Pencil beam kernel-based dose calculations on CT data for a mixed neutron-gamma fission field applying tissue correction factors.

Objective.For fast neutron therapy with mixed neutron and gamma radiation at the fission neutron therapy facility MEDAPP at the research reactor FRM II in Garching, no clinical dose calculation software was available in the past. Here, we present a customized solution for research purposes to overcome this lack of three-dimensional dose calculation.Approach.The applied dose calculation method is based on two sets of decomposed pencil beam kernels for neutron and gamma radiation. The decomposition was performed using measured output factors and simulated depth dose curves and beam profiles in water as reference medium. While measurements were performed by applying the two-chamber dosimetry method, simulated data was generated using the Monte Carlo code MCNP. For the calculation of neutron dose deposition on CT data, tissue-specific correction factors were generated for soft tissue, bone, and lung tissue for the MEDAPP neutron spectrum. The pencil beam calculations were evaluated with reference to Monte Carlo calculations regarding accuracy and time efficiency.Main results.In water, dose distributions calculated using the pencil beam approach reproduced the input from Monte Carlo simulations. For heterogeneous media, an assessment of the tissue-specific correction factors with reference to Monte Carlo simulations for different tissue configurations showed promising results. Especially for scenarios where no lung tissue is present, the dose calculation could be highly improved by the applied correction method.Significance.With the presented approach, time-efficient dose calculations on CT data and treatment plan evaluations for research purposes are now available for MEDAPP.

Radiosensitization to γ-Ray by Functional Inhibition of APOBEC3G.

The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 using an shRNA library and identified apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G: A3G) as a candidate target. APOBEC3G is an innate restriction factor that inhibits HIV-1 infection as a cytidine deaminase. APOBEC3G knockdown with siRNA showed an increased radiosensitivity in several cancer cell lines, including pancreatic cancer MIAPaCa2 cells and lung cancer A549 cells. Cell cycle analysis revealed that APOBEC3G knockdown increased S-phase arrest in MIAPaCa2 and G2/M arrest in A549 cells after γ-irradiation. DNA double-strand break marker γH2AX level was increased in APOBEC3G-knocked-down MIAPaCa2 cells after γ-irradiation. Using a xenograft model of A549 in mice, enhanced radiosensitivity by a combination of X-ray irradiation and APOBEC3G knockdown was observed. These results suggest that the functional inhibition of APOBEC3G sensitizes cancer cells to radiation by attenuating the activation of the DNA repair pathway, suggesting that APOBEC3G could be useful as a target for the radiosensitization of cancer therapy.

Proton therapy monitoring: spatiotemporal emission reconstruction with prompt gamma timing and implementation with PET detectors.

Objective. In this study we introduce spatiotemporal emission reconstruction prompt gamma timing (SER-PGT), a new method to directly reconstruct the prompt photon emission in the space and time domains inside the patient in proton therapy.Approach. SER-PGT is based on the numerical optimisation of a multidimensional likelihood function, followed by a post-processing of the results. The current approach relies on a specific implementation of the maximum-likelihood expectation maximisation algorithm. The robustness of the method is guaranteed by the complete absence of any information about the target composition in the algorithm.Main results. Accurate Monte Carlo simulations indicate a range resolution of about 0.5 cm (standard deviation) when considering 107primary protons impinging on an homogeneous phantom. Preliminary results on an anthropomorphic phantom are also reported.Significance. By showing the feasibility for the reconstruction of the primary particle range using PET detectors, this study provides significant basis for the development of an hybrid in-beam PET and prompt photon device.

Enhancement of Radiation Response Associated With Metformin in Hepatocellular Carcinoma: Preclinical Animal and Clinical Cohort Study.

