Combination of paclitaxel, bevacizumab and MEK162 in second line treatment in platinum-relapsing patient derived ovarian cancer xenografts

Abstract

Advanced ovarian cancer is very responsive to first line platinum therapy, however almost invariably it relapses with a resistant disease. We have reported that patient derived ovarian xenografts (PDXs), independently from the degree of the initial response to cisplatin (DDP), show a significantly lower response to a second DDP cycle. We here report the effect of new combination regimens containing a MEK inhibitor (MEK), bevacizumab (BEV) and paclitaxel (PTX) as second line therapy in platinum-relapsing PDXs.

We selected three DDP-relapsing PDX models based on the presence of activation of the RAS/RAF/MEK/ERK axis, mutated p53, lack of PTEN expression and activation of the PI3K pathway. In all the selected xenograft models, the antitumor efficacy of the doublets can be summarized as PTX/BEV > BEV/MEK > PTX/MEK and the antitumor activity of the triple combination was higher than any double combination. All the different combinations were well tolerated. The present data corroborate the activity of bevacizumab in combination with chemotherapy for the treatment of relapsing ovarian tumors and suggest that the addition of another targeted agents (MEK inhibitor) can further increase the antitumor activity without any increase in toxicity. PDX models represent a useful model to test second line therapy after failure of DDP first line.

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Incidence and survival of childhood cancer in the French islands of Reunion and Mayotte (2005–2011)

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): J. Ramiandrisoa, M. Jehanne, F. Sauvat, Y. Reguerre, A. Chamouine, E. Chirpaz
The aim of this study is to describe childhood cancer incidence and survival in the French islands of Reunion and Mayotte for the period 2005–2011. Data were taken from the population-based Cancer Registry of Reunion Island. All incident cases of malignant tumours and benign tumours of the Central Nervous System diagnosed between 2005 and 2011 in children under the age of 15 and living in Reunion or Mayotte were included. A total of 236 cases were registered (176 in Reunion, 60 in Mayotte). Age-standardised incidence rates (ASRs, world standard) for all cancers were 125.0 and 101.8 per million for Reunion and Mayotte, respectively. ASRs for the main cancer groups were lower than those described in mainland France for the same period. The 5-year overall survival rate for all patients was 78.5% (95%CI 71.9- 83.7), slightly lower than that reported in mainland France.



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Prostate Cancer With Isolated Bony Metastasis: Sternal Struggle

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Mark T. Corkum




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Treatment-Related Toxicity in Patients With Early-Stage Non-Small Cell Lung Cancer and Coexisting Interstitial Lung Disease: A Systematic Review

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Hanbo Chen, Suresh Senan, Esther J. Nossent, R. Gabriel Boldt, Andrew Warner, David A. Palma, Alexander V. Louie
PurposeDefinitive treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC) is usually well tolerated. Patients with ES-NSCLC and coexisting interstitial lung disease (ILD) are at increased risk of severe treatment-related toxicity after definitive therapy. The main objective of this systematic review is to provide a pooled estimation of treatment-related mortality and ILD-specific toxicity in this population of patients and to identify trends for further study.Methods and MaterialsThe MEDLINE and Embase databases were queried from respective dates of inception to January 2016. Studies that included patients who underwent definitive treatment for ES-NSCLC not combined with other treatments were included. Patients with oligometastases who were treated with aggressive palliation were included if it did not constitute the majority of patients in a specific study. The results were summarized with weighted proportions according to the sample size of individual studies.ResultsOverall, 3056 records were reviewed and 50 journal articles were included in the abstraction. The weighted proportion of treatment-related mortality (and ILD-specific toxicity) in primarily medically inoperable patients was as follows: stereotactic ablative radiation therapy (SABR) 15.6% (25%), particle beam therapy 4.3% (18.2%) and radiofrequency ablation (RFA) 8.7% (25%). The data for medically operable patients who underwent surgery were extracted for reference. Treatment-related mortality and ILD-specific toxicity were 2.2% and 12%, respectively, in the surgical population. On analysis of reported SABR dose parameters, V20 ≤ 6.5% and mean lung dose ≤4.5 Gy were found to be metrics associated with reduced mortality.ConclusionA consistently high level of treatment-related mortality and ILD-specific toxicity was observed in primarily medically inoperable patients treated with SABR, particle beam therapy, and RFA. For these patients, curative treatment should be considered in the context of the high toxicity rates and overall poor prognosis. Stringent radiation dosimetric parameters may result in reduced toxicity.



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Treat All Known Disease

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Peter J. Hoskin




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Intriguing, but Not the Right Setting

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Kevin L. Stephans, Rupesh Kotecha




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External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Robert H. Press, Danielle M. Boselli, James T. Symanowski, Scott P. Lankford, Robert J. McCammon, Benjamin J. Moeller, John H. Heinzerling, Carolina E. Fasola, Stuart H. Burri, Kirtesh R. Patel, Anthony L. Asher, Ashley L. Sumrall, Walter J. Curran, Hui-Kuo G. Shu, Ian R. Crocker, Roshan S. Prabhu
BackgroundA scoring system using pretreatment factors was recently published for predicting the risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm³, with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population.MethodsWe reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence.ResultsThe low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm³ (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53).ConclusionThe 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted.



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Miscalculations can lead to misinterpretation of the results

Publication date: Available online 30 May 2017
Source:Cancer Epidemiology
Author(s): Leena Derwish




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Integration Pattern of Human Papillomavirus Is a Strong Prognostic Factor for Disease-Free Survival After Radiation Therapy in Cervical Cancer Patients

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Jungnam Joo, Hye-Jin Shin, Boram Park, Seog-Yun Park, Chong-Woo Yoo, Kyong-Ah Yoon, Sun-Young Kong, Youn-Jae Kim, Sang Soo Kim, Joo-Young Kim
PurposeThe standard chemoradiation therapy currently used for locally advanced cervical cancer (LACC) patients does not reflect the biological heterogeneity of this disease, and there is an increasing need for the development of biomarkers that can help guide the individualized treatment regimens. The purpose of this study was to investigate the prognostic value of the integration pattern of human papillomavirus (HPV) in LACC patients.Methods and MaterialsThe HPV integration pattern was determined by in situ hybridization and polymerase chain reaction, and the tumors were classified as the episomal pattern (group A), as the single-copy integrated or multicopy tandem repetition–integrated pattern (group B), or as undetectable HPV (group C). Ninety-eight LACC patients were included in a development dataset and 106 independent patients in a validation dataset. The multivariate Cox model was used to examine the effect of the HPV integration pattern on disease-free survival (DFS). The model was validated internally by the leave-one-out cross-validation method and externally by an independent dataset.ResultsAfter adjustment for significant prognostic factors (stage, histologic grade, histologic type, and tumor size), the HPV integration pattern was significantly associated with DFS in the development (P=.032) and validation (P=.023) datasets. Survival was worst in group C and best in group A. The multivariate model with HPV integration pattern as an explanatory variable showed good discrimination ability and could separate patients with different risk profiles.ConclusionsThis study identified the HPV integration pattern, as determined by in situ hybridization and polymerase chain reaction, as a strong prognostic biomarker for DFS in LACC patients treated by chemoradiation therapy. This finding may open the possibility of personalized treatment of these patients.



