Local Control Of Tumor Growth Research Articles

Effect of pseudoprogression of vestibular schwannomas on dynamics of trigeminal and facial nerves dysfunction after stereotactic radiosurgery

The use of stereotactic radiosurgery (SRS) in the treatment of vestibular schwannomas (VS) is due to a high level of local control of tumor growth, a lower level of functional impairment, a relatively low cost of treatment compared to microsurgery, and the preservation of a high quality of life [1–7]. The development of post-radiation pseudoprogression of the VS can lead to increased compression of adjacent brain structures, including the trigeminal and facial nerves with the appearance of their irritation or lack of function. The purpose of the study: to investigate the effect of post-radiation pseudoprogression on the function of cranial nerves 5 and 7 after SRS. Material and methods. The analysis included 128 patients with 3 or more control MRIs and a follow-up period of 12 months and over, who had at least 3 control examinations by a neurologist and otoneurologist. The median clinical follow-up was 52 months. The analyzed patients (n=128) were divided into 2 main groups: group 1 (n=99) — without previous microsurgery (MS), group 2 (n=29) — previously operated patients. Results. Irritation of nerves 5 and 7 is observed after SRS for VS exclusively against the background of pseudoprogression. Persistent de novo facial nerve failure after SRS is a rare complication (0.9 %). Symptoms of dysfunction of the 5th and 7th nerves predominate in the group of large VS (stages C and D according to Hasegawa) (p<0.0001). The prolonged course of pseudoprogression determines a tendency to longer dysfunction of the cranial nerves, but does not affect the final result. Conclusion. Irritation of the 5th and 7th nerves, relieved by anticonvulsants, is not an indication for surgical removal of the tumor or re-irradiation, as it goes away on its own due to subsequent natural shrinkage of the tumor. However, the pharmacoresistant course of trigeminal neuralgia may be due to compression of the trigeminal nerve root between the tumor and petrous apex, and therefore subtotal tumor removal may be justified for root decompression.

Focused Ultrasound for Blood-Brain Barrier Opening and Delivery of Anti-PD1 in Diffuse Midline Gliomas

Diffuse midline glioma with H3K27 mutation is a fatal pediatric brain tumor, most commonly arising in the brainstem. This tumor remains universally fatal, despite a multitude of clinical trials, with a median overall survival of only 9-12 months. While immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors, delivery past the blood brain barrier (BBB) remains challenging. Programmed cell death protein 1 (PD1) is an immune checkpoint protein expressed on the surface of activated T cells; interaction with its ligand, PDL1, is tumor-protective, dampening T cell response. Recent phase I clinical trials have shown that ICIs targeting proteins along the PD1/PDL1 axis are well tolerated in patients with DMG; however, efficacy remains low. The blood-brain barrier (BBB) poses a major challenge to the efficacious delivery of therapeutic agents with large molecular size, such as anti-PD1. We hypothesize that BBB opening (BBBO) using focused ultrasound (FUS), a form of non-ionizing acoustic radiation, can enhance delivery and efficacy of anti-PD1 for treatment of DMG. We established a syngeneic mouse DMG model with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). Magnetic resonance imaging (MRI) was utilized to evaluate BBBO and tumor progression. We measured delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1. We demonstrate that delivery of anti-PD1 can be enhanced over 3.5-fold after reversible BBBO with FUS and concurrent microbubble administration. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrate that combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival. Our results support that FUS-mediated BBBO can increase treatment efficacy of anti-PD1 in a DMG murine model, due to improved targeted delivery to the tumoral region after systemic antibody administration. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.

Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor.

Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3- NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL.