BACKGROUND/AIM: This study examined whether metformin can enhance the radiation response in a hepatocellular carcinoma (HCC) xenograft mice model and patient population. MATERIALS AND METHODS: Huh-7 human HCC-bearing xenograft mice were treated with gamma-ray, metformin, neutron therapy, and their combinations. Tumour growth and lung colonies were assessed. Overall, 145 patients who underwent radiotherapy for HCC were retrospectively analysed. RESULTS: The combinations of gamma-ray and metformin and neutron radiation and metformin inhibited tumour growth and metastatic lung nodule formation when compared to the monotherapy and gamma-ray groups, respectively. In patients who received radiotherapy for HCC, the overall survival rate was higher in the metformin-treated group than in the non-metformin group. CONCLUSION: Metformin inhibited tumour growth and metastasis in HCC by enhancing the radiation response in animal experiments. Additionally, metformin was also found to be associated with a higher survival outcome in patients with HCC.

Low-dose but not high-dose γ-irradiation elicits the dominant-negative effect of mutant p53 in vivo.

Contrary to high doses irradiation (HDR), the biological consequences of dose irradiation (LDR) in breast cancer remain unclear due to the complexity of human epidemiological studies. LDR induces DNA damage that activates p53-mediated tumor-suppressing pathways promoting DNA repair, cell death, and growth arrest. Monoallelic p53 mutations are one of the earliest and the most frequent genetic events in many subtypes of cancer including ErbB2 breast cancer. Using MMTV/ErbB2 mutant p53 (R172H) heterozygous mouse model we found differential p53 genotype-specific effect of LDR vs. HDR on mammary tumorigenesis. Following LDR, mutant p53 heterozygous tumor cells exhibit aberrant ATM/DNA-PK signaling with defects in sensing of double-strand DNA brakes and deficient DNA repair. In contrast, HDR-induced genotoxic stress is sufficient to reach the threshold of DNA damage that is necessary for wtp53 induced DNA repair and cell cycle arrest. As a result, mutant p53 endows dominant-negative effect promoting mammary tumorigenesis after low-impact DNA damage leading to the selection of a genetically unstable proliferative population, with negligible mutagenic effect on tumors carrying wtp53 allele.

The Interference of Gamma Rays With Bone Mineral Density Measurements in 177Lu-PSMA and DOTATATE Therapy.

The main purpose was to describe the interference of gamma radiation emitted by 177Lu with simultaneous bone mineral density BMD measures for patients undergoing 177Lu-PSMA and 177Lu DOTATATE therapy. A cohort of 9 patients underwent 177Lu-PSMA therapy were randomly selected to speculate the activity in the abdominopelvic region. So that, SPECT/CT scan at 24 h was used with attenuation and scatter correction. The activities were derived from the delineated ROIs over the abdominopelvic zone showing a range of 34-274 MBq. Next, a water path was placed under spine phantom mimicking L1-L4 vertebrae and followed by consecutive DEXA scans made by Hologic 4500 W and GE-Lunar DPX-NT systems. Five scans were performed without/and with different Lu-177 activities 37, 185, 370 and 555 MBq under the same geometric conditions. The obtained BMD readings of L1-L4 by the Hologic device were 1.027, 1.024, 1.021, 1.013, and 1.006 g/cm2 with presence of 0, 37, 185, 370, and 555 MBq 177Lu activity, respectively. Whereas, in Lunar device, it was found as higher as 1.163, 1.121, 1.09, 1.072, and 1.043, respectively. There was no statistically significant difference between both devices (pvalue ≥ 0.05). The fluctuation ranges in the L1-L4 BMD readings at the presence of 37-555 MBq were 0.3%-2%, and 3.6%-10.3% for Hologic and Lunar systems, respectively. It was emphasized that gamma radiation emitted by 177Lu relatively influence DEXA scans and the yielded BMD measures. Postponing DEXA scans as early as 8 d after 177Lu-PMSA and 11 d after 177Lu-DOTATATE therapies is recommended to avoid the erroneous contribution of gamma radiation and provide precise bone assessment.

An Investigation of the Effect of Irradiation on the Biomechanical Properties of Fibular Grafts.

