Publications by authors named "Stanislav Lazarev"

29 Publications

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Insurer's Black Box: Inexplicable Barriers to Proton Therapy Access for Young Adults.

Int J Radiat Oncol Biol Phys 2021 Aug;110(5):1538-1539

Department of Radiation Oncology, New York Proton Center, New York, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2021.04.006DOI Listing
August 2021

Geospatial Disparities in Access to Proton Therapy in the Continental United States.

Cancer Invest 2021 Jul-Aug;39(6-7):582-588. Epub 2021 Jul 5.

Navari Family Center for Digital Scholarship, University of Notre Dame, Notre Dame, IN, USA.

Proton therapy (PT) is an important component of therapy for select cancers, but no formal study of geospatial access to PT has been conducted to date. Population data for 320.7 million people in 32,644 zip codes were analyzed. Median travel time was 1.61 (IQR 0.67-3.36) hours for children and 1.64 (IQR 0.69-3.33) hours for adults. Significant variation in travel time to nearest PT center was observed between states. The West has a longer median travel time of 3.51 (IQR 1.15-7.13) hours when compared to the Midwest (1.70, IQR 0.79-2.69), South (1.60, IQR 0.61-3.12) and Northeast (1.04, IQR 0.57-2.01).
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http://dx.doi.org/10.1080/07357907.2021.1944180DOI Listing
July 2021

The Holman Research Pathway in Radiation Oncology: 2010 to 2019.

Int J Radiat Oncol Biol Phys 2021 Jun 18. Epub 2021 Jun 18.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: There has not been an assessment of the Holman Research Pathway (HRP) in radiation oncology (RO) in nearly 10 years. In this study, we sought to review the demographic characteristics, research productivity during and after residency, job placements, and National Institutes of Health (NIH) grant funding of RO residents who completed the HRP in the modern era.

Methods And Materials: We created a comprehensive database of RO residents who completed the HRP between 2010 and 2019. Using a variety of data sources, we obtained demographic information, first-author manuscripts published in residency, and first- and last-author manuscripts published in the first 30 months after residency for each resident. In addition, we identified the first and current job and NIH grant funding for each resident.

Results: Ninety-seven RO residents who graduated from 50 medical schools and 25 residency programs were included. The majority were male (82.5%), had a PhD (92.8%), and identified as white (64.9%). Collectively, these residents published 212 first-author, PubMed-searchable manuscripts during residency (mean: 2.2) and 142 first- or last-author, PubMed-searchable manuscripts in the first 30 months after completion of residency (mean: 1.5). The number of first-author publications authored by HRP graduates during residency was highly correlated (r = 0.62; P < .01) with the number of first- and last-author publications they authored during the first 30 months after completing residency. Ninety-six of the 97 residents (99.0%) were employed in full-time clinical positions after completing residency. Seventy-six HRP residents (78.4%) obtained an academic position as their first job after residency, only 4 of whom have since left academia, and 20 (20.6%) obtained a nonacademic position. Of the 75 HRP graduates currently employed in an academic position, 39 (52.0%) have their own laboratories. Twenty-three of the 96 HRP residents (24.0%) who secured employment in full-time clinical positions after residency switched jobs over the study period. Lastly, 33 of the 97 HRP residents (34.0%) have thus far received 47 extramural NIH research grants, 15 of which were R-01 grants.

Conclusions: Over the past decade, the HRP has proven successful in training a new cohort of physician investigators in RO. Although productive, HRP residents have had relatively homogenous sex, educational, and racial backgrounds. Ensuring sufficient representation of residents from a variety of backgrounds in the HRP in the future will be crucial.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.020DOI Listing
June 2021

In Reply to Jones et al.

Int J Radiat Oncol Biol Phys 2021 04;109(5):1660-1661

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2020.11.072DOI Listing
April 2021

Where are we with proton beam therapy for thoracic malignancies? Current status and future perspectives.

Lung Cancer 2021 02 31;152:157-164. Epub 2020 Dec 31.

New York Proton Center, New York, NY, United States.

Radiation therapy (RT) plays an important role in the curative treatment of a variety of thoracic malignancies. However, delivery of tumoricidal doses with conventional photon-based RT to thoracic tumors often presents unique challenges. Extraneous dose deposited along the entrance and exit paths of the photon beam increases the likelihood of significant acute and delayed toxicities in cardiac, pulmonary, and gastrointestinal structures. Furthermore, safe dose-escalation, delivery of concomitant systemic therapy, or reirradiation of a recurrent disease are frequently not feasible with photon RT. In contrast, protons have distinct physical properties that allow them to deposit a high irradiation dose in the target, while leaving a negligible exit dose in the adjacent organs at risk. Proton beam therapy (PBT), therefore, can reduce toxicities with similar antitumor effect or allow for dose escalation and enhanced antitumor effect with the same or even lower risk of adverse events, thus potentially improving the therapeutic ratio of the treatment. For thoracic malignancies, this favorable dose distribution can translate to decreases in treatment-related morbidities, provide more durable disease control, and potentially prolong survival. This review examines the evolving role of PBT in the treatment of thoracic malignancies and evaluates the data supporting its use.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.025DOI Listing
February 2021

Proton and Heavy Particle Intracranial Radiosurgery.

Biomedicines 2021 Jan 3;9(1). Epub 2021 Jan 3.

Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA.