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Radiobiology and the Renewed Potential for Nanoparticles

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Brian Marples, Shanta Dhar




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Prostate-Specific Membrane Antigen PET Before Aggressive Local Therapy to the Sternum

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Shankar Siva




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Issue Highlights

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3





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Sternum First, Perhaps Pelvis Later

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Brian J. Davis, Sean S. Park




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Long-Term Survival Analysis of Stereotactic Ablative Radiotherapy Versus Liver Resection for Small Hepatocellular Carcinoma

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Ting-Shi Su, Ping Liang, Jian Liang, Huan-Zhen Lu, Hua-Yan Jiang, Tao Cheng, Yong Huang, Yang Tang, Xin Deng
PurposeTo compare the efficacy of stereotactic ablative radiation therapy (SABR) versus liver resection for small hepatocellular carcinoma (HCC) ≤5 cm with Child-Pugh A cirrhosis.Methods and MaterialsThis retrospective study included 117 patients with small HCCs with 1 or 2 nodules. Eighty-two patients received SABR (SABR group), and 35 patients underwent liver resection (resection group). Overall survival (OS) and progression-free survival (PFS) were analyzed. One-to-one matched pairs between the 2 groups were created using propensity score matching to reduce the potential confounding effect of treatment and selection bias.ResultsThere was no between-group difference in OS and PFS. Before propensity score matching, the 1-, 3-, and 5-year OS was 96.3%, 81.8%, and 70.0% in the SABR group and 93.9%, 83.1%, and 64.4% in the resection group, respectively (P=.558). The 1-, 3- and 5-year PFS was 81.4%, 50.2%, and 40.7% in the SABR group and 68.0%, 58.3%, and 40.3% in the resection group, respectively (P=.932). After propensity score matching, 33 paired patients were selected from the SABR and resection groups. The 1-, 3-, and 5-year OS was 100%, 91.8%, and 74.3% in the SABR group and 96.7%, 89.3%, and 69.2% in the resection group, respectively (P=.405). The 1-, 3-, and 5-year PFS was 84.4%, 59.2%, and 43.9% in the SABR group and 69.0%, 62.4%, and 35.9% in the resection group, respectively (P=.945). There was a similarity of hepatotoxicity between the 2 groups. The SABR group showed fewer complications, such as hepatic hemorrhage, hepatic pain, and weight loss. Acute nausea was significantly more frequent in the SABR group than in the resection group.ConclusionFor patients with small primary HCC with 1 or 2 nodules and Child-Pugh A cirrhosis, SABR has local effects that are similar to those with liver resection. Stereotactic ablative radiation therapy has an advantage over resection in being less invasive.



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Advancing Our Practice Through the Advanced Practice Radiation Therapist Model: Catching Up With Canada

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Neha Vapiwala, Meredith Giuliani, Nicole Harnett




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Conservative Treatments of Ocular Melanomas: Technology Used Wisely

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Juliette Thariat, Joel Herault, Frederic Mouriaux




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In Reply to Peñagarícano

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Oliver Micke, M. Heinrich Seegenschmiedt, Irenaeus A. Adamietz, Guenter Kundt, Khashayar Fakhrian, Ulrich Schaefer, Ralph Muecke




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Radiation Therapy in Palestine: Not Only Money, But Also Real Accessibility

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Maurizio Portaluri, Niveen Abu-Rmeileh, Emilio Gianicolo




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Is It Time for New Target Volumes in Radiation Oncology?

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): David Palma




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Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Shulian Wang, Jeff Campbell, Matthew H. Stenmark, Jing Zhao, Paul Stanton, Martha M. Matuszak, Randall K. Ten Haken, Feng-Ming (Spring) Kong
Purpose and ObjectivesWe previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-β1 (TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines.Methods and MaterialsOne hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment.ResultsSixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone.ConclusionsWe validated that a combination of mean lung dose, pre IL-8 level, and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone.



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Directly Improving the Quality of Radiation Treatment Through Peer Review: A Cross-sectional Analysis of Cancer Centers Across a Provincial Cancer Program

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Julie Rouette, Eric Gutierrez, Jennifer O'Donnell, Lindsay Reddeman, Margaret Hart, Sophie Foxcroft, Gunita Mitera, Padraig Warde, Michael D. Brundage
PurposeTo describe the outcomes of peer review across all 14 cancer centers in Ontario.Methods and MaterialsWe identified all peer-reviewed, curative treatment plans delivered in Ontario within a 3-month study period from 2013 to 2014 using a provincial cancer treatment database and collected additional data on the peer-review outcomes.ResultsConsiderable variation was found in the proportion of peer-reviewed plans across the centers (average 70.2%, range 40.8%-99.2%). During the study period, 5561 curative plans underwent peer review. Of those, 184 plans (3.3%) had changes recommended. Of the 184 plans, the changes were major (defined as requiring repeat planning or having a major effect on planning or clinical outcomes, or both) in 40.2% and minor in 47.8%. For the remaining 12.0%, data were missing. The proportions of recommended changes varied among disease sites (0.0%-7.0%). The disease sites with the most recommended changes to treatment plans after peer review and with the greatest potential for benefit were the esophagus (7.0%), uterus (6.7%), upper limb (6.3%), cervix and lower limb (both 6.0%), head and neck and bilateral lung (both 5.9%), right supraclavicular lymph nodes (5.7%), rectum (5.3%), and spine (5.0%). Although the heart is an organ at risk in left-sided breast treatment plans, the proportions of recommended changes did not significantly differ between the left breast treatment plans (3.0%, 95% confidence interval 2.0%-4.5%) and right breast treatment plans (2.4%, 95% confidence interval 1.5%-3.8%). The recommended changes were more frequently made when peer review occurred before radiation therapy (3.8%) than during treatment (1.4%-2.8%; P=.0048). The proportion of plans with recommended changes was not significantly associated with patient volume (P=.23), peer-review performance (P=.36), or center academic status (P=.75).ConclusionsPeer review of treatment plans directly affects the quality of care by identifying important clinical and planning changes. Provincial strategies are underway to optimize its conduct in radiation oncology.