PURPOSE: Irradiation of fibular grafts for jaw reconstruction following mandibulectomy can be associated with increased graft failure and implant instability. The objective of this study is to investigate the effect of isolated irradiation on the biomechanical properties of ex-vivo porcine fibula grafts. It was hypothesized that the isolated irradiation (without biological response) will not significantly influence the biomechanical properties of the fibular grafts. METHODS: Forty porcine fibular grafts (n = 20 irradiated and n = 20 nonirradiated) were obtained. The irradiated group was subjected to a single dose of 60 Gy of irradiation with cesium 137. Both groups underwent 3-point bending tests with cyclic loading for 1500 cycles (50 to 500 N at 2 Hz) followed by push to failure. Rate of damage (mm/s), stiffness (N/mm), modulus of elasticity (MPa), maximum load (N), maximum displacement (mm), and maximum stress (MPa) were compared between the 2 groups using independent t tests (P < .05). RESULTS: No significant differences were found between the irradiated and nonirradiated groups for any of the biomechanical parameters (all P values > 0.05). CONCLUSIONS: The results of this study support our hypothesis that even high levels of isolated irradiation do not significantly affect the biomechanical properties of fibular bone grafts. This work allows us to exclude acute structural changes in the bone due to irradiation as a possible factor leading to bone/implant instability following jaw reconstruction with fibular grafts. Further studies need to be conducted to better understand the range of factors that may lead to implant instability, including the biological response after radiation therapy.

A comparative study on hypofractionated whole-breast irradiation with sequential or simultaneous integrated boost on different positions after breast-conserving surgery.

This study explored the dosimetric difference between hypofractionated whole-breast irradiation (HFWBI) with sequential boost (SEB) and simultaneous integrated boost (SIB) based on supine and prone positions to identify the superior boost mode and superior position. Thirty breast cancer patients eligible for HFWBI after breast-conserving surgery were enrolled. All patients underwent 3DCT simulation scanning in both supine and prone positions. For the SEB-HFWBI plan, the dose prescribed for the planning target volume (PTV) of whole breast (WB) was 2.67 Gy per fraction with a total of 15 fractions, followed by a sequential boost of 3.2 Gy per fraction to the PTV of tumor bed (TB) in 3 fractions. For the SIB-HFWBI plan, the dose prescribed for the PTV of WB was 2.67 Gy per fraction with a total of 15 fractions, with a simultaneously integrated boost of 3.2 Gy per fraction to the PTV of TB with a total of 15 fractions. Regardless of the position, for the PTV of TB, the conformal index (CI) in the SIB-HFWBI plans was greater than those in the SEB-HFWBI plans (T = - 8.114, - 8.114; both P < 0.05). The CI for the PTV of WB increased significantly in the prone position relative to the supine position in both two plans(Z = - 3.340, - 3.501; all P < 0.05). The study suggested that prone SIB-HFWBI might be more suitable for postoperative radiotherapy after breast-conserving surgery for early-stage breast cancer patients.

Encapsulated Gamma Source Contact Dose Conversion Factors: Updating NCRP-40 Guidance.

ABSTRACT: Secondary electron generation on the surface of encapsulated gamma sources can play a large role in the dose measured near the surface of the encapsulation. The National Council on Radiation Protection and Measurements Report No. 40 contains contact dose rate conversion factors for encapsulated gamma sources, along with recommended secondary electron correction factors. However, secondary electron correction factors were based on experiments performed in the 1930s and 1940s with encapsulated radium sources, and the correction factors for the other sources listed in the report were estimated based on these radium source measurements. Monte Carlo simulations were performed using the Particle and Heavy Ion Transport code System (PHITS) to calculate the contact dose rate conversion factors for each encapsulated gamma source presented in NCRP-40, taking into account the dose from both gamma rays and secondary electrons. These simulations showed that the contact dose rate conversion factors are much lower than those presented in NCRP-40, and the secondary electron contribution was much greater than the values proposed by NCRP-40. The original research used results from encapsulated 226Ra experiments to determine the secondary electron correction factors for NCRP-40. To support the current Monte Carlo calculations, experiments were conducted using an encapsulated 137Cs source, rare earth magnet, and ion chamber detector to show that the secondary electron correction factors presented in NCRP-40 were not applicable to the geometry of tissue in direct contact with the encapsulation. In this work, contact dose conversion factors for common encapsulated radionuclide sources are presented.

