Radiation therapy and immunotherapy-a potential combination in cancer treatment.

Background: Radiation therapy (rt) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells. Methods: The aim of the present work was to review current concepts of rt and immunotherapy synergism, the abscopal effect, and the molecular effects of rt in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response. Results: Up-to-date literature concerning the mechanisms, interactions, and latest knowledge about rt and immunotherapy was reviewed and summarized, and is presented here. Conclusions: The possibility of using hyperfractionated rt to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments.

Quantitative SPECT imaging and biodistribution point to molecular weight independent tumor uptake for some long-circulating polymer nanocarriers.

Polymeric nanocarriers are promising entities for cancer diagnosis and therapy. The aim of such nanocarriers is to selectively accumulate in cancerous tissue that is difficult to visualize or treat. The passive accumulation of a nanocarrier in a tumor through extravasation is often attributed to the enhanced permeation and retention (EPR) effect and the size and shape of the nanocarrier. However, the tumor microenvironment is very heterogeneous and the intratumoral pressure is usually high, leading to different opinions about how the EPR of nanocarriers through the irregular vasculature of a tumor leads to accumulation. In order to investigate this topic, we studied methods for the determination of pharmacokinetic parameters, biodistribution and the tumor uptake of nanocarriers. More specifically, we used non-invasive quantitative Single-Photon Emission Computed Tomography/Computed Tomography (qSPECT/CT) imaging of hyperbranched polyglycerols (HPGs) to explore the specific biodistribution and tumor uptake of six model nanocarriers in Rag2m mice. We were interested to see if a distinct molecular weight (MW) of nanocarriers (HPG 25, 50, 100, 200, 300, 500 kDa) is favoured by the tumor. To trace the model nanocarriers, HPGs were covalently linked to the strong chelator desferrioxamine (DFO), and radiolabeled with the gamma emitter 67Ga (EC = 100%, E γ = 185 keV (21.4%), 300 keV (16.6%), half-life = 3.26 d). Without the need for blood collection, but instead using qSPECT/CT imaging inside the heart, the blood circulation half-lives of the 67Ga labeled HPGs were determined and increased from 9.9 ± 2.9 to 47.8 ± 7.9 hours with increasing polymer MW. Total tumor accumulation correlated positively with the circulation time of the HPGs. Comparing the tumor-to-blood ratio dynamically revealed how blood and tumor concentrations of the nanocarrier change over time and when equilibrium is reached. The time of equilibrium is size-dependent and increases with molecular weight. Furthermore, the data indicate that for larger MWs, nanocarrier uptake and retention by the tumor is size independent. Further studies are necessary to advance our understanding of the interplay between MW and nanoparticle accumulation in tumors.

BCL2 and MYC are expressed at high levels in canine diffuse large B-cell lymphoma but are not predictive for outcome in dogs treated with CHOP chemotherapy.

Diffuse large B-cell lymphoma (DLBCL) is the most common haematopoietic malignancy in dogs. Recently, MYC and BCL2 expression levels determined with immunohistochemistry (IHC) were found to be prognostic in people with DLBCL. We hypothesized that canine DLBCL can be similarly subdivided into prognostic subtypes based on expression of MYC and BCL2. Cases of canine DLBCL treated with CHOP chemotherapy were retrospectively collected and 43 dogs had available histologic tissue and complete clinical follow-up. Median values of percent immunoreactive versus immunonegative cells were used to determine positive or negative expression status. Completion of CHOP was significantly associated with a positive outcome. Compared with human patients, our canine DLBCL patients had high IHC expression of both MYC and BCL2, and relative expression levels of one or both markers were not associated with clinical outcome.

Imaging study of using radiopharmaceuticals labeled with cyclotron-produced 99mTc.

Cyclotron-produced 99mTc (CPTc) has been recognized as an attractive and practical substitution of reactor/generator based 99mTc. However, the small amount of 92-98Mo in the irradiation of enriched 100Mo could lead to the production of other radioactive technetium isotopes (Tc-impurities) which cannot be chemically separated. Thus, these impurities could contribute to patient dose and affect image quality. The potential radiation dose caused by these Tc-impurities produced using different targets, irradiation conditions, and corresponding to different injection times have been investigated, leading us to create dose-based limits of these parameters for producing clinically acceptable CPTc. However, image quality has been not considered. The aim of the present work is to provide a comprehensive and quantitative analysis of image quality for CPTc. The impact of Tc-impurities in CPTc on image resolution, background noise, and contrast is investigated by performing both Monte-Carlo simulations and phantom experiments. Various targets, irradiation, and acquisition conditions are employed for investigating the image-based limits of CPTc production parameters. Additionally, the relationship between patient dose and image quality of CPTc samples is studied. Only those samples which meet both dose- and image-based limits should be accepted in future clinical studies.