SURG-06. ENHANCED DELIVERY OF ANTI-PD1 FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA USING FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING

Abstract Diffuse midline glioma with H3K27 mutation is a fatal central nervous system tumor, most commonly arising in the brainstem. Despite a multitude of clinical trials, prognosis remains poor with a median overall survival of 9-12 months. Immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors. Programmed cell death protein 1 (PD1) is an immune checkpoint protein expressed on the surface of activated T cells; interaction with its ligand, PDL1, is tumor-protective, dampening T cell response. Recent phase I clinical trials have shown that ICIs targeting proteins along the PD1/PDL1 axis are well tolerated in patients with DMG; however, efficacy remains low. The blood-brain barrier (BBB) poses a major challenge to the efficacious delivery of therapeutic agents with large molecular size, such as anti-PD1. Here we show that delivery of anti-PD1 can be enhanced over 3.5-fold using low intensity focused ultrasound (FUS) and concurrent microbubble administration to achieve reversible blood-brain barrier opening (BBBO) in a syngeneic mouse DMG model established with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). We measured this increased delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrated that this combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.

Surgical and interventional treatment options in unresectable gastrointestinal cancer

Abstract Palliative care comprehends a crucial interdisciplinary approach for affected patients. Control of local tumor growth and cancer-related symptoms, improved survival and quality life are the most relevant goals within palliative therapy. Surgery can contribute to palliative care addressing all three above-mentioned issues. This review article, based on a systematic literature search in Medline, Web of Science, and Cochrane Library summarizes current surgical and interventional therapies as part of best care of patients with palliative gastrointestinal cancer.

Metastasectomy and Targeted Therapy for Patients With Spinal Metastases of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is an aggressive malignant disease that frequently metastasizes to the spine. The main purpose of our study is to evaluate the influence of surgery as well as targeted therapy on the survival of patients with RCC metastases of the spine. Retrospective cohort study. We identified 100 patients with spinal RCC metastases who were retrospectively reviewed for preoperative conditions, treatment, and survival. Metastasectomy was performed in 39 cases, and 61 patients underwent decompression procedures with stabilization. Only 26 patients had adjuvant targeted therapy (7 with metastasectomy, 19 with palliative decompression). Pain, neurological status, survival time (from operation to death or last follow up), and local progression-free survival were evaluated. Neurological function recovery and reported significant pain relief were observed. There was no significant difference in overall survival for the patients with metastasectomy and palliative decompression (P = .750). Metastasectomy provided better local control of disease compared with decompression (P = .043). There was a statistically significant difference in overall survival for the patients who received targeted therapy (P = .012). Metastasectomy is effective for local control of tumors. Targeted therapy can potentially prolong overall survival for patients with spinal RCC metastases. 3. Our findings suggest that spinal metastasectomy is useful for local control of tumor growth but not for live expectancy. Effective systemic therapy is key role in stopping of disease progression.

P14.103 Patterns of diffuse glioma progression

Abstract BACKGROUND According to WHO 2016 Classification, all gliomas are considered potentially malignant. Earlier it was thought that the ultimate goal for treatment is local control of tumor growth: maximal surgical resection with subsequent local radiotherapy +/- chemotherapy. Disease progression was primarily linked only to local relapse. In the recent years, different progression patterns of diffuse glioma were identified: from distant growth into an anatomically unrelated area far from primary lesion, to bone metastases and even to visceral organ metastases. MATERIAL AND METHODS In this study we analyzed glioblastoma progression patterns in a cohort of 170 patients, who received radiation therapy as one of the treatment options for local relapse in Burdenko Neurosuregry Institute. All patients had a first relapse of glioblastoma at the age of 16 to 74 years old, 72 patients were female and 98 male. All patients initially underwent surgery and local radiotherapy (in combination with temozolomide) for a solitary supratentorial lesion of glioblastoma. Various methods of radiotherapy (including radiosurgery and hypofractionated radiation therapy) were used as one of the treatment options for recurrent tumor. One of our aims was to evaluate glioblastoma progression patterns in this cohort. RESULTS Comparing neuroimaging data at the time of tumor progression with initial MRI we found that in 127 of 170 patients disease progression was identified anatomically close to the primary tumor site, i.e. disease progressed as a local relapse. Recurrent lesions without obvious anatomical relation to primary site were identified in 33 patients (19.4%); in particular, 7 patients had a lesion in contralateral hemisphere, one patient had spinal subarachnoid dissemination. A combination of local and distant tumor progression was identified in 10 of these 33 patients. CONCLUSION We identified the following progression patterns for diffuse glioma based to these data and previous clinical experience: (a) local brain relapse - anatomically close to the primary lesion; (b) brain and spinal subarachnoid spread; (c) distant relapse - anatomically unrelated to primary tumor (can be both in ipsilateral or contralateral brain hemisphere); (d) local tumor progression as infiltration of soft tissues of the head and cranial bones; (e) regional lymph node metastases; (f) distant metastases - skeletal bone metastases and/or visceral organ metastases. Naturally, different combinations of these diffuse malignant glioma progression patterns are possible. A quite high incidence and differences between diffuse glioma progression patterns require a more thorough evaluation both because of treatment strategies as well as to understand the origins of glial tumors (e.g. Why in some cases of complete remission at the primary tumor site there is tumor progression in contralateral hemisphere?)

