes for the nomograms to predict 2-year LRC and PFS were 0.816 and 0.804, respectively, in model group, and were 0.729 and 0.731, respectively, in the validation group. Calibration plots also showed that the model performed well.

Conclusions

Tumor of larger size and higher SUV_max predisposed patients to early onset of locoregional and distant progression. The nomogram developed in our study would be helpful in clinical decision-making and selection of patients who may benefit from more rigorous follow-up and aggressive systemic treatment plan.

http://ift.tt/2nOm9Dy