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Miscalculations can lead to misinterpretation of the results

Publication date: Available online 30 May 2017
Source:Cancer Epidemiology
Author(s): Leena Derwish




http://ift.tt/2skuHm2

Incidence and survival of childhood cancer in the French islands of Reunion and Mayotte (2005–2011)

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): J. Ramiandrisoa, M. Jehanne, F. Sauvat, Y. Reguerre, A. Chamouine, E. Chirpaz
The aim of this study is to describe childhood cancer incidence and survival in the French islands of Reunion and Mayotte for the period 2005–2011. Data were taken from the population-based Cancer Registry of Reunion Island. All incident cases of malignant tumours and benign tumours of the Central Nervous System diagnosed between 2005 and 2011 in children under the age of 15 and living in Reunion or Mayotte were included. A total of 236 cases were registered (176 in Reunion, 60 in Mayotte). Age-standardised incidence rates (ASRs, world standard) for all cancers were 125.0 and 101.8 per million for Reunion and Mayotte, respectively. ASRs for the main cancer groups were lower than those described in mainland France for the same period. The 5-year overall survival rate for all patients was 78.5% (95%CI 71.9- 83.7), slightly lower than that reported in mainland France.



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Integration Pattern of Human Papillomavirus Is a Strong Prognostic Factor for Disease-Free Survival After Radiation Therapy in Cervical Cancer Patients

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Jungnam Joo, Hye-Jin Shin, Boram Park, Seog-Yun Park, Chong-Woo Yoo, Kyong-Ah Yoon, Sun-Young Kong, Youn-Jae Kim, Sang Soo Kim, Joo-Young Kim
PurposeThe standard chemoradiation therapy currently used for locally advanced cervical cancer (LACC) patients does not reflect the biological heterogeneity of this disease, and there is an increasing need for the development of biomarkers that can help guide the individualized treatment regimens. The purpose of this study was to investigate the prognostic value of the integration pattern of human papillomavirus (HPV) in LACC patients.Methods and MaterialsThe HPV integration pattern was determined by in situ hybridization and polymerase chain reaction, and the tumors were classified as the episomal pattern (group A), as the single-copy integrated or multicopy tandem repetition–integrated pattern (group B), or as undetectable HPV (group C). Ninety-eight LACC patients were included in a development dataset and 106 independent patients in a validation dataset. The multivariate Cox model was used to examine the effect of the HPV integration pattern on disease-free survival (DFS). The model was validated internally by the leave-one-out cross-validation method and externally by an independent dataset.ResultsAfter adjustment for significant prognostic factors (stage, histologic grade, histologic type, and tumor size), the HPV integration pattern was significantly associated with DFS in the development (P=.032) and validation (P=.023) datasets. Survival was worst in group C and best in group A. The multivariate model with HPV integration pattern as an explanatory variable showed good discrimination ability and could separate patients with different risk profiles.ConclusionsThis study identified the HPV integration pattern, as determined by in situ hybridization and polymerase chain reaction, as a strong prognostic biomarker for DFS in LACC patients treated by chemoradiation therapy. This finding may open the possibility of personalized treatment of these patients.



http://ift.tt/2skzJ23

Radiobiology and the Renewed Potential for Nanoparticles

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Brian Marples, Shanta Dhar




http://ift.tt/2r9v6Kf

Prostate Cancer With Isolated Bony Metastasis: Sternal Struggle

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Mark T. Corkum




http://ift.tt/2qEgbo1

Treatment-Related Toxicity in Patients With Early-Stage Non-Small Cell Lung Cancer and Coexisting Interstitial Lung Disease: A Systematic Review

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Hanbo Chen, Suresh Senan, Esther J. Nossent, R. Gabriel Boldt, Andrew Warner, David A. Palma, Alexander V. Louie
PurposeDefinitive treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC) is usually well tolerated. Patients with ES-NSCLC and coexisting interstitial lung disease (ILD) are at increased risk of severe treatment-related toxicity after definitive therapy. The main objective of this systematic review is to provide a pooled estimation of treatment-related mortality and ILD-specific toxicity in this population of patients and to identify trends for further study.Methods and MaterialsThe MEDLINE and Embase databases were queried from respective dates of inception to January 2016. Studies that included patients who underwent definitive treatment for ES-NSCLC not combined with other treatments were included. Patients with oligometastases who were treated with aggressive palliation were included if it did not constitute the majority of patients in a specific study. The results were summarized with weighted proportions according to the sample size of individual studies.ResultsOverall, 3056 records were reviewed and 50 journal articles were included in the abstraction. The weighted proportion of treatment-related mortality (and ILD-specific toxicity) in primarily medically inoperable patients was as follows: stereotactic ablative radiation therapy (SABR) 15.6% (25%), particle beam therapy 4.3% (18.2%) and radiofrequency ablation (RFA) 8.7% (25%). The data for medically operable patients who underwent surgery were extracted for reference. Treatment-related mortality and ILD-specific toxicity were 2.2% and 12%, respectively, in the surgical population. On analysis of reported SABR dose parameters, V20 ≤ 6.5% and mean lung dose ≤4.5 Gy were found to be metrics associated with reduced mortality.ConclusionA consistently high level of treatment-related mortality and ILD-specific toxicity was observed in primarily medically inoperable patients treated with SABR, particle beam therapy, and RFA. For these patients, curative treatment should be considered in the context of the high toxicity rates and overall poor prognosis. Stringent radiation dosimetric parameters may result in reduced toxicity.



http://ift.tt/2qElNOU

Treat All Known Disease

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Peter J. Hoskin




http://ift.tt/2r9uDIa

Prostate-Specific Membrane Antigen PET Before Aggressive Local Therapy to the Sternum

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Shankar Siva




http://ift.tt/2qEx7e1

Intriguing, but Not the Right Setting

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Kevin L. Stephans, Rupesh Kotecha




http://ift.tt/2r9r0BU

Issue Highlights

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3





http://ift.tt/2qEm04T

Sternum First, Perhaps Pelvis Later

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Brian J. Davis, Sean S. Park




http://ift.tt/2qEkBeA

Long-Term Survival Analysis of Stereotactic Ablative Radiotherapy Versus Liver Resection for Small Hepatocellular Carcinoma