Stereotactic radiosurgery (SRS) involves the delivery of a highly conformal ablative dose of radiation to both benign and malignant targets. This has traditionally been accomplished in a single fraction; however, fractionated approaches involving five or fewer treatments have been delivered for larger lesions, as well as lesions in close proximity to radiosensitive structures. The clinical utilization of SRS has overwhelmingly involved photon-based sources via dedicated radiosurgery platforms (e.g., Gamma Knife and Cyberknife) or specialized linear accelerators. While photon-based methods have been shown to be highly effective, advancements are sought for improved dose precision, treatment duration, and radiobiologic effect, among others, particularly in the setting of repeat irradiation. Particle-based techniques (e.g., protons and carbon ions) may improve many of these shortcomings. Specifically, the presence of a Bragg Peak with particle therapy at target depth allows for marked minimization of distal dose delivery, thus mitigating the risk of toxicity to organs at risk. Carbon ions also exhibit a higher linear energy transfer than photons and protons, allowing for greater relative biological effectiveness. While the data are limited, utilization of proton radiosurgery in the setting of brain metastases has been shown to demonstrate 1-year local control rates >90%, which are comparable to that of photon-based radiosurgery. Prospective studies are needed to further validate the safety and efficacy of this treatment modality. We aim to provide a comprehensive overview of clinical evidence in the use of particle therapy-based radiosurgery.
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http://dx.doi.org/10.3390/biomedicines9010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823941PMC
January 2021

Optimal timing of radiotherapy in high risk prostate cancer: Do missed days matter?

Clin Transl Radiat Oncol 2021 Jan 25;26:47-54. Epub 2020 Nov 25.

New York Proton Center, New York, NY, USA.

Introduction: High-risk prostate cancer is associated with poorer overall survival (OS) and biochemical control compared to more favorable risk groups. External beam radiation therapy (EBRT) is widely used; however, outcomes data are limited with respect to time elapsed between diagnosis and initiation of EBRT.

Methods: The National Cancer Database was queried from 2004 to 2015 for patients diagnosed with high-risk adenocarcinoma of the prostate who received androgen deprivation therapy (ADT) and definitive EBRT. Logistic regression was utilized to determine covariates associated with missing EBRT treatments. OS was analyzed using multivariate cox proportional hazards models and propensity score matching.

Results: 9,610 patients met inclusion criteria with median follow-up of 40.6 months and median age of 72 years. Median PSA was 8.7 and median EBRT dose was 78 Gy. ADT was initiated at a median of 36 days and EBRT at a median of 63 days post-diagnosis. Median number of prolonged treatment days was 2.2. Black race (OR: 1.40;  < 0.01), treatment at a community clinic (OR: 1.32; p < 0.01), and living in an urban/densely populated area were associated with prolonged treatment. Time elapsed between ADT and EBRT > 74 days (HR: 1.20;  = 0.01) and prolonged treatment>3 days of EBRT (HR: 1.26;  = 0.005) were associated with an increased hazard of death. The 5-year OS was 79.6% and 82.9% for patients with prolonged treatment of 3 days or more of EBRT and those missing 3 days or less, respectively ( = 0.0006).

Conclusion: In this hypothesis-generating study, prolonged treatment delays and missing three or more EBRT treatments was associated with poorer OS in patients with high-risk adenocarcinoma of the prostate.
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http://dx.doi.org/10.1016/j.ctro.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718118PMC
January 2021

Radiation Oncology Resident Research Productivity in the United States: 2015 to 2019.

Int J Radiat Oncol Biol Phys 2021 03 24;109(4):1111-1118. Epub 2020 Oct 24.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: Multiple efforts have been made in recent years to establish national benchmarks for research productivity among US radiation oncology residents. Morgan et al found a mean of 1.01 first-author, PubMed-searchable articles published by US radiation oncology residents over 4 years of residency between 2002 and 2007, whereas Verma et al found a mean of 1.97 first-author, PubMed-searchable articles published by members of the graduating US radiation oncology residency classes of 2014 and 2015. In this study, we sought to establish new national benchmarks for US radiation oncology resident research productivity and characterize the scholarly work produced by graduating US radiation oncology residents.

Methods And Materials: We built a database of US radiation oncology residents who graduated between 2015 and 2019 using multiple sources of publicly available data. We subsequently searched the PubMed database to identify all first-author publications for every resident in our database from the start of residency until 3 months after the completion of residency. Publications were categorized by type (original research, review, case report, or commentary) and content. We performed a secondary analysis to identify factors associated with an increased probability of publishing during residency.

Results: We identified 909 US radiation oncology residency graduates from 89 residency programs between 2015 and 2019. Collectively, these graduates published 2637 first-author, PubMed-searchable articles (mean: 2.90; median: 2.0; range, 0-58; interquartile range, 1-4) in 392 distinct peer-reviewed journals during their residency, and 69.7% of the first-author publications comprised original research. On multivariable analysis, only residency size was predictive of publishing a first-author manuscript during residency. Among residents with at least 1 first-author manuscript, male sex, lack of a doctorate degree, and residency size were all significant predictors of the number of first-author manuscripts published during residency.

Conclusions: US radiation oncology resident research productivity, as measured by the number of first-author, PubMed-searchable publications, has increased compared with historical data. However, substantial variability exists in resident research productivity nationwide.
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http://dx.doi.org/10.1016/j.ijrobp.2020.10.020DOI Listing
March 2021

Safety and Efficacy of Liver Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma After Segmental Transarterial Radioembolization.

Int J Radiat Oncol Biol Phys 2019 12 16;105(5):968-976. Epub 2019 Sep 16.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Purpose: With increasing use of radiation for hepatocellular carcinoma (HCC) through transarterial radioembolization (TARE) and stereotactic body radiation therapy (SBRT), there is concern for increased radiation-related complications when using SBRT after TARE. This study compares safety of SBRT after segmental TARE versus transarterial chemoembolization (TACE).

Methods And Materials: A retrospective review identified patients receiving SBRT after TACE or TARE for HCC from 2011 to 2017. TARE was delivered subselectively to individual segments using yttrium-90 with Theraspheres. Patients were assessed over time for Child-Turcott-Pugh (CTP)/albumin-bilirubin (ALBI) scores, and Common Terminology Criteria for Adverse Events version 4.0 grade ≥3 events. Linear mixed models were used to examine the trend of CTP and ALBI over time and compare groups. Secondary endpoints were objective response rate via modified Response Evaluation Criteria in Solid Tumors (RECIST), local control, and overall survival.