Analysis of the EF-14 Phase 3 Trial Reveals That Tumor-Treating Fields Alter Progression Patterns in Glioblastoma

The EF-14 [NCT00916409] trial showed that addition of alternating electric fields (Tumor Treating Fields, TTFields) to Temozolomide (TMZ) resulted in improved survival in newly diagnosed Glioblastoma (GBM) patients with supratentorial tumors treated compared to TMZ alone. TTFields delivery is planned to optimize dose at the tumor bed, leading to the hypothesis that TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorial brain where TTFields dose is minimal when targeting the supratentorium. Here we present analysis of the EF-14 trial testing this hypothesis. Patients on treatment for more than two months who had an MRI that exhibited progression were included in the study (treatment: N=280/466, control: N=122/229). Regions of enhancing tumor, necrosis, and resection were contoured on T1 contrast MRIs acquired at baseline and at the date of first progression. New lesions at progression were classified as distal if they appeared outside of a Proximal Boundary Zone (PBZ) of 20 mm surrounding the lesions identified in the baseline MRI. The rate of occurrence of distal progressions in the TTFields-treated arm was compared to the rate observed in the control arm. Patients with (distal) infratentorial progression were identified. Distal progressions were more common in the treatment arm (49/280 (18%) vs. 10/122 (8%) P<0.02; chi-squared). Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs. 0 patients in the control (P<0.002 t-test). Distal lesions at progression were more distant from the original lesion in the TTFields treated arm (58.57 + 28.12 mm vs 46.61 + 20.48 mm, P<0.02; Wilcoxon rank sum test. The relative tumor growth rates in TTFields treated patients were significantly slower than those observed in the control arm (0.036+ 0.126 ml/day vs. 0.036+ 0.183 ml/day P<0.03; t-test). This analysis indicates that adding TTFields to TMZ could impact GBM growth patterns. The results suggest that TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease.

Abstract CT205: Tumor Treating Fields alters progression patterns in glioblastoma: An imaging analysis of the EF-14 Phase III trial

