Effect of stereotactic radiation (SBRT) on survival in a preclinical model of spontaneous pancreatic cancer with induction gemcitabine/nab-paclitaxel.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 273-273
Author(s):  
Cullen M. Taniguchi ◽  
Jessica Molkentine ◽  
Tara N Fujimoto ◽  
Lauren Elizabeth Colbert ◽  
Amit Deorukhkar ◽  
...  
Keyword(s):  
Small Animal ◽  
Pancreatic Tumors ◽  
Preclinical Model ◽  
Metastatic Progression ◽  
P53 Expression ◽  
Preclinical Trial ◽  
Stereotactic Radiation ◽  
Kaplan Meier ◽  
Local Progression ◽  
Accelerated Repopulation

273 Background: There are no useful preclinical models that resemble relevant fractionated radiation, such as SBRT, with relevant chemotherapy. Most preclinical studies use a single fraction of radiation to large fields, causing significant toxicity and/or insufficient dose which leads to accelerated repopulation and worsened outcomes. Here, we employ mice with spontaneous pancreatic tumors, and treat them in a preclinical trial utilizing gemcitabine/nab-paclitaxel +/-SBRT. Methods: Mice with an activated KRas (G12D) allele and heterozygous for p53 expression only in the pancreas (KPC) were created and spontaneous tumors were diagnosed via weekly palpation and ultrasound. Mice with single tumors that were between 3-7mm at diagnosis were sequentially randomized to received either no treatment, gemcitabine/nab-paclitaxel x 2 weeks, or gemcitabine/nab-paclitaxel x 2 weeks followed by 8Gy x 5 daily fractions of SBRT to the pancreatic tumor. SBRT was delivered using X-RAD 225Cx (Precision X-Ray, Inc) small animal irradiator under image guidance by cone beam micro CT using AP/PA technique with a 10mm collimator. Every mouse was subjected to necropsy and a cause of death assigned. Tumor growth was monitored by small animal ultrasound. Kaplan-Meier survival analysis was performed to assess efficacy of treatments. Results: A total of 40 mice were enrolled with 12 receiving chemotherapy alone, 13 receiving chemotherapy +SBRT and 15 mice had no further treatment. The addition of induction chemotherapy improves lifespan compared to untreated mice. The addition of SBRT further improved survival. Causes of death in untreated animals of the gemcitabine/nab-paclitaxel group were largely from local progression, whereas the addition of SBRT provided local control causing most of the mice in this cohort to die from metastatic progression. Conclusions: SBRT improves survival when added to gem/nab-paclitaxel in a preclinical model, which may reflect favorable biology for this approach. Our novel system employs similar SBRT fields and doses, and may thus be useful for the evaluation of other chemotherapeutic regimens with SBRT.

Invasive penile carcinoma: Are p16, p53 and HPV ISH prognostically significant?

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 394-394
Author(s):  
Jasreman Dhillon ◽  
Anders E. Berglund ◽  
Julio Pow-Sang ◽  
Philippe E. Spiess ◽  
Anthony M. Magliocco
Keyword(s):  
Tumor Cells ◽  
Staining Intensity ◽  
Hpv Infection ◽  
Clinicopathological Characteristics ◽  
Hazard Ratio ◽  
Penile Carcinoma ◽  
P53 Expression ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Low Incidence

394 Background: Penile carcinoma accounts for 0.4% to 0.6% of all malignancies in men. Due to its low incidence the prognostic role of clinicopathological characteristics, p16, p53 and HPV infection remains unclear. We report our experience with p16, p53 and HPV ISH (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66) in determining the aggressive nature of this carcinoma. Methods: A tissue microarray (TMA) of 57 cases of invasive penile squamous cell carcinomas was immunohistochemically stained with immunohistochemical stains p16 and p53. HPV ISH was performed as well. The TMA slides were scored semi quantitatively by a specialized genitourinary surgical pathologist. The H score was calculated for p53 using a combination of staining intensity and extent according to the following formula: H score = 1 x % of tumor cells with weak staining + 2 x % of tumor cells with moderate staining + 3 x % of tumor cells with strong staining, resulting in a total score of 0 – 300. Calculations for p53 were done considering values above 0 as positive. For p16 and HPV ISH, the results were recorded as negative or positive. The overall survival curves for up to 60 months were estimated by Kaplan-Meier (KM) method. Results: HPV ISH was positive in 23 cases and p16 was positive in 23 cases as well. However, there were 9 discordant cases between the two (p16+/HPV ISH- = 5; p16-/HPV ISH+ = 4). p53 was positive in 39 cases. Tumors positive for HPV ISH had a better survival as compared to HPV ISH negative tumors (p = 0.0040; Hazard ratio 4.991). Whereas p16 (p = 0.206; Hazard ratio 1.838) and p53 (p = 0.1582; Hazard ratio 0.5198) were not significantly associated with survival at 60 months. Conclusions: Overall HPV positive penile carcinomas appear to have a distinct biology with better prognosis. There is no significant difference in survival for tumors with different p16 and p53 expression.