Results: Ninety-nine patients met criteria with median follow-up of 9.8 months (range, 0.9-47): 31 had SBRT after segmental TARE and 68 patients post-TACE. The groups were well balanced with regard to etiology of HCC, baseline CTP and ALBI scores, and SBRT dose, but there were significant differences in baseline Eastern Cooperative Oncology Group performance status, Barcelona Clinic Liver Cancer staging, and median follow-up. There was a significant increase in post-SBRT CTP and ALBI scores (P < .0001) for both groups. However, there was no significant difference in rise in CTP (P = .11) or ALBI score (P = .82) over time between SBRT post-TACE versus post-segmental TARE. There was no significant increase in ≥grade 3 toxicity postsegmental TARE. There was also no significant difference in local controls (P = 1.0) and overall survival (P = .26) between cohorts, but objective response rate was worse post-TARE.

Conclusions: SBRT after segmental TARE with Theraspheres appears to have acceptable tolerability and is effective compared with SBRT after TACE. Longer follow-up with larger numbers is needed to verify these data.
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http://dx.doi.org/10.1016/j.ijrobp.2019.09.006DOI Listing
December 2019

Adjuvant Radiation Therapy for Thoracic Soft Tissue Sarcomas: A Population-Based Analysis.

Ann Thorac Surg 2020 01 11;109(1):203-210. Epub 2019 Sep 11.

Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York; Department of Thoracic Surgery, Health Quest, Poughkeepsie, New York. Electronic address:

Background: The role of adjuvant radiation therapy (RT) in the management of thoracic soft tissue sarcomas (STSs) remains unclear. We aimed to study the characteristics of patients with thoracic STS who received RT after surgical resection and investigate the impact of RT on survival outcomes.

Methods: We queried National Cancer Database to identify patients with surgically resected thoracic STS from 2004 to 2012. Factors associated with receiving adjuvant RT were identified. Analyses were performed to identify prognostic factors and compare overall survival (OS) in both unmatched and propensity score-matched cohorts.

Results: Overall, 1215 patients were identified, of whom 557 (45.8%) received adjuvant RT. Tumor grade (odds ratio [OR], 2.87; 95% confidence interval [CI], 2.18-3.77), tumor size (OR, 1.82; 95% CI, 1.36-2.42), and tumor margins (OR, 1.97; 95% CI, 1.43-2.72) were found to be significant predictors of receiving RT. Mean OS of patients receiving RT in the unmatched cohort was 91 months vs 88 months for patients who did not (P = .556). When adjusted for all variables, adjuvant RT was found to be associated with improved survival (hazard ratio, 0.79; 95% CI, 0.61-0.96). Survival analysis of the matched cohort also demonstrated improved survival with adjuvant RT (120 months vs 100 months; P = .02). Subgroup analysis in both the unmatched and matched cohorts showed patients with high-grade tumors more likely to benefit from adjuvant RT.

Conclusions: This population-based analysis is the largest dataset of primary thoracic STSs to date and suggests significant survival benefit associated with adjuvant RT. The improvement in OS was more notable in patients with high-grade tumors. Randomized prospective studies are warranted to further understand the benefit of RT in this group.
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http://dx.doi.org/10.1016/j.athoracsur.2019.07.075DOI Listing
January 2020

Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review.

Adv Radiat Oncol 2019 Jul-Sep;4(3):520-531. Epub 2019 Mar 30.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG.

Methods And Materials: A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items "diffuse intrinsic pontine glioma" and 221 articles using search items "diffuse brainstem glioma radiotherapy." Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT.

Results: We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months.

Conclusions: As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.
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http://dx.doi.org/10.1016/j.adro.2019.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639749PMC
March 2019

Rapid in-field failures following adjuvant radiation for buccal squamous cell carcinoma.

Laryngoscope 2020 02 25;130(2):413-417. Epub 2019 Apr 25.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, U.S.A.

Objectives/hypothesis: Squamous cell carcinoma originating in the buccal mucosa and retromolar trigone (RMT) have historically poor outcomes. Difficulties in discriminating tumor origin often result in these subsites being combined in surgical and pathological reports. We aimed to determine if making this anatomical distinction has implications for treatment design and clinical outcomes.

Study Design: Retrospective case series.

Methods: We identified 27 tumors from either the buccal mucosa patients or RMT patients who underwent surgery followed by radiation. For patients who developed a local failure, we fused the pretreatment imaging, simulation computed tomography, and follow-up imaging to determine the location of failures relative to the radiation field. We calculated the 2-year locoregional control and 2-year disease-free survival.

Results: The median time from surgery to radiation was 50 days (range, 32-133 days). The 2-year locoregional control for buccal mucosa versus RMT, respectively, were 35.9% versus 68.4% (P = .252). The 2-year disease-free survival rates were 32.7% versus 68.4%, respectively (P = .196). The median times to failure were 12.00 months (range, 4.9-115.0 months) versus 18.5 months (range, 4.5-61.0 months), respectively. All buccal mucosa failures occurred within the high-dose planning target volume, with a median dose of 60 Gy within the failure region. Following locoregional failure, 10 of the 12 patients have died, with a median time from local failure to death of 3.6 months (range, 1-17.6 months).

Conclusions: Squamous cell carcinomas of the buccal mucosa appear to have a poor prognosis characterized by rapid in-field failure. Therefore, differentiating tumor origin may be important for prognostication and treatment.

Level Of Evidence: 3 Laryngoscope, 130:413-417, 2020.
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http://dx.doi.org/10.1002/lary.27996DOI Listing
February 2020

Utilization Patterns of Single Fraction Radiation Therapy for Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2019 05 22;19(5):e238-e246. Epub 2019 Feb 22.