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Ting-Shi Su, Ping Liang, Jian Liang, Huan-Zhen Lu, Hua-Yan Jiang, Tao Cheng, Yong Huang, Yang Tang, Xin Deng
PurposeTo compare the efficacy of stereotactic ablative radiation therapy (SABR) versus liver resection for small hepatocellular carcinoma (HCC) ≤5 cm with Child-Pugh A cirrhosis.Methods and MaterialsThis retrospective study included 117 patients with small HCCs with 1 or 2 nodules. Eighty-two patients received SABR (SABR group), and 35 patients underwent liver resection (resection group). Overall survival (OS) and progression-free survival (PFS) were analyzed. One-to-one matched pairs between the 2 groups were created using propensity score matching to reduce the potential confounding effect of treatment and selection bias.ResultsThere was no between-group difference in OS and PFS. Before propensity score matching, the 1-, 3-, and 5-year OS was 96.3%, 81.8%, and 70.0% in the SABR group and 93.9%, 83.1%, and 64.4% in the resection group, respectively (P=.558). The 1-, 3- and 5-year PFS was 81.4%, 50.2%, and 40.7% in the SABR group and 68.0%, 58.3%, and 40.3% in the resection group, respectively (P=.932). After propensity score matching, 33 paired patients were selected from the SABR and resection groups. The 1-, 3-, and 5-year OS was 100%, 91.8%, and 74.3% in the SABR group and 96.7%, 89.3%, and 69.2% in the resection group, respectively (P=.405). The 1-, 3-, and 5-year PFS was 84.4%, 59.2%, and 43.9% in the SABR group and 69.0%, 62.4%, and 35.9% in the resection group, respectively (P=.945). There was a similarity of hepatotoxicity between the 2 groups. The SABR group showed fewer complications, such as hepatic hemorrhage, hepatic pain, and weight loss. Acute nausea was significantly more frequent in the SABR group than in the resection group.ConclusionFor patients with small primary HCC with 1 or 2 nodules and Child-Pugh A cirrhosis, SABR has local effects that are similar to those with liver resection. Stereotactic ablative radiation therapy has an advantage over resection in being less invasive.



http://ift.tt/2qEsfG1

Advancing Our Practice Through the Advanced Practice Radiation Therapist Model: Catching Up With Canada

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Neha Vapiwala, Meredith Giuliani, Nicole Harnett




http://ift.tt/2r9y3uy

Conservative Treatments of Ocular Melanomas: Technology Used Wisely

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Juliette Thariat, Joel Herault, Frederic Mouriaux




http://ift.tt/2qEvDQR

In Reply to Peñagarícano

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Oliver Micke, M. Heinrich Seegenschmiedt, Irenaeus A. Adamietz, Guenter Kundt, Khashayar Fakhrian, Ulrich Schaefer, Ralph Muecke




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Radiation Therapy in Palestine: Not Only Money, But Also Real Accessibility

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Maurizio Portaluri, Niveen Abu-Rmeileh, Emilio Gianicolo




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Is It Time for New Target Volumes in Radiation Oncology?

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): David Palma




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Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Shulian Wang, Jeff Campbell, Matthew H. Stenmark, Jing Zhao, Paul Stanton, Martha M. Matuszak, Randall K. Ten Haken, Feng-Ming (Spring) Kong
Purpose and ObjectivesWe previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-β1 (TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines.Methods and MaterialsOne hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment.ResultsSixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone.ConclusionsWe validated that a combination of mean lung dose, pre IL-8 level, and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone.



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Directly Improving the Quality of Radiation Treatment Through Peer Review: A Cross-sectional Analysis of Cancer Centers Across a Provincial Cancer Program

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Julie Rouette, Eric Gutierrez, Jennifer O'Donnell, Lindsay Reddeman, Margaret Hart, Sophie Foxcroft, Gunita Mitera, Padraig Warde, Michael D. Brundage
PurposeTo describe the outcomes of peer review across all 14 cancer centers in Ontario.Methods and MaterialsWe identified all peer-reviewed, curative treatment plans delivered in Ontario within a 3-month study period from 2013 to 2014 using a provincial cancer treatment database and collected additional data on the peer-review outcomes.ResultsConsiderable variation was found in the proportion of peer-reviewed plans across the centers (average 70.2%, range 40.8%-99.2%). During the study period, 5561 curative plans underwent peer review. Of those, 184 plans (3.3%) had changes recommended. Of the 184 plans, the changes were major (defined as requiring repeat planning or having a major effect on planning or clinical outcomes, or both) in 40.2% and minor in 47.8%. For the remaining 12.0%, data were missing. The proportions of recommended changes varied among disease sites (0.0%-7.0%). The disease sites with the most recommended changes to treatment plans after peer review and with the greatest potential for benefit were the esophagus (7.0%), uterus (6.7%), upper limb (6.3%), cervix and lower limb (both 6.0%), head and neck and bilateral lung (both 5.9%), right supraclavicular lymph nodes (5.7%), rectum (5.3%), and spine (5.0%). Although the heart is an organ at risk in left-sided breast treatment plans, the proportions of recommended changes did not significantly differ between the left breast treatment plans (3.0%, 95% confidence interval 2.0%-4.5%) and right breast treatment plans (2.4%, 95% confidence interval 1.5%-3.8%). The recommended changes were more frequently made when peer review occurred before radiation therapy (3.8%) than during treatment (1.4%-2.8%; P=.0048). The proportion of plans with recommended changes was not significantly associated with patient volume (P=.23), peer-review performance (P=.36), or center academic status (P=.75).ConclusionsPeer review of treatment plans directly affects the quality of care by identifying important clinical and planning changes. Provincial strategies are underway to optimize its conduct in radiation oncology.



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External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Robert H. Press, Danielle M. Boselli, James T. Symanowski, Scott P. Lankford, Robert J. McCammon, Benjamin J. Moeller, John H. Heinzerling, Carolina E. Fasola, Stuart H. Burri, Kirtesh R. Patel, Anthony L. Asher, Ashley L. Sumrall, Walter J. Curran, Hui-Kuo G. Shu, Ian R. Crocker, Roshan S. Prabhu
BackgroundA scoring system using pretreatment factors was recently published for predicting the risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm³, with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population.MethodsWe reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence.ResultsThe low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm³ (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53).ConclusionThe 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted.



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The HGF/c-MET pathway is a driver and biomarker of VEGFR-inhibitor resistance and vascular remodeling in non-small cell lung cancer.

Purpose: Resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors.<br /><br />Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes.<br /><br />Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In cancer patients receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. <br /><br />Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor-resistance and vascular remodeling in NSCLC.