Abstract Introduction: Tumor Treating Fields (TTFields) are alternating electric fields delivered via transducer arrays placed on the scalp The EF-14 [NCT00916409] trial showed improved survival outcomes in newly diagnosed Glioblastoma (GBM) patients treated with TTFields plus Temozolomide (TMZ) versus TMZ alone We analysed EF-14 data to test the hypothesis that because TTFields delivery is planned to optimize dose at the tumor bed: TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorium, the region where TTFields dose is minimal when planning treatment to target primary tumors in the supratentorium Tumor growth rates are slower in patients treated with TMZ+TTFields Methods: Patients on treatment for more than two months who exhibited radiological progression were included in the study (treatment: N=280/466, control: N=122/229) Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs taken at baseline and at the date of first progression reported by the treating center Progressions were classified into three groups: Local progressions: &amp;lt;3mm from the original tumor or resection cavity; Distal progressions: &amp;gt;3 mm from the original tumor or resection cavity; Combined local and distal progressions: both local and distal progressions were visible The growth rate of the tumor was estimated and the distance between the original lesions and new distal lesions was measured Patients with (distal) infratentorial progression were identified. Results: More cases of non local (distal or combined local and distal) progression were observed in the treatment arm The difference between the groups was not statistically significant (69/280 vs 23/122 P&amp;lt;0 15 chi-squared) Distal lesions at progression were more distant from the original lesion in the TTFields treated arm Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs 0 patients in the control (P&amp;lt;0 002 t-test) Mean tumor growth rate was higher in the control arm (control: 0 078 ml/day, TTFields: 0 036 ml/day P&amp;lt;0 05 Wilcoxon rank sum test). Conclusions: This imaging analysis of the EF-14 Phase III trial demonstrates that adding TTFields to TMZ has substantial impact on GBM growth patterns and rate In addition to prolongation of survival times during TTFields treatment, this is another validation for the local efficacy of TTFields therapy TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease Further studies are needed to elucidate the association between progression and TTFields dose distributions. Citation Format: Suriya Jeyapalan, Steven A. Toms, Andreas Hottinger, Lawrence Kleinberg, Erqi Pollom, Scott G. Soltys, Martin Glas. Tumor Treating Fields alters progression patterns in glioblastoma: An imaging analysis of the EF-14 Phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT205.

Analysis of the EF-14 phase III trial reveals that tumor treating fields alter progression patterns in glioblastoma.

2055 Background: The EF-14 [NCT00916409] trial showed that addition of alternating electric fields (Tumor Treating Fields, TTFields) to Temozolomide (TMZ) resulted in improved survival in newly diagnosed Glioblastoma (GBM) patients with supratentorial tumors treated compared to TMZ alone. TTFields delivery is planned to optimize dose at the tumor bed, leading to the hypothesis that TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorial brain where TTFields dose is minimal when targeting the supratentorium. Here we present analysis of the EF-14 trial testing this hypothesis. Methods: Patients on treatment for more than two months who had an MRI that exhibited progression were included in the study (treatment: N=280/466, control: N=122/229). Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs acquired at baseline and at the date of first progression. New lesions at progression were classified as distal if they appeared outside of a Proximal Boundary Zone (PBZ) of 20 mm surrounding the lesions identified in the baseline MRI. The rate of occurrence of distal progressions in the TTFields-treated arm was compared to the rate observed in the control arm. Patients with (distal) infratentorial progression were identified. Results: Distal progressions were more common in the treatment arm (49/280 (18%) vs. 10/122 (8%) P&lt;0.02; chi-squared). Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs. 0 patients in the control (P&lt;0.002 t-test). Distal lesions at progression were more distant from the original lesion in the TTFields treated arm (58.57 + 28.12 mm vs 46.61 + 20.48 mm, P&lt;0.02; Wilcoxon rank sum test. The relative tumor growth rates in TTFields treated patients were significantly slower than those observed in the control arm (0.036+ 0.126 ml/day vs. 0.036+ 0.183 ml/day P&lt;0.03; t-test). Conclusions: This analysis indicates that adding TTFields to TMZ could impact GBM growth patterns. The results suggest that TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease. Clinical trial information: NCT00916409.

Combining abiraterone and radiotherapy in metastatic castration-resistant prostate cancer: a review of current evidence.