Department of Radiation Oncology, Mount Sinai Hospital, New York, NY.

Background: Patients with multiple myeloma (MM) are living longer than ever before thanks to new therapies. As a consequence, radiation therapy (RT) is increasingly important in the management of bone lesions from MM. Current American Society for Radiation Oncology guidelines recommend greater usage of 8 Gy in 1 fraction for treatment of these lesions. The objective of this study is to analyze utilization of 8 Gy in 1 fraction for treatment of MM bone lesions in the United States utilizing the National Cancer Data Base (NCDB).

Materials And Methods: The NCDB was used to identify patients with MM treated with palliative RT for painful bony lesions in the period between 2004 and 2014. Utilization rate of RT in this patient population as well as single-fraction (SFRT) versus multiple-fraction RT (MFRT) was compared according to demographic, socioeconomic, and logistic details.

Results: A total of 95,190 patients met our inclusion criteria. Of these, 10,261 (10.8%) patients received RT, and a total of 243 (2.4%) of these patients received SFRT over the 10-year period. There was an 11.73% annual increase (P = .0001) in SFRT utilization from 2004 to 2014. Older age, black race, longer distance from the treatment facility, lower degree of education, treatment at an academic or integrated healthcare network, worse comorbidities, and more recent diagnoses were all associated with increased usage of SFRT.

Conclusion: SFRT for the management of MM painful bony metastases remains underutilized. Trends show that radiation oncologists do not appear to be changing their approach to treating this disease.
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http://dx.doi.org/10.1016/j.clml.2019.02.010DOI Listing
May 2019

Dosimetric Correlates of Pulmonary Toxicity in Patients with Malignant Pleural Mesothelioma Receiving Radiation Therapy to the Intact Lungs.

Pract Radiat Oncol 2019 May 15;9(3):e331-e337. Epub 2019 Jan 15.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Purpose: We aimed to determine dose-volume constraints that correlate with severe (grade ≥3) radiation pneumonitis (RP) in patients diagnosed with malignant pleural mesothelioma, treated using volumetric modulated arc therapy.

Methods And Materials: Data from 40 patients with malignant pleural mesothelioma who underwent pleurectomy decortication and adjuvant radiation therapy at our institution between December 2010 and October 2016 were retrospectively analyzed. Dosimetric variables for the absolute volume and percentage volume of the ipsilateral lung, contralateral lung, and heart were recorded. Events of RP were assessed using the Common Terminology Criteria for Toxicity and Adverse Events, version 4.0. The statistical analysis with Wilcoxon rank-sum, Spearman rank correlation, and receiver operating characteristic curves was computed using MATLAB V9.1, RV3.4, and SAS V9.4.

Results: Of the 40 patients, 26 patients (65%) were male. The median age at the time of diagnosis was 66.5 years (range, 44-84 years). The median prescription dose was 45 Gy (range, 30-54 Gy). Five patients (12.5%) had grade ≥3 RP. The incidence of grade≥ 3 RP showed a significant correlation (P < .05) with the absolute volume and percentage volume of the ipsilateral lung spared of ≥20 Gy (55 cc; 7%) and spared of ≥30 Gy (200 cc; 23%). Dosimetric variables of the contralateral lung, total lung, and heart did not show a correlation with incidence of grade ≥3 RP.

Conclusions: In our cohort, sparing the ipsilateral lung of at least 55 cc of 20 Gy and 200 cc of 30 Gy correlated with a reduced incidence of severe (grade ≥3) RP.
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http://dx.doi.org/10.1016/j.prro.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500743PMC
May 2019

Stereotactic body radiation therapy for centrally located hepatocellular carcinoma: outcomes and toxicities.

J Cancer Res Clin Oncol 2018 Oct 7;144(10):2077-2083. Epub 2018 Aug 7.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, 1184 5th Ave, New York, NY, 10029, USA.

Purpose: To examine safety and efficacy of stereotactic body radiation therapy (SBRT) for centrally located hepatocellular carcinoma (CL-HCC).

Methods: Fifty-three patients with CL-HCC were treated with SBRT from 2011 to 2017 in our institution. CL-HCC was defined as a tumor sited in segments 4, 5, or 8 adjacent to the hepatic hilum, or < 1.5 cm from main portal branches. Primary endpoints were treatment response, local control (LC), and hepatobiliary toxicity (HBT).

Results: Thirty-three (62.3%) patients had Child-Turcotte-Pugh score A, 20 (37.77%)-score B. Albumin-bilirubin grade 1 constituted 6 (11.3%) cases, grade 2-32 (60.4%), grade 3-15 (28.3%). Median tumor diameter was 34 mm. Median BED10 was 72 Gy. Complete/partial response was observed in 40 (75.5%) lesions, stable disease-in 9 (17.0%). At a median follow-up of 12.2 months, there were 6 (11.3%) local failures. The actuarial 2-year LC rate was 87.9%. 2-year LC was better with higher BED10 (> 70 vs ≤ 70 Gy) 96.9 vs 72.5%, p = 0.01. The 2-year rates for disease-specific and overall survival were 53.2 and 39.1%, respectively. The incidence of any Grade ≥ 3 AE was 9 (17.0%). There were no grade 5 AEs. There was a trend toward an increased risk of grade ≥ 3 AE with mean liver dose > 10 Gy (p = 0.07).

Conclusions: In the present cohort, SBRT to the CL-HCC produced excellent treatment response with acceptable HBT and LC. Select HCC patients who are not candidates for surgery or other locoregional therapies can be considered for SBRT to the central liver.
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http://dx.doi.org/10.1007/s00432-018-2729-yDOI Listing
October 2018

Short Hypofractionated Radiation Therapy in Palliation of Pediatric Malignancies: Outcomes and Toxicities.