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Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis

Purpose: We determined if quantifying neuroblastoma (NB)-associated mRNAs (NB-mRNA) in bone marrow (BM) and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory NB. <br /><br />Patients and Methods: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in BM and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold [Ct] for the geometric mean of genes from the TaqMan® Low Density Array NB5 assay) and morphologically-defined tumor cell percentage in BM, ¹²³I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between DCt and progression-free survival (PFS). <br /><br />Results: NB-mRNA was detectable in 83% of BM (185/223) and 63% (89/142) of blood specimens, and their DCts were correlated (Spearman r=0.67, p<0.0001) although BM Ct was 7.9±0.5 Ct stronger than blood Ct. When BM morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of BMs. When all three were negative, NB-mRNA was detected in 55% (11/20) of BMs. BM NB-mRNA correlated with BM morphology or MIBG positivity (p<0.0001 and p=0.007). BM and blood Cts correlated with PFS (p<0.001; p=0.001) even when BM was morphologically negative (p=0.001; p=0.014). Multivariate analysis showed that BM and blood Cts were associated with PFS independently of clinical disease and MYCN gene status (p<0.001; p=0.055). <br /><br />Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory NB.

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The HGF/c-MET pathway is a driver and biomarker of VEGFR-inhibitor resistance and vascular remodeling in non-small cell lung cancer.

Purpose: Resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors.<br /><br />Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes.<br /><br />Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In cancer patients receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. <br /><br />Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor-resistance and vascular remodeling in NSCLC.

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Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis

Purpose: We determined if quantifying neuroblastoma (NB)-associated mRNAs (NB-mRNA) in bone marrow (BM) and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory NB. <br /><br />Patients and Methods: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in BM and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold [Ct] for the geometric mean of genes from the TaqMan® Low Density Array NB5 assay) and morphologically-defined tumor cell percentage in BM, ¹²³I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between DCt and progression-free survival (PFS). <br /><br />Results: NB-mRNA was detectable in 83% of BM (185/223) and 63% (89/142) of blood specimens, and their DCts were correlated (Spearman r=0.67, p<0.0001) although BM Ct was 7.9±0.5 Ct stronger than blood Ct. When BM morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of BMs. When all three were negative, NB-mRNA was detected in 55% (11/20) of BMs. BM NB-mRNA correlated with BM morphology or MIBG positivity (p<0.0001 and p=0.007). BM and blood Cts correlated with PFS (p<0.001; p=0.001) even when BM was morphologically negative (p=0.001; p=0.014). Multivariate analysis showed that BM and blood Cts were associated with PFS independently of clinical disease and MYCN gene status (p<0.001; p=0.055). <br /><br />Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory NB.

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Findings May Lead to New Strategies for GVHD [News in Brief]

A study in mice suggests that activating the RIG-I and STING signaling pathways has a protective effect on the gut.

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Basal subtype is predictive for response to cetuximab treatment in patient derived xenografts of squamous cell head and neck cancer

Abstract

Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after three weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs BA 0.78 (MS vs BA, unpaired t test p0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient derived xenografts. This article is protected by copyright. All rights reserved.

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Risk Stratification and Long-term Risk Prediction of E6 Oncoprotein in a Prospective Screening Cohort in China

Abstract

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five-year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA), and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five and ten year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and ten year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only approximately 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year ten, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (OR_adjusted=40.0 and 21.2 respectively). E6 oncoprotein can serve as a low-cost, highly specific, strongly indicative point-of-care method in the triage and treatment of HPV positive women. This article is protected by copyright. All rights reserved.

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What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients

Abstract

We asked what preoperative radiotherapy/chemoradiotherapy (PRT/PCRT) has brought to patients in terms of perioperative and long-term outcomes over the past decades. A systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to PRT/PCRT and surgical resection and which analyzed survival, postoperative and quality of life outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. Data from 106 comparative studies based on 80 different trials enrolling 41,121 patients were included in our study. Based on our overall analyses, PRT/PCRT significantly improved patients' local recurrence-free survival (LRFS), but neither overall survival (OS) nor metastasis-free survival (MFS) showed improvement. In addition, PRT significantly increased the postoperative morbidity and mortality but PCRT did not have a significant effect. Furthermore, PRT/PCRT significantly increased the risk of postoperative wound complications but not anastomotic leakage and bowel obstruction. Our comprehensive subgroup analyses further supported the aforementioned results. Meanwhile, long-term anorectal symptoms (impaired squeeze pressures, use of pads, incontinence and urgency) and erectile dysfunction were also significantly increased in patients after PRT/PCRT. The benefits of PRT/PCRT as applied over the last several decades have not been sufficient to improve OS. Metastases of primary tumor and postoperative adverse effects were the two primary obstacles for an improved OS. In fact, the greatest advantage of PRT/PCRT is still local tumor control and a significantly improved LRFS. This article is protected by copyright. All rights reserved.

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Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

Abstract

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin, or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group versus chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, P < 0.001) and 0.48 (95% CI, 0.29–0.78, P = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group, and the gefitinib group was 82.5%, 32.5%, and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, P = 0.016) or gefitinib (HR = 0.36, P = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations. This article is protected by copyright. All rights reserved.

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Basal subtype is predictive for response to cetuximab treatment in patient derived xenografts of squamous cell head and neck cancer

Abstract

Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after three weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs BA 0.78 (MS vs BA, unpaired t test p0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient derived xenografts. This article is protected by copyright. All rights reserved.

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Risk Stratification and Long-term Risk Prediction of E6 Oncoprotein in a Prospective Screening Cohort in China

Abstract

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five-year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA), and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five and ten year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and ten year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only approximately 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year ten, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (OR_adjusted=40.0 and 21.2 respectively). E6 oncoprotein can serve as a low-cost, highly specific, strongly indicative point-of-care method in the triage and treatment of HPV positive women. This article is protected by copyright. All rights reserved.

http://ift.tt/2rSLbFq

What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients

Abstract

We asked what preoperative radiotherapy/chemoradiotherapy (PRT/PCRT) has brought to patients in terms of perioperative and long-term outcomes over the past decades. A systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to PRT/PCRT and surgical resection and which analyzed survival, postoperative and quality of life outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. Data from 106 comparative studies based on 80 different trials enrolling 41,121 patients were included in our study. Based on our overall analyses, PRT/PCRT significantly improved patients' local recurrence-free survival (LRFS), but neither overall survival (OS) nor metastasis-free survival (MFS) showed improvement. In addition, PRT significantly increased the postoperative morbidity and mortality but PCRT did not have a significant effect. Furthermore, PRT/PCRT significantly increased the risk of postoperative wound complications but not anastomotic leakage and bowel obstruction. Our comprehensive subgroup analyses further supported the aforementioned results. Meanwhile, long-term anorectal symptoms (impaired squeeze pressures, use of pads, incontinence and urgency) and erectile dysfunction were also significantly increased in patients after PRT/PCRT. The benefits of PRT/PCRT as applied over the last several decades have not been sufficient to improve OS. Metastases of primary tumor and postoperative adverse effects were the two primary obstacles for an improved OS. In fact, the greatest advantage of PRT/PCRT is still local tumor control and a significantly improved LRFS. This article is protected by copyright. All rights reserved.

http://ift.tt/2qzfY6j

Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

Abstract

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin, or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group versus chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, P < 0.001) and 0.48 (95% CI, 0.29–0.78, P = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group, and the gefitinib group was 82.5%, 32.5%, and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, P = 0.016) or gefitinib (HR = 0.36, P = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations. This article is protected by copyright. All rights reserved.