Prostate cancer is the second most frequent cancer worldwide, with a very high rate of progression despite treatment. The most aggressive form of the disease is known as castration-resistant prostate cancer, which carries a poor prognosis. We reviewed available literature regarding the combination of abiraterone acetate antihormonal drug and ablative radiation therapy for the treatment of metastatic castration-resistant prostate cancer. This dual treatment may enhance the effects of second-line hormonal therapy, as radiotherapy renders cancer cells more prone to immune-mediated cytotoxicity. Moreover, radiotherapy exerts its effect both on directly irradiated cells and on other distant tissues, with an abscopal effect, already demonstrated in other solid tumors. This combination treatment is safe and effective, with few adverse events. Moreover, it is of paramount importance in patients with oligoprogression of the primary disease, when current guidelines recommend continuing abiraterone treatment. Ablative radiation therapy is a noninvasive, nontoxic treatment with very high efficacy on local tumor growth control. In the available literature, the combination of radiation therapy and abiraterone acetate has prolonged both overall survival and progression-free survival, with a positive impact also on locoregional recurrence and distant metastases.

Radiation effects on antitumor immune responses: current perspectives and challenges.

Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies.

Effects of proton beam irradiation on mitochondrial biogenesis in a human colorectal adenocarcinoma cell line.

Proton beam therapy has recently been used to improve local control of tumor growth and reduce side-effects by decreasing the global dose to normal tissue. However, the regulatory mechanisms underlying the physiological role of proton beam radiation are not well understood, and many studies are still being conducted regarding these mechanisms. To determine the effects of proton beams on mitochondrial biogenesis, we investigated: mitochondrial DNA (mtDNA) mass; the gene expression of mitochondrial transcription factors, functional regulators, and dynamic-related regulators; and the phosphorylation of the signaling molecules that participate in mitochondrial biogenesis. Both the mtDNA/nuclear DNA (nDNA) ratio and the mitochondria staining assays showed that proton beam irradiation increases mitochondrial biogenesis in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced aggressive HT-29 cells. Simultaneously, proton beam irradiation increases the gene expression of the mitochondrial transcription factors PGC-1α, NRF1, ERRα, and mtTFA, the dynamic regulators DRP1, OPA1, TIMM44, and TOM40, and the functional regulators CytC, ATP5B and CPT1-α. Furthermore, proton beam irradiation increases the phosphorylation of AMPK, an important molecule involved in mitochondrial biogenesis that is an energy sensor and is regulated by the AMP/ATP ratio. Based on these findings, we suggest that proton beam irradiation inhibits metastatic potential by increasing mitochondrial biogenesis and function in TPA-induced aggressive HT-29 cells.

Boost of Immune Responses Against NY-ESO-1 Following Local Radiation Therapy in Patients with Multiple Myeloma: A Potential Contribution to Tumor Immunosurveillance