Int J Radiat Oncol Biol Phys 2018 12 2;102(5):1457-1464. Epub 2018 Aug 2.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Purpose: Treatment strategies in palliation of pediatric cancer remain a significant challenge. In this study, we aimed to assess the efficacy and safety of a short course of hypofractionated radiation therapy (RT) for metastatic or recurrent childhood tumors.

Methods And Materials: A total of 104 lesions in 62 pediatric patients with metastatic or recurrent cancer were treated with a short hypofractionation schedule (>1 but ≤5 fractions; ≥3 Gy per fraction) between 2007 and 2017 in our institution. The primary endpoint was local control (LC). Other endpoints included treatment response, overall survival, progression-free survival, and toxicity. Toxicities were assessed using the Common Terminology Criteria for Adverse Events v.4.0.

Results: The most common histologies were neuroblastoma, comprising 50 of the 104 lesions (48.1%); osteosarcoma, 17 lesions (16.4%); and Ewing sarcoma, 13 lesions (12.5%). A median total dose of 24 Gy was delivered in a median of 5 fractions. Of 104 lesions, 26 (25.0%) were treated with stereotactic body radiation therapy, 24 (23.1%) with intensity modulated RT, and 48 (46.2%) with 2-dimensional RT or 3-dimensional conformal RT. A complete or partial response was observed in 63 (60.6%) of lesions, and stable disease was observed in 34 (32.7%). At a median follow-up of 8.7 months, 21 local failures occurred (20.2%). The 1- and 2-year LC rates were 74% and 68%, respectively. LC was better for tumors without previous irradiation (83% vs 57% with previous RT; P = .004). LC rates did not differ between RT techniques or total biologically effective dose with α/β ratio of 10 (BED10) (≤30 vs >30 Gy). At the time of analysis, 38 deaths in the cohort of 62 patients (61.3%) were recorded. The 1-year progression-free survival and overall survival rates were 31% and 44%, respectively. Incidence of any grade ≥3 toxicity was 6.7% (7 of 104). No grade 5 events occurred.

Conclusions: A short hypofractionation scheme yields effective disease control and treatment response with a favorable side effect profile. Select pediatric patients with symptomatic metastases or recurrent disease can be considered for a short course of palliative RT.
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http://dx.doi.org/10.1016/j.ijrobp.2018.07.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359989PMC
December 2018

Premature discontinuation of curative radiation therapy: Insights from head and neck irradiation.

Adv Radiat Oncol 2018 Jan-Mar;3(1):62-69. Epub 2017 Oct 23.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: Factors related to premature discontinuation of curative radiation therapy (PDCRT) are understudied. This study aimed to examine causes and clinical outcomes of PDCRT at our institution by investigating the most common anatomical site associated with PDCRT.

Methods And Materials: Among the 161 patients with PDCRT of various anatomic sites at our institution between 2010 and 2017, 36% received radiation to the head and neck region. Pertinent demographic, clinical, and treatment-related data on these 58 patients were collected. Survival was examined using the life-table method and log-rank test.

Results: The majority of patients were male (81%), white (67%), ≥60 years old (59%), living ≥10 miles away from the hospital (60%), single (57%), with Eastern Cooperative Oncology Group score ≥1 (86%), experiencing significant pain issues (67%), and had treatment interruptions in radiation therapy (RT; 66%). The most common reasons for PDCRT were discontinuation against medical advice (33%), medical comorbidity (24%), and RT toxicity (17%). Of the comorbidities leading to PDCRT, 50% was acute cardiopulmonary issues and 43% was infection. The mean follow-up time was 15.9 months, and the 2-year overall survival and disease-specific survival rates were 61% and 78%, respectively. Patients with illicit substance abuse, cardiovascular disease, and Eastern Cooperative Oncology Group score ≥2 had worse survival. A trend toward improved survival with total completed dose ≥50 Gy versus <50 Gy existed (74% versus 44%, respectively; = .07).

Conclusions: In this largest-to-date, modern analysis of PDCRT, the most common cause of discontinuation was discontinuation against medical advice, which underscores the importance of patient education, optimization of RT symptoms, involvement of social work, and integration of other supportive services early in treatment. Survival remains suboptimal after PDCRT for H&N tumors, with a 2-year overall survival rate of 61%. Completing >50 Gy appears to confer a relative therapeutic benefit.
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http://dx.doi.org/10.1016/j.adro.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856974PMC
October 2017

Low-dose-rate brachytherapy for prostate cancer: outcomes at >10 years of follow-up.

BJU Int 2018 05 30;121(5):781-790. Epub 2018 Jan 30.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Objective: To examine biochemical control, survival, and late morbidity with definitive low-dose-rate brachytherapy (LDR-BT) for patients with prostate cancer surviving for >10 years after treatment.

Patients And Methods: We identified 757 men with localised prostate cancer who underwent definitive LDR-BT in the period 1990-2006 and were followed for >10 years at our institution. Biochemical failure-free survival (BFFS), distant metastases-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were selected as study endpoints. Survival was examined using the log-rank test, Kaplan-Meier method, and Cox regression modelling. Urinary, quality of life (QoL), and potency scores at baseline and last follow-up were recorded.

Results: The median follow-up was 12.5 years (range, 10.1-21.8 years). At the time of analysis, 88.6% of patients were alive, 1.5% died from prostate cancer and 13.9% developed biochemical failure, with 82% of failures occurring in the first decade of follow-up. Overall, 2.3% developed distant metastases. On multivariate analyses, stage T3a-T3b, prostate-specific antigen level of >20 ng/mL, intermediate- and high-risk disease predicted worse BFFS; whereas age >70 years at diagnosis and stage T3a-T3b predicted worse OS. A total biologically effective dose of ≥150 Gy and androgen-deprivation therapy were associated with improved BFFS, but not OS. The overall 17-year rates for BFFS, DMFS, PCSS, and OS were 79, 97, 97, and 72%, respectively. Respective 17-year BFFS rates for low-, intermediate- and high-risk patients were 86, 80, and 65% (P < 0.001), whereas OS rates for the same groups were 82, 73, and 60%, respectively (P = 0.09). Amongst those patients who were potent at baseline, 25% remained potent at the last follow-up. Urinary function and QoL were mainly unaffected.