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Epithelial-to-mesenchymal transition in tumor progression

Abstract

The epithelial-to-mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal state with invasive capacities. However, the EMT program is involved in both physiological and pathological processes. Cancer-associated EMT is known to contribute to increase invasiveness and metastasis, resistance to therapies, and generation of cell populations with stem cell-like characteristics and therefore is deeply involved in tumor progression. This process is finely orchestrated by multiple signaling pathways and regulatory transcriptional networks. The hallmark of EMT is the loss of epithelial surface markers, mainly E-cadherin, and the acquisition of mesenchymal phenotype. These events can be mediated by EMT transcription factors which can cooperate with several enzymes to repress the E-cadherin expression and regulate EMT at the epigenetic and post-translational level. A growing body of evidence indicates that cancer cells can reside in various phenotypic states along the EMT spectrum, where cells can jointly retain epithelial traits with mesenchymal ones. This type of phenotypic plasticity endows cancer cells with tumor-initiating potential. The identification of the signaling pathways and modulators that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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Epithelial-to-mesenchymal transition in tumor progression

Abstract

The epithelial-to-mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal state with invasive capacities. However, the EMT program is involved in both physiological and pathological processes. Cancer-associated EMT is known to contribute to increase invasiveness and metastasis, resistance to therapies, and generation of cell populations with stem cell-like characteristics and therefore is deeply involved in tumor progression. This process is finely orchestrated by multiple signaling pathways and regulatory transcriptional networks. The hallmark of EMT is the loss of epithelial surface markers, mainly E-cadherin, and the acquisition of mesenchymal phenotype. These events can be mediated by EMT transcription factors which can cooperate with several enzymes to repress the E-cadherin expression and regulate EMT at the epigenetic and post-translational level. A growing body of evidence indicates that cancer cells can reside in various phenotypic states along the EMT spectrum, where cells can jointly retain epithelial traits with mesenchymal ones. This type of phenotypic plasticity endows cancer cells with tumor-initiating potential. The identification of the signaling pathways and modulators that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1-expression: a pilot study

Abstract

Melanocytic BAP1-associated intradermal tumors (MBAITs) can either be sporadic or associated with a cancer-predisposition syndrome. In this study we explored the clinical status of 136 patients in which at least one MBAIT was found. 49/136 (36%) of them gave their signed consent for an oncogenetic BAP1 blood test. 28/136 patients (20%) diagnosed with an MBAIT had other MBAITs and/or a personal or familial history of BAP1-related cancers that could clinically designate them as potential carriers of a BAP1 germline mutation. 17 of these 28 patients underwent oncogenetic testing. A deleterious mutation of BAP1 was confirmed in 12/17 cases. 4/17 cases were wild-type; all had a single MBAIT and a history of skin melanoma. A variant of unknown significance was found in one case with multiple MBAITs. Among the 12 mutated cases, multiple MBAITs were present in 10/12 cases and were the only clinical sign in 4/12 cases. The remaining 32/49 blood-tested cases with an isolated MBAIT were wild type for BAP1 in 25/32 cases or showed a variant of unknown significance in 7/32 cases. We recommend, following the diagnosis of a MBAIT, performing a BAP1 immunohistochemistry in all other cutaneous melanocytic tumors removed previously or simultaneously and all skin melanomas. This screening could help clinicians prioritize which patients would most benefit from oncogenetic testing. This article is protected by copyright. All rights reserved.

http://ift.tt/2rCs6Yt

Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1-expression: a pilot study

Abstract

Melanocytic BAP1-associated intradermal tumors (MBAITs) can either be sporadic or associated with a cancer-predisposition syndrome. In this study we explored the clinical status of 136 patients in which at least one MBAIT was found. 49/136 (36%) of them gave their signed consent for an oncogenetic BAP1 blood test. 28/136 patients (20%) diagnosed with an MBAIT had other MBAITs and/or a personal or familial history of BAP1-related cancers that could clinically designate them as potential carriers of a BAP1 germline mutation. 17 of these 28 patients underwent oncogenetic testing. A deleterious mutation of BAP1 was confirmed in 12/17 cases. 4/17 cases were wild-type; all had a single MBAIT and a history of skin melanoma. A variant of unknown significance was found in one case with multiple MBAITs. Among the 12 mutated cases, multiple MBAITs were present in 10/12 cases and were the only clinical sign in 4/12 cases. The remaining 32/49 blood-tested cases with an isolated MBAIT were wild type for BAP1 in 25/32 cases or showed a variant of unknown significance in 7/32 cases. We recommend, following the diagnosis of a MBAIT, performing a BAP1 immunohistochemistry in all other cutaneous melanocytic tumors removed previously or simultaneously and all skin melanomas. This screening could help clinicians prioritize which patients would most benefit from oncogenetic testing. This article is protected by copyright. All rights reserved.

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Towards standardization of 18 F-FET PET imaging: do we need a consistent method of background activity assessment?

Abstract

Background

PET with O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical ¹⁸F-FET PET reading.

The background activity of 20 ¹⁸F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans.

Results

Compared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more.

Conclusions

The commonly applied methods for background activity assessment show different variability which might hamper ¹⁸F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines.

http://ift.tt/2rSTRMe

Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using 111 In-bevacizumab

Abstract

Background

The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of ¹¹¹In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin.

Specificity of ¹¹¹In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of ¹¹¹In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody (¹¹¹In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of ¹¹¹In-bevacizumab in comparison to ¹¹¹In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy.

Results

Specific uptake of ¹¹¹In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of ¹¹¹In-bevacizumab (68%) but not ¹¹¹In-IgGκ and corresponded with increased intratumoural VEGF₁₆₅.

Conclusions

¹¹¹In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects.

http://ift.tt/2qzbfl9

Towards standardization of 18 F-FET PET imaging: do we need a consistent method of background activity assessment?

Abstract

Background

PET with O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical ¹⁸F-FET PET reading.

The background activity of 20 ¹⁸F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans.

Results

Compared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more.

Conclusions

The commonly applied methods for background activity assessment show different variability which might hamper ¹⁸F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines.

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Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using 111 In-bevacizumab

Abstract

Background

The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of ¹¹¹In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin.