IntroductionLocal radiation therapy (RT) is commonly employed to treat bone lesions and/or extramedullary manifestations of multiple myeloma (MM) or solitary bone plasmacytoma (SBP). Besides providing sufficient control of local tumor growth, radiation therapy may also contribute to broader anti-tumor immunity by generating off-site cellular immune responses. Here, we put a focus on tumor-associated antigens (TAAs) well known for their expression in MM such as Wilms' Tumor Protein 1 (WT1), New York esophageal squamous cell carcinoma 1 (NY-ESO-1), human telomerase reverse transcriptase (hTERT), mucin 1 (MUC1), and preferentially expressed antigen of melanoma (PRAME) and assessed CD8-mediated immune responses before and during radiation.MethodsWe prospectively recruited HLA-A*02:01-positive patients with multiple myeloma or solitary plasmacytoma requiring local radiation therapy for bone and extramedullary lesions in this scientific, non-interventional study, supported by a grant of the Wilhelm Sander Foundation, Germany, and approved by our local ethical committee. All patients provided written informed consent. Immune responses against HLA-A*02:01-restricted peptides of WT1, NY-ESO-1, hTERT, MUC1, and PRAME were assessed at three different time points: prior to RT, end of RT and six to eight weeks after RT. CD8+ T lymphocytes were isolated from peripheral blood and stimulated with irradiated, peptide-pulsed T2 cells (174 x CEM.T2; ATCC® CRL-1992™). After extraction of total RNA, Interferon gamma (IFNγ) mRNA expression was analyzed by RT-qPCR. IFNγ mRNA levels were normalized to CD8 mRNA levels. IFNγ mRNA expression of cells stimulated with the irrelevant melanoma antigen Glycoprotein 100 (gp100) served as calibrator. An expression level of 2.0 or more as compared to gp100 was considered as a positive result. Furthermore, an intracellular cytokine staining assay to detect IFNγ release in peptide-stimulated cells was employed to confirm PCR results on a protein level. Peptide-pulsed T2 cells also served as targets in CD107a degranulation assays.ResultsTo date, 19 patients including 16 MM and three SBP patients received fractionated local RT with or without concomitant systemic therapy. 13 patients were previously untreated; three patients received prior allogeneic and five prior autologous hematopoietic stem cell transplantation. At baseline, positive immune responses were frequently detected against NY-ESO-1 (10 out of 17 assessed patients; 58.8%) but interestingly not against hTERT, WT1, MUC1 or PRAME (see Figure). Consequently, baseline immune responses against NY-ESO-1 were significantly higher (p<0.001) as compared to all other TAAs investigated (Kruskal Wallis test). These median response levels against NY-ESO-1 further increased in the course of radiation therapy and were confirmed by flow cytometry on a protein level. The functionality and specificity of these responses could be demonstrated in degranulation assays suggesting the ability to deliver efficient anti-tumor immunity.ConclusionsImmunity against NY-ESO-1 was preexisting in the majority of patients and was undergoing marked expansion under local radiotherapy. This phenomenon was not found for any other TAA investigated suggesting that NY-ESO-1 carries a unique immunogenicity justifying most recent attempts to employ NY-ESO-1 as a target for genetically engineered T lymphocytes. Finally, this tumor-specific immunity is likely to contribute to immunosurveillance of multiple myeloma additionally supported by immune modulatory drugs applied for treatment such as IMiDs and proteasome inhibitors. [Display omitted] DisclosuresKnop:Takeda: Consultancy. Einsele:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau. Mielke:MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Novartis: Consultancy; Celgene: Other: Travel grants, Speakers Bureau; JAZZ Pharma: Speakers Bureau.

Inhibitory effects of proton beam irradiation on integrin expression and signaling pathway in human colon carcinoma HT29 cells.

Proton radiotherapy has been established as a highly effective modality used in the local control of tumor growth. Although proton radiotherapy is used worldwide to treat several types of cancer clinically with great success due to superior targeting and energy deposition, the detailed regulatory mechanisms underlying the functions of proton radiation are not yet well understood. Accordingly, in the present study, to assess the effects of proton beam on integrin-mediated signaling pathways, we investigated the expression of integrins related to tumor progression and integrin trafficking, and key molecules related to cell adhesion, as well as examining phosphorylation of signaling molecules involved in integrin-mediated signaling pathways. Proton beam irradiation inhibited the increase in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced integrin β1 protein expression and the gene expression of members of the integrin family, such as α5β1, α6β4, αvβ3, and αvβ6 in human colorectal adenocarcinoma HT-29 cells. Simultaneously, the gene expression of cell adhesion molecules, such as FAK and CDH1, and integrin trafficking regulators, such as RAB4, RAB11, and HAX1, was decreased by proton beam irradiation. Moreover, proton beam irradiation decreased the phosphorylation of key molecules involved in integrin signaling, such as FAK, Src, and p130Cas, as well as PKC and MAPK, which are known as promoters of cell migration, while increased the phosphorylation of AMPK and the gene expression of Rab IP4 involved in the inhibition of cell adhesion and cell spreading. Taken together, our findings suggest that proton beam irradiation can inhibit metastatic potential, including cell adhesion and migration, by modulating the gene expression of molecules involved in integrin trafficking and integrin-mediated signaling, which are necessary for tumor progression.