Conclusions: LDR-BT yields excellent survival rates, with a 17-year PCSS rate of 97%. In all, 18% of patients with biochemical relapse failed at >10 years after implantation, which justifies their continued follow-up.
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http://dx.doi.org/10.1111/bju.14122DOI Listing
May 2018

Preoperative vs postoperative radiation therapy in localized soft tissue sarcoma: Nationwide patterns of care and trends in utilization.

Pract Radiat Oncol 2017 Nov - Dec;7(6):e507-e516. Epub 2017 Apr 18.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Purpose: The timing of perioperative radiation therapy (RT) in the treatment of soft tissue sarcoma (STS) varies among institutions. This study examines patterns of care, trends in utilization, and survival with preoperative versus postoperative RT for primary STS.

Methods And Materials: Using the National Cancer Data Base, we identified patients with stage I-III STS who underwent definitive surgery with either preoperative or postoperative RT between 2004 and 2012. Univariate, bivariate, and multivariate analyses were performed to identify factors predicting receipt of preoperative versus postoperative RT. Overall survival (OS) was analyzed using the log-rank test, Kaplan-Meier method, and Cox proportional-hazards model.

Results: This study included 9604 patients: 7246 (75.4%) received postoperative and 2358 (24.6%)-preoperative RT. Chemotherapy was administered to 27.0% patients in the preoperative and 13.0% in the postoperative cohort. Use of preoperative RT increased over time, from 16.8% in 2004 to 29.7% in 2012. Multivariate analysis revealed that preoperative RT utilization increased with the following factors: higher educational attainment, treatment at an academic facility, further distance from facility (>60 miles), receipt of chemotherapy, tumor originating in lower extremities, >10 cm tumors, and myxoid liposarcoma. OS analysis revealed no difference between the 2 treatment cohorts.

Conclusions: Postoperative RT is used much more commonly than preoperative RT in localized STS; however, preoperative RT use has increased in recent years. Multiple demographic and clinicopathologic factors were predictive of preoperative RT use. Consistent with randomized phase 3 data, there was no difference in OS.
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http://dx.doi.org/10.1016/j.prro.2017.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004789PMC
July 2018

Adjuvant radiation in the TORS era: Is there a benefit to omitting the tumor bed?

Pract Radiat Oncol 2017 Mar - Apr;7(2):93-99. Epub 2016 Aug 9.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Purpose: Trans-oral robotic surgery (TORS) followed by adjuvant radiation therapy (RT) is becoming popular in treating node-positive tonsillar squamous cell carcinoma (SCC). One potential benefit is eliminating irradiation of the primary site when the tumor is widely resected, and targeting the neck only. This study assessed whether omitting the tumor bed provides any dosimetric or clinical advantage.

Methods And Materials: We identified 21 patients with primary tonsillar SCC that were treated with TORS followed by RT to the ipsilateral neck and primary (N+P) site. We subsequently replanned each case to allow target coverage to the neck only, excluding the tumor bed. For each case, we created 2 plans: neck only (NO) and N+P. Additionally, we identified patients (n = 7) with primary SCC tonsil who did receive NO irradiation to compare their dosimetry and toxicity profile with those treated to both the primary site and ipsilateral neck. Contralateral neck radiation was not administered in any of these cases.

Results: Despite excluding the primary site in the NO plans, the mean dose to the tumor bed was high: 53.9 Gy. The only significant differences in omitting the primary site were lower doses to the oral cavity, 29.8 Gy in NO plan versus 34.6 Gy in N+P plan, P = .002, and superior constrictors, 42.9 Gy in NO plan versus 46.1 Gy in N+P plan, P = .01. No appreciable differences in toxicities were noted in the limited cohort treated with NO irradiation.

Conclusions: Sparing the primary site after TORS in node-positive tonsillar SCC does not appear to provide any significant dosimetric or clinical advantage. Furthermore, the tumor bed receives a significant but potentially subtherapeutic dose, limiting options for irradiation in a salvage setting. At this time, we do not recommend omitting the tumor bed from the radiation target volume following TORS.
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http://dx.doi.org/10.1016/j.prro.2016.08.002DOI Listing
March 2017

Non-Straub type actin from molluscan catch muscle.

Biochem Biophys Res Commun 2016 05 24;474(2):384-387. Epub 2016 Apr 24.

Laboratory of Cell Biophysics, A.V. Zhirmunsky Institute of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences, 17 Palchevsky Str., Vladivostok 690041, Russia.

We have developed a method of obtaining natural actin from smooth muscles of the bivalves on the example of the Сrenomytilus grayanus catch muscle. The muscles were previously rigorized to prevent a loss of thin filaments during homogenization and washings. Thin filaments were isolated with a low ionic strength solution in the presence of ATP and sodium pyrophosphate. Surface proteins of thin filaments-tropomyosin, troponin, calponin and some minor actin-binding proteins-were dissociated from actin filaments by increasing the ionic strength to 0.6 M KCL. Natural fibrillar actin obtained in that way depolymerizes easily in low ionic strength solutions commonly used for the extraction of Straub-type actin from acetone powder. Purification of natural actin was carried out by the polymerization-depolymerization cycle. The content of inactivated actin remaining in the supernatant is much less than at a similar purification of Straub-type actin. A comparative investigation was performed between the natural mussel actin and the Straub-type rabbit skeletal actin in terms of the key properties of actin: polymerization, activation of Mg-ATPase activity of myosin, and the electron-microscopic structure of actin polymers.
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http://dx.doi.org/10.1016/j.bbrc.2016.04.120DOI Listing
May 2016

Troponin-like regulation in muscle thin filaments of the mussel Crenomytilus grayanus (Bivalvia: Mytiloida).