Specificity of ¹¹¹In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of ¹¹¹In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody (¹¹¹In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of ¹¹¹In-bevacizumab in comparison to ¹¹¹In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy.

Results

Specific uptake of ¹¹¹In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of ¹¹¹In-bevacizumab (68%) but not ¹¹¹In-IgGκ and corresponded with increased intratumoural VEGF₁₆₅.

Conclusions

¹¹¹In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects.

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Malignant Struma ovarii in a 30-year old nulliparous patient

Abstract

Background

Struma ovarii is a rare monodermal germ cell tumor where the ovary is comprised of at least half thyroid tissue. This phenomenon may indicate an embryological origin.

Case presentation

A 30-year old nulliparous woman presented with acute right lower quadrant pain and underwent laparoscopic right salpingo-oophorectomy. The excised ovarian mass showed evidence of struma-derived papillary thyroid carcinoma. Ultrasound of the thyroid showed mild enlargement with two solid nodules. A fine needle aspirate of a thyroid nodule was positive for malignancy and a total thyroidectomy was performed. Microscopic features of the thyroid were consistent with papillary thyroid carcinoma. The two tumours were considered as synchronous independent primaries based on their histological presentation.

Conclusions

We believe that aggressive surgical management followed by radioiodine therapy is best to reduce recurrence risk and optimize survival. The broad scope of interventions needed to treat malignant struma ovarii require a strong interdisciplinary team.

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Malignant Struma ovarii in a 30-year old nulliparous patient

Abstract

Background

Struma ovarii is a rare monodermal germ cell tumor where the ovary is comprised of at least half thyroid tissue. This phenomenon may indicate an embryological origin.

Case presentation

A 30-year old nulliparous woman presented with acute right lower quadrant pain and underwent laparoscopic right salpingo-oophorectomy. The excised ovarian mass showed evidence of struma-derived papillary thyroid carcinoma. Ultrasound of the thyroid showed mild enlargement with two solid nodules. A fine needle aspirate of a thyroid nodule was positive for malignancy and a total thyroidectomy was performed. Microscopic features of the thyroid were consistent with papillary thyroid carcinoma. The two tumours were considered as synchronous independent primaries based on their histological presentation.

Conclusions

We believe that aggressive surgical management followed by radioiodine therapy is best to reduce recurrence risk and optimize survival. The broad scope of interventions needed to treat malignant struma ovarii require a strong interdisciplinary team.

http://ift.tt/2rhCXnu

Comparison of glass slides and various digital-slide modalities for cytopathology screening and interpretation

BACKGROUND

Whole-slide imaging in cytology is limited when glass slides are digitized without z-stacks for focusing. Different vendors have started to provide z-stacking solutions to overcome this limitation. The Panoptiq imaging system allows users to create digital files combining low-magnification panoramic images with regions of interest (ROIs) that are imaged with high-magnification z-stacks. The aim of this study was to compare such panoramic images with conventional whole-slide images and glass slides for the tasks of screening and interpretation in cytopathology.

METHODS

Thirty glass slides, including 10 ThinPrep Papanicolaou tests and 20 nongynecologic cytology cases, were digitized with an Olympus BX45 integrated microscope with an attached Prosilica GT camera. ViewsIQ software was used for image acquisition and viewing. These glass slides were also scanned on an Aperio ScanScope XT at ×40 (0.25 μm/pixel) with 1 z-plane and were viewed with ImageScope software. Digital and glass sides were screened and dotted/annotated by a cytotechnologist and were subsequently reviewed by 3 cytopathologists. For panoramic images, the cytotechnologist manually created digital maps and selected representative ROIs to generate z-stacks at a higher magnification. After 3-week washout periods, panoramic images were compared with Aperio digital slides and glass slides.

RESULTS

The Panoptiq system permitted fine focusing of thick smears and cell clusters. In comparison with glass slides, the average screening times were 5.5 and 1.8 times longer with Panoptiq and Aperio images, respectively, but this improved with user experience. There was no statistical difference in diagnostic concordance between all 3 modalities. Users' diagnostic confidence was also similar for all modalities.

CONCLUSIONS

The Aperio whole-slide scanner with 1 z-plane scanning and the Panoptiq imaging system with z-stacking are both suitable for cytopathology screening and interpretation. However, ROI z-stacks do offer a superior mechanism for overcoming focusing problems commonly encountered with digital cytology slides. Unlike whole-slide imaging, the acquisition of representative z-stack images with the Panoptiq system requires a trained cytologist to create digital files. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2rlua6m

Comparison of glass slides and various digital-slide modalities for cytopathology screening and interpretation

BACKGROUND

Whole-slide imaging in cytology is limited when glass slides are digitized without z-stacks for focusing. Different vendors have started to provide z-stacking solutions to overcome this limitation. The Panoptiq imaging system allows users to create digital files combining low-magnification panoramic images with regions of interest (ROIs) that are imaged with high-magnification z-stacks. The aim of this study was to compare such panoramic images with conventional whole-slide images and glass slides for the tasks of screening and interpretation in cytopathology.

METHODS

Thirty glass slides, including 10 ThinPrep Papanicolaou tests and 20 nongynecologic cytology cases, were digitized with an Olympus BX45 integrated microscope with an attached Prosilica GT camera. ViewsIQ software was used for image acquisition and viewing. These glass slides were also scanned on an Aperio ScanScope XT at ×40 (0.25 μm/pixel) with 1 z-plane and were viewed with ImageScope software. Digital and glass sides were screened and dotted/annotated by a cytotechnologist and were subsequently reviewed by 3 cytopathologists. For panoramic images, the cytotechnologist manually created digital maps and selected representative ROIs to generate z-stacks at a higher magnification. After 3-week washout periods, panoramic images were compared with Aperio digital slides and glass slides.

RESULTS

The Panoptiq system permitted fine focusing of thick smears and cell clusters. In comparison with glass slides, the average screening times were 5.5 and 1.8 times longer with Panoptiq and Aperio images, respectively, but this improved with user experience. There was no statistical difference in diagnostic concordance between all 3 modalities. Users' diagnostic confidence was also similar for all modalities.

CONCLUSIONS

The Aperio whole-slide scanner with 1 z-plane scanning and the Panoptiq imaging system with z-stacking are both suitable for cytopathology screening and interpretation. However, ROI z-stacks do offer a superior mechanism for overcoming focusing problems commonly encountered with digital cytology slides. Unlike whole-slide imaging, the acquisition of representative z-stack images with the Panoptiq system requires a trained cytologist to create digital files. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

BACKGROUND

Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers.

METHODS

Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1.

RESULTS

Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response.

CONCLUSIONS

Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2r8rwjD

Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

BACKGROUND

Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers.

METHODS

Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1.

