Adaptation of the Tumor Antigen Presentation Machinery to Ionizing Radiation.

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), ß2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

Laparoscopic management of an ascending colon hernia through the foramen of Winslow.

Herniation through the foramen of Winslow is rare, with a non-specific clinical presentation and his diagnosis may be difficult. A 44-year-old female was admitted with an acute epigastric abdominal pain. A computed tomography showed an internal hernia of the colon in the lesser sac. Laparoscopic reduction of the herniated contents and the fixation of the ascending colon with several non-absorbable sutures were performed. Twenty months after surgery, the patient has not experienced any recurrence. Computed tomography helps practitioners to the preoperative diagnosis of herniation through the foramen of Winslow, to the viability of the herniated contents and presence of occlusion. In case of herniation through the foramen of Winslow favored by a mobile ascending colon with a misapposition of the right Told fascia, the fixation of the colon with a non-absorbable suture was safe and may prevent the risk of recurrent internal hernia and colonic volvulus.

Tumor Size Matters-Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy.

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.

PURPOSE: Glioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies. METHODS AND MATERIALS: A number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration. RESULTS: Various immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials. CONCLUSIONS: This review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response.

A retrospective cohort study to assess adjuvant concurrent chemoradiation (CCRT) compared to adjuvant radiation therapy (RT) in the treatment of grade 2 and 3 extremity soft tissue sarcomas.

PURPOSE: To evaluate the efficacy and tolerance of adjuvant concurrent chemoradiation (CCRT) as treatment of grade 2 and 3 (G2-3) localized extremity soft tissue sarcomas (STS) by comparing CCRT with standard adjuvant radiation therapy (RT). PATIENTS AND METHODS: This monocentric retrospective study included non-pediatric patients (>16years) treated by adjuvant RT with or without chemotherapy (CT) after conservative resection of non-recurrent G2-3 extremity STS. RESULTS: A total of 80 patients were treated between 1990 and 2012: 51 by RT and 29 by CCRT. Of the 29 CCRT patients, 25 received doxorubicin monotherapy (75mg/m2/3weeks). The CCRT group contained a greater proportion of grade 3 extremity STS (p<0.001). Median follow up was 68months (9-284). Multivariate analysis revealed greater local control in the CCRT group (1 local recurrence vs 8 in the RT group; HR=0.082, 95% CI 0.011-0.321) and incomplete resection as the major risk factor of local recurrence (HR=25.2, 95% CI 4.767-133.226). The two groups exhibited no differences in distant failure-free survival (HR=1.469, 95% CI 0.668-3.228), disease-free survival (HR=1.096, 95% CI 0.519-2.315) or overall survival (HR=1.378, 95% CI 0.498-3.814). Grade 3 was an adverse prognostic factor for overall survival (HR=3.11, 95% CI 1.04-9.32). Our analyses also revealed that CCRT tended to increase the risk of both grade ≥3 acute dermatitis (14 events vs 6 in the RT group; OR=6.99, 95% CI 2.28-21.47) and grade ≥2 late toxicity (6 events vs 3 in the RT group; p=0.0572). CONCLUSION: CCRT could improve local control as part of a limb-preservation strategy. However, with a limited number of patients, CCRT showed no improvement in either distant control or survival and increased toxicity.

Effect of bladder distension on doses to organs at risk in Pulsed-Dose-Rate 3D image-guided adaptive brachytherapy for locally advanced cervical cancer.

PURPOSE: To evaluate the impact of bladder distension on doses to organs at risk in patients treated with 3D image-guided adaptive pulsed-dose-rate (PDR) brachytherapy (BT) for locally advanced cervical cancer. METHODS AND MATERIALS: Twenty-two patients who had previously been treated by external beam radiation therapy (EBRT), underwent BT treatment planning to a pelvic MRI (or a CT scan in case of contraindication) after their bladder was filled with 100 cc of physiological saline (full bladder). This was immediately followed by a CT scan after emptying of the bladder. A fusion of these two examinations was conducted, and the dosimetry was duplicated for the study with an empty bladder. Equieffective doses of 2 Gy per fraction from EBRT and BT of bladder/rectum/sigmoid colon/small bowel were compared. RESULTS: A full bladder condition was found to be non-inferior in terms of the bladder D2cc (a difference of -0.9 Gy; 97.5% CI [-∞; 2.6]), and it resulted in a reduction in the bladder D0.1cc (p = 0.038). Bladder expansion resulted in a significant reduction of maximum doses received by the small bowel, both in terms of the D0.1cc (51.2 Gy vs. 63.4 Gy, p < 0.001) and the D2cc (48.5 Gy vs. 53.6 Gy, p < 0.001). A negative correlation was seen between the difference in the small bowel D2cc and the body mass index; (r = -0.55; p = 0.008). No differences were noted in regard to doses to the rectum and sigmoid colon. CONCLUSIONS: Bladder distension with 100 cc of physiological saline can reduce maximum doses received by the small bowel without the alteration of the doses received by the other organs at risk during a 3D image-guided adaptive PDR BT for locally advanced cervical cancer. However, the maintenance of a predefined bladder volume is difficult to achieve with PDR BT, whereas it could be easily managed before each session in case of high-dose-rate BT.