Biochim Biophys Acta 2015 Oct 26;1854(10 Pt A):1444-50. Epub 2015 Jul 26.

Laboratory of Cell Biophysics, A.V. Zhirmunsky Institute of Marine Biology, Far East Branch of Russian Academy of Sciences, 17, Palchevsky St., 690041 Vladivostok, Russia.

Muscles of bivalve molluscs have double calcium regulation--myosin-linked and actin-linked. While the mechanism of myosin-linked regulation is sufficiently studied, there is still no consensus on the mechanism of actin-linked regulation. Earlier we showed a high degree of Ca2+-sensitivity of thin filaments from the adductor muscle of the mussel Crenomytilus grayanus (Mytiloida). In order to elucidate the nature of this regulation, we isolated the fraction of minor proteins from the mussel thin filaments, which confers Ca2+-sensitivity to reconstituted actomyosin-tropomyosin. Proteins of this fraction, ABP-19, ABP-20, and ABP-28, were chromatographically purified and identified. According to the results of mass spectrometry and Western blot analysis, as well as by their functional properties, these mussel actin-binding proteins appeared to correspond to the troponin components from the skeletal muscles of vertebrates (TnC, TnI and TnT). The reconstituted mussel troponin complex confers to actomyosin-tropomyosin more than 80% Ca2+-sensitivity. The in vivo molar ratio of actin/tropomyosin/troponin was calculated to be 7:1:0.5, i.e., the content of troponin in mussel thin filaments is two times lower than in thin filaments of skeletal muscles of vertebrates. These data demonstrate that troponin-like regulation found in the catch muscle of the mussel C. grayanus is present at least in two suborders of bivalves: Pectinoida and Mytiloida.
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http://dx.doi.org/10.1016/j.bbapap.2015.07.010DOI Listing
October 2015

Hybrid and non-hybrid actomyosins reconstituted with actin, myosin and tropomyosin from skeletal and catch muscles.

Biochem Biophys Res Commun 2015 Aug 10;464(2):611-5. Epub 2015 Jul 10.

Laboratory of Cell Biophysics, A.V. Zhirmunsky Institute of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences, 17 Palchevsky Str., Vladivostok 690041, Russia.

In this study, we investigated hybrid and non-hybrid actomyosin models including key contractile proteins: actin, myosin, and tropomyosin. These proteins were isolated from the rabbit skeletal muscle and the catch muscle of the mussel Crenomytilus grayanus. Our results confirmed literature data on an unusual ability of bivalve's tropomyosin to inhibit Mg-ATPase activity of skeletal muscle actomyosin. We have shown that the degree of inhibition depends on the environmental conditions and may vary within a wide range. The inhibitory effect of mussel tropomyosin was not detected in non-hybrid model (mussel myosin + mussel actin + mussel tropomyosin). This effect was revealed only in hybrid models containing mussel tropomyosin + rabbit (or mussel) actin + rabbit myosin. We assume that mussel and rabbit myosins have mismatched binding sites for actin. In addition, mussel tropomyosin interacting with actin is able to close the binding sites of rabbit myosin with actin, which leads to inhibition of Mg-ATPase activity.
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http://dx.doi.org/10.1016/j.bbrc.2015.07.023DOI Listing
August 2015

Mucosal melanoma of the head and neck: a systematic review of the literature.

Int J Radiat Oncol Biol Phys 2014 Dec;90(5):1108-18

Department of Radiation Oncology, Mount Sinai Medical Center, New York, New York. Electronic address:

Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN.
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http://dx.doi.org/10.1016/j.ijrobp.2014.03.042DOI Listing
December 2014

Functional genomic screen identifies novel mediators of collagen uptake.

Mol Biol Cell 2014 Mar 8;25(5):583-93. Epub 2014 Jan 8.

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 Department of Medicine, University of California, San Francisco, San Francisco, CA 94158 Lung Biology Center, University of California, San Francisco, San Francisco, CA 94158 Department of Pathology, University of California, San Francisco, San Francisco, CA 94158 MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.

Tissue fibrosis occurs when matrix production outpaces matrix degradation. Degradation of collagen, the main component of fibrotic tissue, is mediated through an extracellular proteolytic pathway and intracellular pathway of cellular uptake and lysosomal digestion. Recent studies demonstrate that disruption of the intracellular pathways can exacerbate fibrosis. These pathways are poorly characterized. Here we identify novel mediators of the intracellular pathway of collagen turnover through a genome-wide RNA interference screen in Drosophila S2 cells. Screening of 7505 Drosophila genes conserved among metazoans identified 22 genes that were required for efficient internalization of type I collagen. These included proteins involved in vesicle transport, the actin cytoskeleton, and signal transduction. We show further that the flotillin genes have a conserved and central role in collagen uptake in Drosophila and human cells. Short hairpin RNA-mediated silencing of flotillins in human monocyte and fibroblasts impaired collagen uptake by promoting lysosomal degradation of the endocytic collagen receptors uPARAP/Endo180 and mannose receptor. These data provide an initial characterization of intracellular pathways of collagen turnover and identify the flotillin genes as critical regulators of this process. A better understanding of these pathways may lead to novel therapies that reduce fibrosis by increasing collagen turnover.
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http://dx.doi.org/10.1091/mbc.E13-07-0382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937085PMC
March 2014

Molluscan smooth catch muscle contains calponin but not caldesmon.

J Muscle Res Cell Motil 2013 Feb 19;34(1):23-33. Epub 2012 Oct 19.