Percutaneous cryoablation for inoperable malignant lung tumors: Midterm results

ObjectiveTo retrospectively analyze the efficacy and short- to mid-term survival rate of cryoablation for malignant lung tumors. MethodsPercutaneous CT-guided cryoablation for 45 malignant lung tumors in 26 patients during 41 sessions from 2009 to 2013 were performed. Follow up CT-scan were used to determine local tumor progression. Survival rate, local tumor control rate and associated risk factors were analyzed. ResultsThe immediate during and short-term complications with CTCAE grade 2 or upper include pneumothorax (15%), pleural effusion (20%), pulmonary hemorrhage (24%), pneumonitis (15%), hemothorax (15%), hemoptysis (10%), pain (20%), bronchopleural fistula (n=1), and empyema (n=2). Life-threatening bleeding or hemodynamic instability was not observed. There was no procedural-related mortality. Overall survival rate of 1, 2, 3years are 96%, 88%, 88%. For curative intent, local tumor control (LTC) rate of 1, 2, 3years are 75%, 72%, 72%. ConclusionCryoablation for malignant lung tumors is effective and feasible in local control of tumor growth, with good short- to mid-term survival rate, as an alternative option for inoperable patients.

Impact of Radiation Therapy on Stem Cell Harvest in Multiple Myeloma

Background:Bone disease is a hallmark of multiple myeloma (MM) and destructive osteolytic bone lesions affect more than 80 % of patients resulting in pain, spinal cord compression and a reduced quality of life. Local radiation therapy (RT) is generally used to achieve rapid improvement of bone pain, control of local tumor growth and recalcification of osseous lesions. However, patients with a high tumor burden, eligible for high dose therapy and autologous stem cell transplantation (ASCT) require systemic treatment with three to four cycles of induction therapy followed by stem cell harvest and high dose therapy. So far, it remains uncertain, if RT prior to mobilization influences stem cell harvest in newly diagnosed patients with MM.Methods:We retrospectively analyzed the impact of RT on stem cell harvest and outcome in 168 transplant-eligible patients with newly diagnosed symptomatic MM (median age 57 years, range 28-73 years). All patients received RT to symptomatic lytic bone lesions before (n=114) or after (n=54) stem cell harvest and high dose therapy. A median of three cycles induction therapy was applied followed by mobilization therapy before stem cell harvest and high dose therapy. We analyzed, whether RT before stem cell collection influenced the number of leukaphereses needed to achieve stem cell yield, the number of stem cells collected per leukapheresis and the total number of collected stem cells. Additionally, we investigated if timing of RT influenced progression-free (PFS) and overall survival (OS) after high-dose therapy and ASCT.Results:Patients receiving RT before stem cell harvest needed more than one leukapheresis to collect the planned number of stem cells (before: 68.8%; after: 44.2%; p=0.09). The median number of stem cells collected per leukapheresis was significantly lower in patients treated with RT before harvest (before: 2.6 x 106 CD34+ cells per kg / bodyweight, after: 3.8 x 106 CD34+ cells per kg / bodyweight; p<0.001). Also the total median number of collected stem cells was significantly lower in the group treated with RT before stem cell harvest (before: 9.0 x 106 CD34+ cells per kg/bodyweight, after: 10.3 x 106CD34+ cells per kg/bodyweight; p<0.02). Patients treated with RT after stem cell harvest showed a longer PFS (48.9 months) compared to the group receiving RT before harvest (36.3 months; p=0.09). No effect on OS was observed.Conclusion:We demonstrate that RT before stem cell harvest negatively influences stem cell collection in patients with symptomatic MM. Furthermore, we observed a negative trend towards shorter PFS in the group treated with RT before stem cell collection. Therefore, we suggest applying RT after stem cell mobilization in transplant-eligible patients with MM if clinically possible. DisclosuresWuchter:Sanofi: Honoraria; ETICHO: Consultancy, Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