A window of opportunity trial of atorvastatin in p53-mutant and p53 wild type malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3165-TPS3165 ◽  
Author(s):  
Mohammad Telfah ◽  
Tomoo Iwakuma ◽  
Andres Bur ◽  
Lisa Shnayder ◽  
Terry Tsue ◽  
...  
Keyword(s):  
Pilot Trial ◽  
Xenograft Model ◽  
Post Treatment ◽  
Rational Approach ◽  
Cancer Center ◽  
Preclinical Model ◽  
Window Of Opportunity ◽  
Wild Type ◽  
P53 Expression ◽  
Pre Treatment

TPS3165 Background: Mutations in p53 contribute to tumor progression. A rational approach is to destabilize mutant (m) p53. The group at the University of Kansas Cancer Center screened compounds that suppress m p53 in a preclinical model. Luciferase-based reporter assay identified statins as suppressors of m p53 expression. In vitro validation assay demonstrated atorvastatin (A) suppressed m p53 level and cell growth selectively; and depletion of mevalonic acid lead to degradation of m p53. These effects were limited to mutations in the conformation of p53, while wild-type and DNA contact mutations were not as sensitive to statin-induced degradation of p53. M p53 xenograft model confirmed that A could suppress tumor growth at a concentration that can decrease LDL level. The primary objective of this trial is to determine if A decreases the level of conformational m p53. The secondary objective is to assess the effects of A on Ki-67 and caspase-3 in conformational m p53 tumors. Methods: This is an open-label, window of opportunity pilot trial to see if A given for 1 to 4 weeks at a dose of 80 mg/day is sufficient to reduce the levels of conformational m p53 in the tumor tissues. Subjects with new diagnosis of malignancy with a planned surgical therapy, and subjects with previously treated AML, in between treatment regimens, are eligible. Tissues from solid tumors, and bone marrow or peripheral blood samples from AML will be used to screen for m p53 by immunohistochemistry (IHC). Subjects will receive A at 80 mg/day po for 1 to 4 weeks. Pharmacokinetics at pre-dose and 1-hour post-dose on Day 1 and on the day of surgery will be done. Mutational analysis using exome sequencing technique will be done on m p53. Using IHC, the amount of p53 in pre-treatment and post-treatment samples will be measured and compared simultaneously. The levels of Ki67 and caspace-3 will be tested and compared between pre-treatment and post-treatment samples in subjects with conformational m p53, between conformational and non-conformational m p53, and in wild-type p53 tumors. The trial is actively enrolling subjects. The results of this trial will determine further investigations on the role of atorvastatin in tumors with p53 mutations in a placebo-controlled, randomized trial. Clinical trial information: NCT03560882.

Prognostic role of β-catenin and p53 expression in the metastatic progression of sporadic colorectal cancer

2010 ◽  
Vol 41 (6) ◽  
pp. 867-876 ◽  
Author(s):  
Massimo Pancione ◽  
Nicola Forte ◽  
Alessandra Fucci ◽  
Lina Sabatino ◽  
Antonio Febbraro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Sporadic Colorectal Cancer ◽  
Metastatic Progression ◽  
Prognostic Role ◽  
P53 Expression

MR-guided Gated Stereotactic Radiation Therapy Delivery for Lung, Adrenal, and Pancreatic Tumors: A Geometric Analysis

2018 ◽  
Vol 102 (4) ◽  
pp. 858-866 ◽  
Author(s):  
John R. van Sörnsen de Koste ◽  
Miguel A. Palacios ◽  
Anna M.E. Bruynzeel ◽  
Ben J. Slotman ◽  
Suresh Senan ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Geometric Analysis ◽  
Pancreatic Tumors ◽  
Stereotactic Radiation Therapy ◽  
Stereotactic Radiation ◽  
Therapy Delivery

scholarly journals Clinical Effects of Stereotactic Body Radiation Therapy Targeting the Primary Tumor of Liver-Only Oligometastatic Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoqin Ji ◽  
Yulu Zhao ◽  
Chenglong He ◽  
Siqi Han ◽  
Xixu Zhu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Propensity Score ◽  
Primary Tumor ◽  
Performance Status ◽  
Clinical Effects ◽  
Metastatic Progression ◽  
Efficacy And Safety ◽  
Good Performance Status ◽  
Local Progression ◽  
Head Of Pancreas