Laboratory of Cell Biophysics, A.V. Zhirmunsky Institute of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia.

We isolated Ca(2+)-regulated thin filaments from the smooth muscle of the mussel Crenomytilus grayanus and studied the protein composition of different preparations from this muscle: whole muscle, heat-stable extract, fractions from heat-stable extract, thin filaments and intermediate stages of thin filaments purification. Among the protein components of the above-listed preparations, we did not find caldesmon (CaD), although two isoforms of a calponin-like (CaP-like) protein, which along with CaD is characteristic of vertebrate smooth muscle, were present in thin filaments. Thus, CaD is not Ca(2+)-regulator of thin filaments of this muscle. On the other hand, the mussel CaP-like protein is also not such Ca(2+)-regulator since we have shown that this protein can be selectively removed from isolated mussel thin filaments without loss of their Ca(2+)-sensitivity. We suggest that thin filaments in the smooth catch muscle possess other type of Ca(2+)-regulation, different from that in vertebrate smooth muscles.
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http://dx.doi.org/10.1007/s10974-012-9329-2DOI Listing
February 2013

Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjögren's syndrome.

Lab Invest 2012 Apr 9;92(4):556-70. Epub 2012 Jan 9.

Francis I Proctor Foundation, University of California at San Francisco, San Francisco, CA 94143, USA.

Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjögren's syndrome (SS)-associated SQM, we identified CD4(+) T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4(+) T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4(+) T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4(+) T cells. In the eye, IL-1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4(+) T-cell infiltration was only observed in the presence of IL-1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4(+) T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4(+) T cells, we observed SQM hallmarks in local tissues-corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4(+) T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study indicated a central role for IL-1 in orchestrating a functional interplay between immune cells and resident cells of SS-targeted tissues in the pathogenesis of SQM.
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http://dx.doi.org/10.1038/labinvest.2011.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725338PMC
April 2012

Interleukin-1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjögren's syndrome.

Am J Pathol 2010 Sep 9;177(3):1333-43. Epub 2010 Aug 9.

University of California, San Francisco, Francis I. Proctor Foundation, San Francisco, CA 94143, USA.

Chronic inflammation of the ocular surface in Sjögren's syndrome (SS) is associated with a vision-threatening, phenotypic change of the ocular surface, which converts from a nonkeratinized, stratified squamous epithelium to a nonsecretory, keratinized epithelium. This pathological process is known as squamous metaplasia. Based on a significant correlation between ocular surface interleukin (IL)-1beta expression and squamous metaplasia in patients with SS, we investigated the role of IL-1 in the pathogenesis of squamous metaplasia in an animal model that mimics the clinical characteristics of SS. Using autoimmune-regulator (aire)-deficient mice, we assessed lacrimal gland and ocular surface immunopathology by quantifying the infiltration of major histocompatibility complex class II(+) (I-A(d+)) dendritic cells and CD4(+) T cells. We examined squamous metaplasia using a biomarker of keratinization, small proline-rich protein 1B. We used lissamine green staining as a readout for ocular surface epitheliopathy and Alcian blue/periodic acid-Schiff histochemical analysis to characterize goblet cell muco-glycoconjugates. Within 8 weeks, the eyes of aire-deficient mice were pathologically keratinized with significant epithelial damage and altered mucin glycosylation. Although knockdown of IL-1 receptor 1 did not attenuate lymphocytic infiltration of the lacrimal gland or eye, it significantly reduced ocular surface keratinization, epitheliopathy, and muco-glycoconjugate acidification. These data demonstrate a phenotypic modulation role for IL-1 in the pathogenesis of squamous metaplasia and suggest that IL-1 receptor 1-targeted therapies may be beneficial for treating ocular surface disease associated with SS.
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http://dx.doi.org/10.2353/ajpath.2010.100227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928966PMC
September 2010

Cigarette smoke induces epidermal growth factor receptor-dependent redistribution of apical MUC1 and junctional beta-catenin in polarized human airway epithelial cells.

Am J Pathol 2010 Sep 22;177(3):1255-64. Epub 2010 Jul 22.

University of California, San Francisco, Francis I. Proctor Foundation, San Francisco, CA 94143, USA.

Cigarette smoke (CS) accounts for nearly 90% of lung cancer deaths worldwide; however, an incomplete understanding of how CS initiates preneoplastic changes in the normal airway hinders early diagnosis. Short-term exposure to CS causes aberrant activation of epidermal growth factor receptor (EGFR) and canonical Wnt/beta-catenin signaling pathways in human bronchial epithelial (HBE) cells. We hypothesize that this response is elicited through the disruption of spatially segregated cell membrane proteins in the polarized airway epithelium. Using an in vitro model of highly differentiated HBE cells, we observed membrane characteristics consistent with the native airway, including the presence of a membrane mucin, MUC1, at the apical cell pole, beta-catenin at the apical-lateral membrane, and EGFR at the basolateral membrane. Following exposure to smoke, intercellular spaces enlarge and cilia disappear. This histopathology is accompanied by molecular events that include perinuclear trafficking of basolateral EGFR, EGFR phosphorylation, pEGFR-mediated phosphorylation of MUC1's cytoplasmic tail (CT), loss of E-cadherin/beta-catenin complexes at the adherens junctions (AJs), intracellular formation and nuclear shuffling of beta-catenin/MUC1-CT complexes, and, ultimately, up-regulation and nuclear localization of Wnt nuclear effector, Lef-1. In the presence of EGFR inhibitor, AG1478, CS-induced histopathology and molecular events were inhibited. These data point to EGFR as a portal through which CS mediates its damaging effects on AJ-mediated cell polarity and activation of canonical Wnt/beta-catenin signaling.
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http://dx.doi.org/10.2353/ajpath.2010.091129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928959PMC
September 2010
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