High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors.

PURPOSE: The use of high-dose per fraction radiotherapy delivered as stereotactic body radiotherapy is a standard of care for prostate cancer. It is hypothesized that high-dose radiotherapy may enhance or suppress tumor-reactive immunity. The objective of this study was to assess both antitumor and immunosuppressive effects induced by high-dose radiotherapy in prostate cancer coclinical models, and ultimately, to test whether a combination of radiotherapy with targeted immunotherapy can enhance antitumor immunity. EXPERIMENTAL DESIGN: We studied the effects of high-dose per fraction radiotherapy with and without anti-Gr-1 using syngeneic murine allograft prostate cancer models. The dynamic change of immune populations, including tumor-infiltrating lymphocytes (TIL), T regulatory cells (Treg), and myeloid-derived suppressive cells (MDSC), was evaluated using flow cytometry and IHC. RESULTS: Coclinical prostate cancer models demonstrated that high-dose per fraction radiotherapy induced a rapid increase of tumor-infiltrating MDSCs and a subsequent rise of CD8 TILs and circulating CD8 T effector memory cells. These radiation-induced CD8 TILs were more functionally potent than those from nonirradiated controls. While systemic depletion of MDSCs by anti-Gr-1 effectively prevented MDSC tumor infiltration, it did not enhance radiotherapy-induced antitumor immunity due to a compensatory expansion of Treg-mediated immune suppression. CONCLUSIONS: In allograft prostate cancer models, high-dose radiotherapy induced an early rise of MDSCs, followed by a transient increase of functionally active CD8 TILs. However, systemic depletion of MDSC did not augment the antitumor efficacy of high-dose radiotherapy due to a compensatory Treg response, indicating blocking both MDSCs and Tregs might be necessary to enhance radiotherapy-induced antitumor immunity.

Proton therapy range verification method via delayed γ-ray spectroscopy of a molybdenum tumour marker.

In this work, a new method of range verification for proton therapy (PT) is experimentally demonstrated for the first time. If a metal marker is implanted near the tumour site, its response to proton activation will result in the emission of characteristic γ rays. The relative intensity of γ rays originating from competing fusion-evaporation reaction channels provides a unique signature of the average proton energy at the marker, and by extension the beam's range, in vivo and in real time. The clinical feasibility of this method was investigated at the PT facility at TRIUMF with a proof-of-principle experiment which irradiated a naturally-abundant molybdenum foil at various proton beam energies. Delayed characteristic γ rays were measured with two Compton-shielded LaBr3 scintillators. The technique was successfully demonstrated by relating the relative intensity of two γ-ray peaks to the energy of the beam at the Mo target, opening the door to future clinical applications where the range of the beam can be verified in real time.

Nanogels as prospective Biomaterial: Radio-induced Synthesis, Characterization, and Biological Assays / Los nanogeles como biomateriales prospectivos: síntesis radioinducida, caracterización y ensayos biológicos

Nowadays, there is a growing interest in biodegradable polymers-based materials due to their diverse application in the biomedical field. Most studied systems involve biocompatible micro and nanodevices, such as liposomes, dendrimer, micelles or polymeric nanogels. The use of Radiation Technology, specifically gamma radiation, to produce micro and nanogels raises the possibility to obtain higher purity products, an important feature for biomedical and pharmaceutical applications. The radio-induced synthesis, characterization, cytotoxicity evaluation, and immunological response of nanogels are described in this study. Nanogel synthesis was performed in the absence of oxygen using aqueous polyvinylpyrrolidone solutions. Crosslinking reactions were carried out at 25 °C in a gamma irradiation chamber with a 60Co source. Nanogels properties were analysed by Scanning Electron Microscopy, Attenuated Total Reflection-Fourier Transform Spectroscopy, Dynamic Light Scattering, and Viscosimetry. The cytotoxicity and immunological response were evaluated by MTT test and analysis of the neutrophil respiratory burst. The results showed that nanogels formation strongly depends on the total absorbed dose. The nanogels have an elliptical shape and their chemical structure is similar to the initial polymer. The nanogels are biocompatible and promote a low-intensity neutrophil activation, similar to the well-characterized biomaterial TiO2, suggesting their potential biomedical uses(AU)