Enhance the Absorption of Gamma-ray Energy inside the Tumor Using Gold Nanoparticles and Iodine Particles

The problem of searching ways to enhance efficiency of cancer treatment is extremely important. One of the currently recognized methods of treatment is radiation therapy. However, efficiency of radiotherapy is limited by radiosensitivity of intact tissues surrounding the tumor on the one hand, and by radioresistance of the malignancy on the other hand. The problem of overcoming radiation resistance of tumors is a key element in the local control of tumor growth (1). Introduction of radiosensitizers into a tumor with subsequent irradiation results in secondary radiation inside the tumor, thus increasing the effect of radiotherapy. Various substances capable of converting ionizing radiation can serve as radiosensitizers. This may be diagnostic preparations containing heavy chemical elements, such as iodine, gadolinium, gold nanoparticles, platinum and other chemicals (5). The aim of our experiment was selection of a drug which would give a significant increase of the secondary radiation in biological tissues when irradiating with gamma rays (GR) with the energy of 1.25 MeV. We used as a radiation sensitizer a drug containing gold nanoparticles and iodine particles which, when introduced directly into a tumor, will increase energy of the radiation inside the tumor without increasing the dose permitted according to the plan of exposure.

The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response—Biological and Clinical Aspects

Radiation therapy remains an imperative treatment modality for numerous malignancies. Enduring significant technical achievements both on the levels of treatment planning and radiation delivery have led to improvements in local control of tumor growth and reduction in healthy tissue toxicity. Nevertheless, resistance mechanisms, which presumably also involve activation of DNA damage response signaling pathways that eventually may account for loco-regional relapse and consequent tumor progression, still remain a critical problem. Accumulating data suggest that signaling via growth factor receptor tyrosine kinases, which are aberrantly expressed in many tumors, may interfere with the cytotoxic impact of ionizing radiation via the direct activation of the DNA damage response, leading eventually to so-called tumor radioresistance. The aim of this review is to overview the current known data that support a molecular crosstalk between the hepatocyte growth factor receptor tyrosine kinase MET and the DNA damage response. Apart of extending well established concepts over MET biology beyond its function as a growth factor receptor, these observations directly relate to the role of its aberrant activity in resistance to DNA damaging agents, such as ionizing radiation, which are routinely used in cancer therapy and advocate tumor sensitization towards DNA damaging agents in combination with MET targeting.

Proton beam irradiation suppresses metastatic capabilities of human cancer cells

Proton radiotherapy has been established as a highly effective modality for the local control of tumor growth. Proton therapy has the advantage over conventional photon beam in that the tumor can be targeted with extreme precision without harming healthy surrounding tissue. The eradication of the metastatic potential of cancer cells is crucial for achieving survival in most patients with cancer. We examined the biological properties of human colorectal adenocarcinoma cells after irradiation with a proton beam to assess their metastatic processes by measuring the cell’s capability to adhere to an extracellular matrix, the expression of integrins, and cell migration. Cell adhesion assays were done to assess cancer cell’s capabilities to adhere to an extracellular matrix, and the capability of human colorectal adenocarcinoma cells irradiated with a proton beam to adhere to an extracellular matrix was large than that of adenocarcinoma cells that had not been irradiated. The mean fluorescence intensity of integrins, which plays a crucial role in cell adhesion to extracellular matrix and cell migration, was analyzed by using flow cytometry analyses. The expression level of β1 integrin was increased after proton beam irradiation. However, the amount of ανβ3 integrin was not changed by proton irradiation. Treatment of human colorectal adenocarcinoma cells with increasing doses of proton irradiation led to a dose-dependent decrease in cell migration. Our data indicated that the metastatic capabilities of human colorectal adenocarcinoma cells may be suppressed by using proton irradiation, which inhibits cancer cell adhesion and migration.