RESULTS

Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response.

CONCLUSIONS

Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017. © 2017 American Cancer Society.

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FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells

Abstract

Background

Autophagy is a conserved catabolic process to degrade cellular organelles. The role of autophagy in cancer development is complex. Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC). Whether fibroblast growth factor 2 (FGF2)/FGFR1 contributes to the regulation of autophagy remains elusive.

Methods

Autophagic activity was evaluated by immunoblotting for microtubule-associated protein 1 light chain 3 (LC3), formation of GFP-LC3 puncta, and monodansylcadaverine (MDC) staining. The effect of autophagy inhibition on cell survival was assessed by cell viability and apoptosis assays.

Results

We elucidated that FGFR1 activation suppressed autophagy. Pharmacological or genetic inhibition of FGFR1 by AZD4547 or FGFR1 short hairpin RNA (shRNA) induced autophagy in FGFR1-amplified non-small cell lung cancer (NSCLC) cells, H1581 and H520 cells. Mechanistic study revealed that the induction of autophagy by FGFR1 inhibition was mediated through inhibiting the ERK/MAPK pathway not by AKT pathway, accompanied by upregulation of beclin-1. Furthermore, activation of ERK/MAPK by transfection with a constitutively active MEK1 (caMEK1) construct or knockdown of beclin-1 by RNAi could attenuate autophagy induced by FGFR1 inhibition. Beclin-1 expression was inversely correlated with MEK1 phosphorylation. Inhibition of autophagy by beclin-1 silencing could enhance apoptosis after AZD4547 treatment in H1581 and H520 cells. High levels of LC3B mRNA was a marker of poor prognosis in NSCLC patients.

Conclusions

Simultaneously inhibiting FGFR1 and autophagy could enhance cell death which should be further explored in vivo.

http://ift.tt/2siPTJ7

FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells

Abstract

Background

Autophagy is a conserved catabolic process to degrade cellular organelles. The role of autophagy in cancer development is complex. Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC). Whether fibroblast growth factor 2 (FGF2)/FGFR1 contributes to the regulation of autophagy remains elusive.

Methods

Autophagic activity was evaluated by immunoblotting for microtubule-associated protein 1 light chain 3 (LC3), formation of GFP-LC3 puncta, and monodansylcadaverine (MDC) staining. The effect of autophagy inhibition on cell survival was assessed by cell viability and apoptosis assays.

Results

We elucidated that FGFR1 activation suppressed autophagy. Pharmacological or genetic inhibition of FGFR1 by AZD4547 or FGFR1 short hairpin RNA (shRNA) induced autophagy in FGFR1-amplified non-small cell lung cancer (NSCLC) cells, H1581 and H520 cells. Mechanistic study revealed that the induction of autophagy by FGFR1 inhibition was mediated through inhibiting the ERK/MAPK pathway not by AKT pathway, accompanied by upregulation of beclin-1. Furthermore, activation of ERK/MAPK by transfection with a constitutively active MEK1 (caMEK1) construct or knockdown of beclin-1 by RNAi could attenuate autophagy induced by FGFR1 inhibition. Beclin-1 expression was inversely correlated with MEK1 phosphorylation. Inhibition of autophagy by beclin-1 silencing could enhance apoptosis after AZD4547 treatment in H1581 and H520 cells. High levels of LC3B mRNA was a marker of poor prognosis in NSCLC patients.

Conclusions

Simultaneously inhibiting FGFR1 and autophagy could enhance cell death which should be further explored in vivo.

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Issue Information

Cover of this issue. Mieap-induced vacuoles eat mitochondria. See also Nakamura et al. (pp. 809–817 of this issue).

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In response to Sharing different perspectives to understand asbestos-induced carcinogenesis: A comment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017)

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Issue Information

Cover of this issue. Mieap-induced vacuoles eat mitochondria. See also Nakamura et al. (pp. 809–817 of this issue).

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In response to Sharing different perspectives to understand asbestos-induced carcinogenesis: A comment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017)

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Radiation-related lymphopenia is associated with spleen irradiation dose during radiotherapy in patients with hepatocellular carcinoma

Abstract

Background

The decrease in peripheral blood lymphocytes induced by radiation lessens the antitumour effect of the immune response, which might cause immunosuppression. We aimed to investigate the correlation between the decrease in peripheral blood lymphocytes during radiotherapy (RT) and the spleen irradiation dose in patients with hepatocellular carcinoma (HCC).

Methods

The subjects were 59 patients with HCC who had received RT from 2005 to 2014. The Min ALC (minimum value of absolute counts for peripheral blood lymphocytes) was collected from the routine workup for each patient prior to RT and weekly during RT. Spleen dose-volume variables, including the percentage of the organ volume receiving ≥ n Gy (V_n) and the mean spleen dose (MSD), were calculated using Eclipse treatment planning. Potential associations between dosimetric variables and the Min ALC were assessed by multiple linear regression analysis.

Results

Peripheral lymphocytes decreased during RT (P < 0.001). The Min ALC correlated with the MSD (P = 0.005), spleen V₅ (P = 0.001), spleen V₂₅ (P = 0.026) and spleen V₃₀ (P = 0.018). Controlling for the Karnofsky performance status (KPS), sex, age, Child-Pugh grade, total dose and tumour stage, a multiple linear regression model with bootstrap analysis of 1000 replicates showed that only the spleen V₅ was correlated with the decrease in the Min ALC (P < 0.05). According to the receiver-operating characteristic (ROC) curve analysis, the predictive cutoff values of the MSD, V₅, V₂₅ and V₃₀ of the spleen for the Min ALC were 227.72 cGy, 17.84, 0.98 and 0.42%, respectively (P = 0.002, P = 0.004, P = 0.007 and P = 0.002, respectively). Furthermore, an MSD ≥ 227.72 cGy (OR = 14.39; 95% CI, 12.18 to 16.60) and V₅ (OR = 7.99; 95% CI, 6.91 to 9.07) of the spleen significantly predicted the Min ALC.

Conclusions

Higher spleen irradiation doses were significantly correlated with lower Min ALC during RT for HCC. V₅ should be limited in clinical practice. Maximum sparing for spleen irradiation during RT is recommended to preserve peripheral blood lymphocytes, which may decrease immunosuppression.

http://ift.tt/2saJ4ds

Prognostic analysis of radiation pneumonitis: carbon-ion radiotherapy in patients with locally advanced lung cancer

Abstract

Background

Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer.

Methods

Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68–76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months.

Results

Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V₅), V₁₀, V₂₀ and V₃₀ were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V₅, V₁₀, V₂₀ and V₃₀ for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V₃₀ ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors.

Conclusions

Our study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.

http://ift.tt/2rBpkCM