En la actualidad existe un interés creciente en los materiales biodegradables basados en polímeros, debido a sus diversas aplicaciones en la esfera de la biomedicina. En la mayoría de los sistemas estudiados participan micro- y nanodispositivos biocompatibles, tales como liposomas, dendrímeros, micelas o nanogeles poliméricos. El uso de la tecnología de radiaciones, en particular de radiaciones gamma, para producir micro- y nanogeles, eleva la posibilidad de obtener productos de mayor pureza, un rasgo importante con vistas a su aplicación biomédica y farmacéutica. El estudio describe la síntesis radioinducida, caracterización, evaluación de la citotoxicidad y respuesta inmunológica de los nanogeles. La síntesis de los nanogeles se realizó en ausencia de oxígeno, usando soluciones acuosas de polivinilpirrolidona. Las reacciones de entrecruzamiento se realizaron a 25 ºC en cámara de irradiación gamma con una fuente de 60Co. Las propiedades de los nanogeles se analizaron mediante microscopía electrónica de barrido, espectroscopia por transformada de Fourier total atenuada, dispersión dinámica de luz y viscosimetría. La citotoxicidad y la respuesta inmunológica se evaluaron mediante prueba MTT y análisis del estallido respiratorio de neutrófilos. Los resultados muestran que la formación de nanogeles depende en gran medida de la dosis total absorbida. Los nanogeles tienen forma elíptica y su estructura química es similar a la del polímero inicial. Los nanogeles son biocompatibles y promueven una activación de neutrófilos de baja intensidad similar al bien caracterizado material TiO2, lo que sugiere usos biomédicos potenciales(AU)

Pro-apoptotic and anti-neoplastic impact of luteolin on solid Ehrlich carcinoma.bearing mice exposed to gamma radiation.

BACKGROUND: Cancer remains a major health issue and the second foremost root of morbidity worldwide behind cardiovascular diseases. Apoptosis had linked to the eradication of possibly malignant cells, hyperplasia, and tumor progression. OBJECTIVE: The present study is an endeavor to evaluate the influence of luteolin, a modifier to apoptotic regulator on the tumor growth and the tumor cell sensitivity to ionizing radiation in Ehrlich solid tumor-bearing mice (E). MATERIALS AND METHODS: Mice were immunized with Ehrlich carcinoma cells (2.5 × 106 cells/mouse), received consecutive equal doses of luteolin, 1.25 mg/mouse/day and exposed to 6.5 Gy of whole-body gamma irradiation (0.46 Gy/min). RESULTS: Luteolin markedly suppresses the developing of tumor in E mice group or mice which bearing tumor with exposure to radiation (E + R group) which has collimated with significant inhibition in protein expression of inflammatory molecules cyclooxygenase 2 and the concentration of (prostaglandin E2). Also, matrix metalloproteinase-2, 9 proteins concentrations significantly decreased with amelioration in apoptotic regulators (Caspase-3 and Granzyme-B activities). The expression of signal transducer and activator of transcription (STAT) and tumor necrosis factor-alpha genes meliorated significantly. Besides, the level of oxidant/antioxidant (reduced glutathione/malondialdehyde) markedly improved. Obviously, the most reduction of changes in all measured parameters has appeared in tumor bearing mice, injected with luteolin and exposed to gamma radiation (E + Luteolin + R group). CONCLUSION: It could be suggested that luteolin has a potential beneficial effect against cancer. This could be due to its ability on the induction of apoptosis, inhibition of inflammatory response, downregulation of angiogenic factors as well as increase sensitivity of tumor cells to gamma radiation.