Molybdenum target specifications for cyclotron production of 99mTc based on patient dose estimates.

In response to the recognized fragility of reactor-produced (99)Mo supply, direct production of (99m)Tc via (100)Mo(p,2n)(99m)Tc reaction using medical cyclotrons has been investigated. However, due to the existence of other Molybdenum (Mo) isotopes in the target, in parallel with (99m)Tc, other technetium (Tc) radioactive isotopes (impurities) will be produced. They will be incorporated into the labeled radiopharmaceuticals and result in increased patient dose. The isotopic composition of the target and beam energy are main factors that determine production of impurities, thus also dose increases. Therefore, they both must be considered when selecting targets for clinical (99m)Tc production. Although for any given Mo target, the patient dose can be predicted based on complicated calculations of production yields for each Tc radioisotope, it would be very difficult to reverse these calculations to specify target composition based on dosimetry considerations. In this article, a relationship between patient dosimetry and Mo target composition is studied. A simple and easy algorithm for dose estimation, based solely on the knowledge of target composition and beam energy, is described. Using this algorithm, the patient dose increase due to every Mo isotope that could be present in the target is estimated. Most importantly, a technique to determine Mo target composition thresholds that would meet any given dosimetry requirement is proposed.

A fast and simple dose-calibrator-based quality control test for the radionuclidic purity of cyclotron-produced (99m)Tc.

Cyclotron production of 99mTc through the (100)Mo(p,2n)99mTc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. Like most radioisotope production methods, cyclotron production of 99mTc will result in creation of unwanted impurities, including Tc and non-Tc isotopes. It is important to measure the amounts of these impurities for release of cyclotron-produced 99mTc (CPTc) for clinical use. Detection of radioactive impurities will rely on measurements of their gamma (γ) emissions. Gamma spectroscopy is not suitable for this purpose because the overwhelming presence of 99mTc and the count-rate limitations of γ spectroscopy systems preclude fast and accurate measurement of small amounts of impurities. In this article we describe a simple and fast method for measuring γ emission rates from radioactive impurities in CPTc. The proposed method is similar to that used to identify (99)Mo breakthrough in generator-produced 99mTc: one dose calibrator (DC) reading of a CPTc source placed in a lead shield is followed by a second reading of the same source in air. Our experimental and theoretical analysis show that the ratio of DC readings in lead to those in air are linearly related to γ emission rates from impurities per MBq of 99mTc over a large range of clinically-relevant production conditions. We show that estimates of the γ emission rates from Tc impurities per MBq of 99mTc can be used to estimate increases in radiation dose (relative to pure 99mTc) to patients injected with CPTc-based radiopharmaceuticals. This enables establishing dosimetry-based clinical-release criteria that can be tested using commercially-available dose calibrators. We show that our approach is highly sensitive to the presence of 93gTc, 93mTc, 94gTc, 94mTc, 95mTc, 95gTc, and 96gTc, in addition to a number of non-Tc impurities.

3D printed plastics for beam modulation in proton therapy.

Two 3D printing methods, fused filament fabrication (FFF) and PolyJet™ (PJ) were investigated for suitability in clinical proton therapy (PT) energy modulation. Measurements of printing precision, printed density and mean stopping power are presented. FFF is found to be accurate to 0.1 mm, to contain a void fraction of 13% due to air pockets and to have a mean stopping power dependent on geometry. PJ was found to print accurate to 0.05 mm, with a material density and mean stopping power consistent with solid poly(methyl methacrylate) (PMMA). Both FFF and PJ were found to print significant, sporadic defects associated with sharp edges on the order of 0.2 mm. Site standard PT modulator wheels were printed using both methods. Measured depth-dose profiles with a 74 MeV beam show poor agreement between PMMA and printed FFF wheels. PJ printed wheel depth-dose agreed with PMMA within 1% of treatment dose except for a distal falloff discrepancy of 0.5 mm.

Treatment of astrocytoma grade III with Photofrin II as a radiosensitizer. A case report.