AimTo investigate the efficacy and safety of stereotactic body radiotherapy (SBRT) targeting the primary tumor for liver-only oligometastatic pancreatic cancer.MethodsWe compared the efficacy and safety of SBRT plus chemotherapy with chemotherapy alone in patients with liver-only oligometastatic pancreatic cancer. The populations were balanced by propensity score-weighted and propensity score-matched analyses based on baseline variables. The primary outcome was overall survival (OS). The secondary outcomes included progression free survival (PFS), local progression, metastatic progression and symptomatic local control.ResultsThis is a retrospective study of 89 pancreatic cancer patients with liver-only oligometastasis. Overall, 34 (38.2%) and 55 (61.8%) patients received SBRT plus chemotherapy and chemotherapy alone, respectively. After propensity score matching, 1-year OS rate was 34.0% (95%CI, 17.8-65.1%) in the SBRT plus chemotherapy group and 16.5% (95%CI, 5.9-46.1%) in chemotherapy alone group (P=0.115). The 6-month PFS rate was 29.4% (95%CI, 15.4-56.1) in SBRT plus chemotherapy and 20.6% (95%CI, 8.8-48.6) in chemotherapy alone group (P=0.468), respectively. Further subgroup analysis indicated that the addition of SBRT improved OS in patients with primary tumor located in the head of pancreas (stratified HR, 0.28; 95% CI, 0.09 to 0.90) or good performance status (stratified HR, 0.24; 95% CI, 0.07 to 0.86). In terms of disease control, SBRT delayed local progression of pancreas (P=0.008), but not distant metastatic progression (P=0.56). Besides, SBRT offered significant abdominal/back pain relief (P=0.016) with acceptable toxicities.ConclusionsThe addition of SBRT to chemotherapy in patients with liver-only oligometastatic pancreatic cancer improves the OS of those with primary tumor located in the head of pancreas or good performance status. In addition, it is a safe and effective method for local progression control and local symptomatic palliation in patients with metastatic pancreatic cancer.

scholarly journals Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection

2020 ◽  
Author(s):  
Kyle Rosenke ◽  
Kimberly Meade-White ◽  
Michael Letko ◽  
Chad Clancy ◽  
Frederick Hansen ◽  
...  
Keyword(s):  
Syrian Hamster ◽  
Treatment Options ◽  
Interleukin 2 ◽  
Small Animal ◽  
Infection Model ◽  
Preclinical Model ◽  
Gamma Chain ◽  
Infectious Dose ◽  
Virus Shedding ◽  
Mild Disease

AbstractFollowing emergence in late 2019, SARS-CoV-2 rapidly became pandemic and is presently responsible for millions of infections and hundreds of thousands of deaths worldwide. There is currently no approved vaccine to halt the spread of SARS-CoV-2 and only very few treatment options are available to manage COVID-19 patients. For development of preclinical countermeasures, reliable and well-characterized small animal disease models will be of paramount importance. Here we show that intranasal inoculation of SARS-CoV-2 into Syrian hamsters consistently caused moderate broncho-interstitial pneumonia, with high viral lung loads and extensive virus shedding, but animals only displayed transient mild disease. We determined the infectious dose 50 to be only five infectious particles, making the Syrian hamster a highly susceptible model for SARS-CoV-2 infection. Neither hamster age nor sex had any impact on the severity of disease or course of infection. Finally, prolonged viral persistence in interleukin 2 receptor gamma chain knockout hamsters revealed susceptibility of SARS-CoV-2 to adaptive immune control. In conclusion, the Syrian hamster is highly susceptible to SARS-CoV-2 making it a very suitable infection model for COVID-19 countermeasure development.One Sentence SummaryThe Syrian hamster is highly susceptible to SARS-CoV-2 making it an ideal infection model for COVID-19 countermeasure development.

Clinical features and outcome in primary breast sarcomas (BS): Analysis of a single-institution experience

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e21520-e21520
Author(s):  
T. Ramon y Cajal ◽  
J. Mazarico ◽  
A. Lopez Pousa ◽  
M. Quintana ◽  
N. Sala ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Univariate Analysis ◽  
Low Grade ◽  
High Grade ◽  
Single Institution ◽  
Local Spread ◽  
Kaplan Meier ◽  
Local Progression ◽  
Clinicopathological Variables

e21520 Background: BS are characterised by local spread and recurrence. Controversy remains about local and adjuvant treatment. The objective of this retrospective study was to analyze clinical and pathological prognostic factors influencing the outcome of BS patients. Methods: We analyzed clinicopathological variables, treatment and outcome of 33 BS patients treated at our institution from 1966 to 2007. A single pathologist reviewed pathologic diagnoses. Kaplan Meier method was used to evaluate outcome. Mean age: 44 years (20–82y. Tumor size 57 (0–230) mm. Pathology: 17 cistosarcoma phylodes (CPh), 9 angiosarcoma, 2 extraesqueletical osteosarcoma, 2 fibrosarcomas, 1 liposarcoma, 1 leiomiosarcoma, 1 malignant fibrous histiocitoma (2.9%). Low-grade in 12, high-grade in 15 pts. Mastectomy in all but 8 patients. Adjuvant chemotherapy and radiotherapy in 9 and 7 patients. Pathological stage I- 12%, II- 65%, III- 9%, IV-3% Results: Median follow-up 71 (5–239) months. Median survival 160 months. Survival was 83%, 74% and 59% at 5, 10 and 15 year. 5/8 (62.5%) local excision patients needed rescue surgery due to local progression. 8/25 (32%) mastectomy patients progressed Local recurrence in 9 pts, distant 4 pts (radical rescue surgery in 10 pts). 7 pts death only 1 phyllodes. Mean 15-year survival for CPh was 169 vs 124 months for other histologies (p 0.06). In the univariate analysis we didn't found statistical differences according to clinical & pathological factors, stage and recurrence, on OS or PFS. Conclusions: CPh have better prognosis than other BS although its stage or size tends to be higher. Radical surgery in BS should be always considered as first treatment option. High-grade non-phylodes BS types may be considered for adjuvant chemotherapy although there were non-statistical differences in OS. No significant financial relationships to disclose.

Identification of distinct phenotypes of locally advanced pancreas cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 369-369
Author(s):  
MinYuen Teo ◽  
Grace Frances Crotty ◽  
Criostoir O'Suilleabhain ◽  
Derek Gerard Power ◽  
Raymond S. McDermott
Keyword(s):  
Radiographic Progression ◽  
Early Recognition ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
Teaching Hospitals ◽  
Rank Test ◽  
Metastatic Progression ◽  
Histologic Diagnosis ◽  
Entire Cohort ◽  
Local Progression

369 Background: A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease (LAPC). Optimal treatment remains controversial. There is no consensus on timing of chemotherapy and radiotherapy. We sought to analyse the clinical course of LAPC in order to identify potential distinct clinical phenotypes. Methods: Patients (pts) diagnosed with LAPC who survived >2 months were identified from prospectively maintained databases from two medical oncology departments in teaching hospitals. Demographics and clinical details were collected. Sequential restaging scans were reviewed for each pts to identify date and pattern of progression. Time to progression (TTP), time from progression to death (TTD) and overall survival (OS) were defined as time from histologic diagnosis to time of radiographic progression, time from radiographic progression to death and the summation of TTP and TTD, respectively. Survival was estimated with Kaplan-Meier method and compared with log-rank test. Results: Between Mar 2005 and Apr 2011, a total of 40 pts were identified. Median age was 66yrs (range: 43 – 74) and 60%(n=24) were males. Median OS for entire cohort was 11.3mos. Of 40 pts, 20(50%) had local only progression (LP) and 16(40%) had metastatic progression (MP) at first documentation of disease progression, while 4 pts (10%) had stable disease (2 died with no evidence of progression and 2 remain on treatment). TTP was 4.0 vs 5.6mos HR 0.97 (95% CI 0.49 – 1.93, p=.94) for LP and MP, respectively. Three of the pts with LP (15%) eventually developed metastatic disease after a median of 4.2 mths (3.7 – 9.6). For MP pts, five had concurrent local progression. Sites of disease were lungs(8), peritoneum(5), liver(3) and bone(1). TTD for LP and MP was 5.6 vs 1.4mos HR 0.62 (95% CI 0.28 – 1.39, p=.24), and OS was 13.2 vs 8.0mos, HR 0.59 (95% CI 0.28 – 1.25, p=.17) respectively. Conclusions: We identified two subgroups of LAPC with clinically distinctive behaviour, one local-dominant progression with low predilection for distant metastases, and another with rapid metastatic development and worse survival. Early recognition of these phenotypes might allow a more tailored treatment approach to improve outcome.

A gene signature to determine metastatic behavior in thymic carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7605-7605
Author(s):  
Yesim Gokmen-Polar ◽  
Robert W. Cook ◽  
Jeffrey Wilkinson ◽  
Derek Maetzold ◽  
John F Stone ◽  
...  
Keyword(s):  
Gene Signature ◽  
Anterior Mediastinum ◽  
Low Risk ◽  
Metastatic Progression ◽  
Kaplan Meier ◽  
Independent Analysis ◽  
Metastatic Behavior ◽  
Asco 2012 ◽  
Prediction Of Metastasis ◽  
Improve Patient Management

7605 Background: Thymomas and thymic carcinomas (TC) are rare epithelial tumors derived from the thymic gland in the anterior mediastinum. Although all histological types of thymomas, albeit with different frequencies, can give rise to metastases, TC have a more aggressive behavior and metastasize earlier and more frequently than thymomas. We previously developed a prognostic gene signature able to accurately determine metastatic behavior of thymomas (Gökmen-Polar et al. ASCO 2012). The signature is currently used in clinical practice to identify patients at high or low risk for metastatic disease. In the current study, we sought to evaluate the utility of this signature for determining risk from TC tumors. Methods: FFPE tissue sections were macrodissected from 35 primary TC. RNA was isolated and RT-PCR was performed to assess the expression of 23 genes (19 test and four reference genes). Predictive modeling was performed using Radial Basis Machine (RBM) software from JMP Genomics (SAS), and survival analysis was done using the Kaplan-Meier method. Results: Samples from the TC cohort ranged from stage II through IVB, with a median age of 54 years. 26 samples had evidence of metastatic progression, while nine samples did not. Prediction of metastasis, based upon comparison to the previously developed thymoma training set and using a 19-gene signature, yielded an ROC = 0.66. Independent analysis of the TC cohort with the thymoma 19-gene signature resulted in a predictive model with an ROC = 0.97 (overall accuracy = 87%, sensitivity = 73% and specificity=100%). Further modeling and gene set reduction revealed a separate ten-gene signature able to segregate metastatic from non-metastatic cases with 100% accuracy. All the cases classified as high risk (n= 26) developed metastasis within 5 years while none of the cases categorized as low-risk (n= 9) had any events at 5 years of follow-up. Conclusions: A ten-gene signature was established that appears to predict metastatic behavior of TC with a high degree of accuracy; however, validation in an independent cohort is necessary. Our data suggests that the biologic determinants of the clinical course of TC maybe distinct from thymoma and could be used to improve patient management.

Multiomic molecular comparison of primary versus metastatic pancreatic tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 213-213
Author(s):  
Gagandeep Brar ◽  
Edik Blais ◽  
R Joseph Bender ◽  
Jonathan Brody ◽  
Davendra Sohal ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Pancreatic Tumors ◽  
Molecular Characteristics ◽  
Metastatic Progression ◽  
Molecular Architecture ◽  
Protein Markers ◽  
Primary Tumors ◽  
Exact Test ◽  
Molecular Alterations ◽  
Metastatic Lesions

213 Background: Pancreatic cancer metastasizes very early, as evidenced by the fact that > 70% of patients with operable disease ultimately develop metastases. Thus, it is likely that the molecular characteristics of primary pancreatic tumors are similar to metastatic lesions. We compared the frequency of genetic alterations and protein expression from primary vs. metastatic pancreatic tumors, and from metastases from different sites. By focusing on actionable genetic and proteomic information, we sought to explore whether targeted therapies could be tailored to patients at metastatic progression based on primary surgical material. Methods: Next generation DNA sequencing (NGS) data of 208 genes and a limited set of protein markers were analyzed from pancreatic tumors of 431 patients enrolled in the Know Your Tumor initiative. Of the 208 genes tested, mutations in 70 were considered potentially actionable based on preclinical and clinical evidence. We compared 146 primary pancreatic tumors against 285 metastatic lesions, and examined subgroups for liver vs. lung vs. other metastatic lesions. Molecular alterations were compared between independent groups for each gene/protein using Fisher’s exact test. Significance was assessed using a false discovery rate adjusted q-value threshold of 0.05. Results: No differences in the specific mutation or expression pattern were observed between primary vs. metastatic lesions, nor across the site of metastasis after correcting for multiple hypotheses. Even the proportion of actionable alterations (including mutations in the homologous recombination DNA repair pathway) was similar across subgroups. Conclusions: Comparison of the muli-omic profile of primary vs. metastatic pancreatic adenocarcinoma reveals that the molecular architecture is very similar, and that actionable alterations are identified at the same frequency. This is unlike the data observed from other solid tumors, (e.g. colon and breast cancer), in which substantial molecular discordance and heterogeneity exists between primary tumors and metastatic sites, but is consistent with the belief that primary pancreatic cancers metastasize early and thus are molecularly indistinguishable from metastatic lesions.

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