A novel methylation signature predicts radiotherapy sensitivity in glioma.

Glioblastoma (GBM) is the most common and malignant cancer of the central nervous system, and radiotherapy is widely applied in GBM treatment; however, the sensitivity to radiotherapy varies in different patients. To solve this clinical dilemma, a radiosensitivity prediction signature was constructed in the present study based on genomic methylation. In total, 1044 primary GBM samples with clinical and methylation microarray data were involved in this study. LASSO-COX, GSVA, Kaplan-Meier survival curve analysis, and COX regression were performed for the construction and verification of predictive models. The R programming language was used as the main tool for statistical analysis and graphical work. Via the integration analysis of methylation and the survival data of primary GBM, a novel prognostic and radiosensitivity prediction signature was constructed. This signature was found to be stable in prognosis prediction in the TCGA and CGGA databases. The possible mechanism was also explored, and it was found that this signature is closely related to DNA repair functions. Most importantly, this signature could predict whether GBM patients could benefit from radiotherapy. In summary, a radiosensitivity prediction signature for GBM patients based on five methylated probes was constructed, and presents great potential for clinical application.

The Effect of Ionizing Radiation on Cognitive Functions in Mouse Models of Alzheimer's Disease.

The present study demonstrates the effect of combined ionizing radiation (γ rays, 0.24 Gy, 661.7 keV, whole body and 12C, 0.18 Gy, 450 MeV, head region) on the behavior of animals in mouse transgenic models of Alzheimer's disease. Significant improvement of spatial learning and stimulation of locomotor and exploratory behavior were observed in wild-type mice after irradiation. However, an anxiolytic effect and stimulation of locomotor and exploratory behavior were revealed in irradiated mice with tauopathy. Mice with cerebral amyloidosis also exhibited improved learning in the odor recognition test. No negative effects of irradiation were detected.

Stochastic growth pattern of untreated human glioblastomas predicts the survival time for patients.

Glioblastomas are highly malignant brain tumors. Knowledge of growth rates and growth patterns is useful for understanding tumor biology and planning treatment logistics. Based on untreated human glioblastoma data collected in Trondheim, Norway, we first fit the average growth to a Gompertz curve, then find a best fitted white noise term for the growth rate variance. Combining these two fits, we obtain a new type of Gompertz diffusion dynamics, which is a stochastic differential equation (SDE). Newly collected untreated human glioblastoma data in Seattle, US, re-verify our model. Instead of growth curves predicted by deterministic models, our SDE model predicts a band with a center curve as the tumor size average and its width as the tumor size variance over time. Given the glioblastoma size in a patient, our model can predict the patient survival time with a prescribed probability. The survival time is approximately a normal random variable with simple formulas for its mean and variance in terms of tumor sizes. Our model can be applied to studies of tumor treatments. As a demonstration, we numerically investigate different protocols of surgical resection using our model and provide possible theoretical strategies.

Spatiotemporal Mislocalization of Nuclear Membrane-Associated Proteins in γ-Irradiation-Induced Senescent Cells.

Cellular senescence, induced by genotoxic or replication stress, is accompanied by defects in nuclear morphology and nuclear membrane-heterochromatin disruption. In this work, we analyzed cytological and molecular changes in the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins in senescence triggered by γ-irradiation. We used human mammary carcinoma and osteosarcoma cell lines, both original and shRNA knockdown clones targeting lamin B receptor (LBR) and leading to LBR and lamin B (LB1) reduction. The expression status and integrity of LINC complex proteins (nesprin-1, SUN1, SUN2), lamin A/C, and emerin were analyzed by immunodetection using confocal microscopy and Western blot. The results show frequent mislocalization of these proteins from the nuclear membrane to cytoplasm and micronuclei and, in some cases, their fragmentation and amplification. The timing of these changes clearly preceded the onset of senescence. The LBR deficiency triggered neither senescence nor changes in the LINC protein distribution before irradiation. However, the cytological changes following irradiation were more pronounced in shRNA knockdown cells compared to original cell lines. We conclude that mislocalization of LINC complex proteins is a significant characteristic of cellular senescence phenotypes and may influence complex events at the nuclear membrane, including trafficking and heterochromatin attachment.