INTRODUCTION: Astrocytomas are neoplasms that originate from glial cells. Anaplastic astrocytoma is classified as WHO III, with 27 % of the individuals with grade III astrocytoma living for at least 5 years even after treatment (radiation and chemotherapy). Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in both in vitro and in vivo tumor models. MATERIAL AND METHODS: This case report presents a woman suffering from an inoperable astrocytoma WHO III since 2004. The patient was treated with radiation therapy and Photofrin II as a radiosensitiser. The patient underwent irradiation with 40 + 20 Gy boost. The patient was given a single intravenous dose of 1 mg/kg Photofrin II 24 h prior to the initiation of radiation therapy. RESULTS: The patient is still alive without any significant side effect with a follow up of 106 months. MRI shows no evidence of disease. CONCLUSION: The follow-up results are encouraging regarding the application of Photofrin II as an effective radiosensitizing agent in the treatment of inoperable WHO III astrocytoma.

Neurolymphomatosis in a dog with B-cell lymphoma.

Lymphoma in the left femoral nerve of a 10-year-old English Cocker Spaniel caused complete paralysis of the affected limb. Neoplastic cells were immunopositive for CD79a and Pax5 and negative for CD3. Neoplastic cells were in multiple lymph nodes and one kidney but spared bone marrow. The clinical and histologic features in this case resemble those of the rare human condition of neurolymphomatosis.

The Application of Photofrin II as a sensitizing agent for ionizing radiation--a new approach in tumor therapy?

Radiosensitizers represent an enticing concept in tumor therapy. As ionizing radiation affects both neoplastic and normal tissues, its effects are generally non-specific. The aim of applying a radiosensitizing agent is to achieve a maximum effect on tumor tissue, while minimizing the damage to normal tissues. A variety of parameters such as the oxygen supply and the state in the cell cycle, need to be taken into account when evaluating a potential radiosensitizer. Most of the previously known radiosensitizers are neither selective nor tumor specific. In this article, we review the properties and radiosensitizing potential of Photofrin II. Photofrin II is well-known as a photosensitizing agent in photodynamic therapy. In recent years, a radiosensitizing potential of the substance has been demonstrated, specifically increasing the sensitivity of solid tumor tissues, especially of radio-resistant, hypoxic tumor cells, to radiation. This radiosensitizing effect has been demonstrated both by in vitro studies and by animal experiments. Several studies with tissue cultures have demonstrated a radiosensitizing effect of Photofrin II in glioblastoma (U-373MG) and bladder cancer cell lines (RT-4). No effect was noted in colon carcinoma cell lines (HT-29). Unpublished data of additional cell lines will be mentioned in the review. Animal experiments with Lewis sarcoma and with bladder cancer have moreover demonstrated an in vivo effect of Photofrin II as a radiosensitizer. The mechanism of this radiosensitizing effect is not completely understood. In vitro data, however, support the hypothesis that the radiosensitizing action involves OH-radicals in addition to a potential impairment of repair mechanisms after sublethal damage of ionizing radiation. Moreover, early results of a phase I trial are available and document the potential feasibility of the application of Phototofrin II as a radiosensitizing agent in clinical practice.

Porphyrins as radiosensitizing agents for solid neoplasms.

The biological effects of radiation affect both neoplastic and normal tissues. The nature and extent of such effects, however, depend on selected biological parameters (e.g., oxygen supply, cell cycle) and can be modified by chemical agents such as radiosensitizers, radioprotectors and chemotherapeutic agents. A precise control of the mode of action of the radiation is important in order to achieve the maximum effect on tumor tissue, while minimizing the effect on normal tissues. Most of the known and routinely used radiosensitizers are neither selective nor tumor specific. This article reviews a new selective and specific modality that increases the sensitivity of solid tumor tissue, especially of radio resistant, hypoxic tumor cells, to radiation. This modality is currently under early clinical evaluation and encompasses the application of Photofrin II, which is already used as a photosensitizer in photodynamic therapy (PDT) at predetermined times prior to irradiation.

Building a model to determine the cost-effectiveness of breast cancer screening in France.

This paper describes the methods and initial validation of a cost-effectiveness model developed to simulate the breast cancer screening situation in France. The first screening pilot programmes were set up in France in 1989 to test the feasibility of a decentralized screening model based in a large number of existing non-dedicated radiology centres. The present cost-effectiveness model was built as a tool to help guide current policy discussions on the future of screening in France. This Markov model compares the costs and effects expected when a screening programme is offered to a given cohort of women to those expected in the absence of screening. The model was initially validated using current results from the Bas-Rhin screening programme and local cancer registry epidemiological data. Over a 20-year period, 315 274 women would attend for screening, of whom 12 491 would be recalled for further assessment. 4423 cancers would be detected, resulting in 637 deaths. Screening allows the detection of 106 additional cancer cases, thereby preventing 92 deaths, and saves 1522 life-years compared with a situation without screening. Breast cancer mortality is reduced by 12.6%, yielding a cost-effectiveness ratio of 137 000 FF per life-year saved. The results of initial analyses suggest that the model is capable of suitably assessing the impact of breast cancer screening in terms of costs and effects. Further scenario analyses are needed to understand the impact of screening policy changes on the costs and effectiveness of future screening programmes.

Feasibility and morbidity of combined hyperthermia and radiochemotherapy in recurrent rectal cancer--preliminary results.

BACKGROUND: The local recurrence rate of colorectal cancer has been significantly reduced due to the use of combined radiochemotherapy. Despite this improvement regarding locally advanced tumour recurrences, the treatment strategy for pre-treated patients remains difficult and unresolved. PATIENTS AND METHODS: We analysed treatment and follow-up data of 14 patients with local recurrence of rectal cancer who were treated with radiation therapy (RT), chemotherapy (CT) and regional hyperthermia (RHT) from November 1997 to December 2001. Nine of these patients had received irradiation and CT (= pre-treated patients) in the past. For this group, 30.6-39.6 Gy RT, 5-fluorouracil (5-FU) as a continuous infusion over 5 days per week (350 mg/m(2)/24 h) combined with RHT twice a week was given. The 5 remaining patients (= not pre-treated) received conformal irradiation of 45 Gy with a boost between 9 and 14.4 Gy, combined with continuous infusion of 5-FU on days 1-4, and 29-33 (500 mg/m(2)/ 24 h), and RHT twice a week. Response to therapy was evaluated by means of computed tomography (CT) or magnetic resonance imaging (MRI) and by clinical follow-up. RESULTS: Among 13 evaluated cases, the overall objective response rate was 54% (5 complete responses, 2 partial responses). At mean follow-up of 13.9 months (range 5-32 months) 7 patients were alive. CONCLUSION: The therapeutic regimen appears to be active in the treatment of local recurrences of rectal cancer. Larger-scaled studies are needed to evaluate the potency of hyperthermia in this therapeutic strategy.

Radio-chemotherapy as a preoperative treatment for advanced rectal cancer. Evaluation of down-staging and morbidity.

BACKGROUND: The standard therapy for patients with clinically resectable rectal cancer is generally considered to be surgery. If the patient is diagnosed with advanced disease, postoperative radio-chemotherapy (RCT) is usually recommended. In our study we aimed to investigate and analyze the effectiveness and toxicity of preoperative pelvic radiotherapy in combination with 5-fluorouracil (5-FU) in locally advanced rectal cancer. PATIENTS AND METHODS: From June 1999 to September 2001 we evaluated 50 consecutive patients [37 male and 13 female; average age 65.1 (range 46-79.5) years] with locally advanced rectal carcinoma. 32 patients were staged as uT3, 14 as uT4, and 4 as uT2. Regarding N-staging, 22 patients were diagnosed as uN0. 2 patients had distant metastases, with liver metastases in both instances. Conformal irradiation was performed with a box technique (4-field technique) with a dose of 45 Gy (5 x 1.8 Gy per week for a total of 25 sessions). From days 1-5 and 29-33, all patients received 5-FU (500 mg/m(2 ) per day, as a continuous i.v. injection). RESULTS: Remission was observed in 28 patients (56%), with down-staging of at least one T-stage. A better success rate was achieved for patients with deep-seated tumors (64% of the patients in this group). Complete remission was observed in 4 patients (8.0%) and progression in 3 (6.0%). 15 patients had no detectable change in tumor staging (30.0%). A surgical R0 resection could be achieved in 43 patients, an R1 resection (minimal margin) in 7. Side effects and toxicity (common toxicity criteria) of RCT included grade I-II dysuria in 5 patients (10%), grade I-II diarrhea in 20 patients (40%), and severe diarrhea in 2 patients (4.0%). Grade I-II skin reaction was noticed in 22 patients (44.0%), severe skin reaction only in 1 patient. Regarding acute postoperative morbidity, abscess and fistula formation was noted in 8 patients (16.0%), with anastomosis leakage in 7 (14%). CONCLUSION: Preoperative radiotherapy appears to be a feasible therapeutic approach with moderate toxicity and the potential to induce down-staging. The data presented in this study confirm the preliminary reports on this neoadjuvant treatment.

[Estimate of regional prevalence of colorectal cancer in France]. / Estimation de la prévalence régionale des tumeurs colorectales en France.

BACKGROUND: Colorectal cancer prevalence is an important determinant of the health demand that completes information provided by cancer incidence. Current estimations established from data for the years 1985 and 1995 can be used to establish a precise description of changing healthcare needs for colorectal cancer. METHOD: Prevalence estimates method were based on incidence data computed on the regional scale by the FRANCIM network and mortality data provided by INSERM. We used the relationship that exists between the net risk of cancer, the net risk of dying of the given cancer and the age-specific prevalence of cancer. RESULTS: In 1995, the prevalence of patients who had a diagnosis of colorectal cancer amounted to 200 000 persons. The estimated number of prevalent cases was never lower than 3500 in any region and in 7 regions this number was higher than 10 000. From 1985 to 1995, there has been an increase of 35% in the prevalence rates. CONCLUSION: The evaluation of the number of persons who have had a diagnosis of colorectal cancer provides knowledge for health care planning. Such information on the regional scale is very useful for the health organisation (SROS). This geographical level induces difficulties not encountered at the national level.

Ten-year trends of dietary intake in a middle-aged French population: relationship with educational level.

OBJECTIVE: To compare dietary intakes at a 10 y interval of a population aged 35-64 living in France. Trends in nutrient intake and food consumption were examined with a special emphasis on the relationships between educational level and dietary behaviour. DESIGN: Two independent surveys conducted in 1985-1987 (S1) and 1995-1997 (S2) in the framework of the WHO MONICA project. Dietary intake was assessed with a 3-day record method and a food frequency questionnaire. The samples analysed included 416 men and 446 women for S1, 393 men and 409 women for S2. RESULTS: A significant improvement of the quality of fat intake was observed between S1 and S2, independently of educational level, with an increase of the age adjusted P/S ratio from 0.42 to 0.50 in men (P=10(-4)) and from 0.41 to 0.50 in women (P=10(-4)), whereas the daily cholesterol intake dropped from 552.0 to 466.9 mg and from 447.2 to 384.6 mg in men and women, respectively (P=10(-4)). These variations were associated with a decrease in the consumption of high-fat foods and an increase in that of low-fat products (poultry, low-fat dairy foods, fish) in all educational classes. By contrast, the consumption of fruit and vegetables, which was highly associated with educational level, varied little over time. CONCLUSIONS: Our results indicate slight improvement in fat quality, independently of educational level, while fruit and vegetable intake, which appeared more dependent on educational level, was only poorly modified over the 10 y interval.

[Lip, oral cavity and pharynx cancers in France: incidence, mortality and trends (period 1975-1995)]. / Les cancers de la lèvre, de la cavité buccale et du pharynx en France: incidence, mortalité et tendance (période 1975-1995).

With 10,882 estimated new cases in 1995 in France, lip, oral cavity and pharynx tumours rank 4th, representing 8.1% of all cancers in men. They are less frequent in women, with a sex ratio of 7. Based on the French cancer registries data which cover 13% of the metropolitan territory in 2000, both incidence and mortality increased until early 1980s to decrease thereafter. The main hypothesis proposed to explain the French leadership world-wide for these tumours deals with alcohol and tobacco consumption. Important differences observed between several areas within Europe, for some subsites, in connection with age or sex, are pointing toward the need of new studies about environment and/or genetics. Until now, comparisons between countries were made at the level of lip, oral cavity and pharynx category as a whole or by large subgroups. In this work we attempt to establish more accurate statistics, in order to comply with the situation of this cancer in France. Present results should encourage the scientific community to conduct site specific epidemiological studies.

[Cervical cancer in Bas-Rhin: trend and prediction of the incidence in 2014]. / Cancer du col de l'utérus dans le Bas-Rhin: tendance et projection de l'incidence jusqu'en 2014.

BACKGROUND: In the world, the cervix cancer is the second commonest cancer in women. Its incidence is decreasing but it is still too frequent. The aim of this study was to predict the incidence of cervix cancer among women in the Department of Bas-Rhin. METHODS: Incidence data were provided by the Bas-Rhin Tumor Registry. The incidence of in situ tumors and invasive cancers was predicted in 2010-2014 by using an age - period - cohort model and a Bayesian approach. RESULTS: The incidence rates predicted by the model, standardized to the European population, were 99.7 per 10(5)population in 2000-2004 (CI 95%: [82.7-118.5]) and 177.1 per 10(5) population in 2010-2014 (CI 95%: [103.7-288.5]) for in situ and 13.0 per 10(5) population (CI 95%: [9.5-17.2]) in 2000-2004 and 11.1 per 10(5)population (CI 95%: [4.5-22.7]) in 2010-2014 for invasive tumors. CONCLUSIONS: The decrease of invasive tumors is due to screening. The improvement of the quality of the screening and treatment of in situ tumors would allow the number of incident cases of cervix cancer to decrease.