Peripheral T-cell lymphoma with gastrointestinal involvement and indolent T-lymphoproliferative disorders of the gastrointestinal tract.

The 2017 WHO classification includes a new provisional entity of indolent T-lymphoproliferative disorders of the gastrointestinal tract (ITLPD-GIT). We investigated GI involvement of peripheral T-cell lymphoma (PTCL). Eighty-two patients were diagnosed with PTCL during 2007-2017. Eleven patients (13 %) had histologically-confirmed GI tract involvement {3 monomorphic epitheliotropic intestinal lymphoma (MEITL), 3 extranodal NK-/T-cell lymphoma nasal type (ENKL), 2 PTCL, not otherwise specified, 1 adult T-cell leukemia-lymphoma, 2 ITLPD-GIT}. Three patients each had lesions in the small intestine and multiple lesions, two each in the stomach and colon, and one in the duodenum. Six of the 11 patients remained alive. No perforation/stenosis was observed after chemo-radiotherapy, although one patient with ENKL developed gastric bleeding during chemotherapy. One patient with ITLPD-GIT (CD4-/CD8+/Ki67Low) with a colonic lesion showing diffuse edema and multiple aphtha by endoscope and diarrhea, initially diagnosed with MEITL, had active but stable disease after various chemotherapies for 1 year and no therapy for the next 5 years. Another patient with ITLPD-GIT (CD4+/CD8+/Ki67Low) with a localized gastric lesion and slight epigastralgia was in remission for 1 year after radiation. In conclusion, about 10 % of PTCLs were complicated by GI tract lesions and most had a poor prognosis. ITLPD-GIT should be considered as a differential diagnosis based on histology and clinical course. Local complications after chemo/radiotherapy in PTCL with GI involvement were not frequent.

Amelioration of adjuvant-induced arthritis by exposure to low dose gamma radiation and resveratrol administration in rats.

Purpose: Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of low dose radiation with the minimum exposure level in arthritic rats by concurrent administration of resveratrol (RSV) as an adjunctive therapy with anti-inflammatory properties.Materials and methods: Rats were rendered arthritic by sub-plantar injection of Freund's complete adjuvant (FCA) and exposed to low dose radiation at a total exposure level of 0.5 Gy (2 × 0.25). During the exposure course, RSV (50 mg/kg) was orally administered once daily for two weeks. Diclofenac (3 mg/kg) was administered as a standard anti-inflammatory drug. Paw volume was measured every 4 days. After 28 days of induction, rats were sacrificed and serum was collected for estimation of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), thiobarbituric acid reactive substances (TBARS), and total nitrate/nitrite (NOx). Furthermore, paws were dissected for histopathological examinations and immuno-histochemical estimation of nuclear factor-kappa B p65 (NF-κB p65) expression.Results: Administration of RSV during the low dose radiation exposure course produced a significant decrease in the paw swelling and a potentiated inhibition in the serum levels of TNF-α, IL-1ß, TBARs, and NOx. The dual treatment strategy alleviated the histopathological damage to a greater extent than that produced by each treatment. Moreover, a pronounced suppression of NF-κB p65 expression in the synovial tissue was observed in the combination group. The combination treatment showed a nearly similar potency to that observed in the diclofenac treated group.Conclusion: Administration of RSV augmented the modulatory activity of low dose radiation with minimum exposure level on the disease progression.

Targeting AKT/PKB to improve treatment outcomes for solid tumors.

The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBß) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA, RAS, PDPK1, and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy.