Post-mastectomy radiation therapy after breast reconstruction: from historic dogmas to practical expert agreements based on a large literature review of surgical and radiation therapy considerations.

Breast reconstruction (BR) after mastectomy is important to consider for a woman's body image enhancement and psychological well-being. Although post-mastectomy radiation (PMRT) significantly improves the outcome of patients with high-risk breast cancer (BC), PMRT after BR may affect cosmetic outcomes and may compromise the original goal of improving quality of life (QoL). With the lack of practical guidelines, it seems essential to work on a consensus and provide some "expert agreements" to offer patients the best option for PMRT after BR. We report a global "expert agreement" that results from a critical review of the literature on BR and PMRT during the 6th international multidisciplinary breast conference in March 2023.

Treg-targeted IL-2/anti-IL-2 complex controls graft-versus-host disease and supports anti-tumor effect in allogeneic hematopoietic stem cell transplantation.

Modulating an immune response in opposite directions represents the holy grail in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to avoid insufficient reactivity of donor T cells and hematologic malignancy relapse while controlling the potential development of graft-versus-host disease (GVHD), in which donor T cells attack the recipient's tissues. IL-2/anti-IL-2 complexes (IL-2Cx) represent a therapeutic option to selectively accentuate or dampen the immune response. In dedicated experimental models of allo-HSCT, including also human cells injected in immunodeficient NSG mice, we evaluated side-by-side the therapeutic effect of two IL-2Cx designed either to boost regulatory T cells (Treg) or alternatively to activate effector T cells (Teff), on GVHD occurrence and tumor relapse. We also evaluated the effect of the complexes on the phenotype and function of immune cells in vivo. Unexpectedly, both pro-Treg and pro-Teff IL-2Cx prevented GVHD development. They both induced Treg expansion and reduced CD8+ T-cell numbers, compared to untreated mice. However, only mice treated with the pro-Treg IL-2Cx, showed a dramatic reduction of exhausted CD8+ T cells, consistent with a potent anti-tumor effect. When evaluated on human cells, pro-Treg IL-2Cx also preferentially induced Treg expansion in vitro and in vivo, while allowing the development of a potent anti-tumor effect in NSG mice. Our results demonstrate the clinical relevance of using a pro-Treg, but not a pro-Teff IL2Cx to modulate alloreactivity after HSCT, while promoting a graft-versus-leukemia effect.

Pathologic Response to Neoadjuvant Sequential Chemoradiation Therapy in Locally Advanced Breast Cancer: Preliminary, Translational Results from the French Neo-APBI-01 Trial.

BACKGROUND: Radiation therapy (RT), a novel approach to boost the anticancer immune response, has been progressively evaluated in the neoadjuvant setting in breast cancer (BC). PURPOSE: We aimed to evaluate immunity-related indicators of response to neoadjuvant chemoradiation therapy (NACRT) in BC for better treatment personalization. PATIENTS AND METHODS: We analyzed data of the first 42 patients included in the randomized phase 2 Neo-APBI-01 trial comparing standard neoadjuvant chemotherapy (NACT) and NACRT regimen in locally advanced triple-negative (TN) and luminal B (LB) subtype BC. Clinicopathological parameters, blood counts and the derived parameters, total tumor-infiltrating lymphocytes (TILs) and their subpopulation, as well as TP53 mutation status, were assessed as predictors of response. RESULTS: Twenty-one patients were equally assigned to each group. The pathologic complete response (pCR) was 33% and 38% in the NACT and NACRT groups, respectively, with a dose-response effect. Only one LB tumor reached pCR after NACRT. Numerous parameters associated with response were identified, which differed according to the assigned treatment. In the NACRT group, baseline hemoglobin of ≥13 g/dL and body mass index of <26 were strongly associated with pCR. Higher baseline neutrophils-to-lymphocytes ratio, total TILs, and T-effector cell counts were favorable for pCR. CONCLUSION: This preliminary analysis identified LB and low-TIL tumors as poor responders to the NACRT protocol, which delivered RT after several cycles of chemotherapy. These findings will allow for amending the selection of patients for the trial and help better design future trials of NACRT in BC.

Effect of lethal total body irradiation on bone marrow chimerism, acute graft-versus-host disease, and tumor engraftment in mouse models: impact of different radiation techniques using low- and high-energy X-rays.

PURPOSE: Effects of X­ray energy levels used for myeloablative lethal total body irradiation (TBI) delivery prior to bone marrow transplantation (BMT) in preclinical mouse models were examined. MATERIALS AND METHODS: In mouse models, single-fraction myeloablative TBI at a lethal dose was delivered using two different X­ray devices, either low (160 kV cabinet irradiator) or high energy (6 MV linear accelerator), before semi-allogeneic hematopoietic stem-cell transplantation (HSCT) to ensure bone marrow (BM) chimerism, graft-versus-host disease (GVHD), and tumor engraftment. Recipient mice were clinically followed for 80 days after bone marrow transplantation (BMT). Flow cytometry was performed to assess donor chimerism and tumor engraftment in recipient mice. RESULTS: Both X­ray irradiation techniques delivered a 10 Gy single fraction of TBI, presented a lethal effect, and could allow near-complete early donor chimerism on day 13. However, low-energy irradiation increased T cells' alloreactivity compared to high-energy irradiation, leading to clinical consequences for GVHD and tumor engraftment outcomes. The alloreactive effect differences might be attributed to the distinction in inflammatory status of irradiated recipients at donor cell infusion (D0). Delaying donor cell administration (D1 after lethal TBI) attenuated T cells' alloreactivity and clinical outcomes in GVHD mouse models. CONCLUSION: Different X­ray irradiation modalities condition T cell alloreactivity in experimental semi-allogeneic BMT. Low-energy X­ray irradiator induces a post-TBI inflammatory burst and exacerbates alloreactive reactions. This technical and biological information should be considered in interpreting GVHD/ graft-versus-leukemia effect results in mice experimental models of BMT.

Genomic Prostate Score: A New Tool to Assess Prognosis and Optimize Radiation Therapy Volumes and ADT in Intermediate-Risk Prostate Cancer.

Genomic classifiers such as the Genomic Prostate Score (GPS) could help to personalize treatment for men with intermediate-risk prostate cancer (I-PCa). In this study, we aimed to evaluate the ability of the GPS to change therapeutic decision making in I-PCa. Only patients in the intermediate NCCN risk group with Gleason score 3 + 4 were considered. The primary objective was to assess the impact of the GPS on risk stratification: NCCN clinical and genomic risk versus NCCN clinical risk stratification alone. We also analyzed the predictive role of the GPS for locally advanced disease (≥pT3+) and the potential change in treatment strategy. Thirty patients were tested for their GPS between November 2018 and March 2020, with the median age being 70 (45-79). Twenty-three patients had a clinical T1 stage. Eighteen patients were classified as favorable intermediate risk (FIR) based on the NCCN criteria. The median GPS score was 39 (17-70). Among the 23 patients who underwent a radical prostatectomy, Gleason score 3 + 4 was found in 18 patients. There was a significant correlation between the GPS and the percentage of a Gleason grade 4 or higher pattern in the surgical sample: correlation coefficient r = 0.56; 95% CI = 0.2-0.8; p = 0.005. In this study, the GPS combined with NCCN clinical risk factors resulted in significant changes in risk group.

TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation.

BACKGROUND: Targeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet. METHOD: We developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD. RESULTS: Using experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation. CONCLUSIONS: These results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.

Radiation therapy for triple-negative breast cancer: emerging role of microRNAs as biomarkers and radiosensitivity modifiers. A systematic review.

PURPOSE: Radiation therapy (RT) for triple-negative breast cancer (TNBC) treatment is currently delivered in the adjuvant setting and is under investigation as a booster of neoadjuvant treatments. However, TNBC radioresistance remains an obstacle, so new biomarkers are needed to select patients for any integration of RT in the TNBC therapy sequence. MicroRNAs (miRs) are important regulators of gene expression, involved in cancer response to ionizing radiation (IR) and assessable by tumor tissue or liquid biopsy. This systematic review aimed to evaluate the relationships between miRs and response to radiation in TNBC, as well as their potential predictive and prognostic values. METHODS: A thorough review of studies related to miRs and RT in TNBC was performed on PubMed, EMBASE, and Web of Science. We searched for original English articles that involved dysregulation of miRs in response to IR on TNBC-related preclinical and clinical studies. After a rigorous selection, 44 studies were chosen for further analysis. RESULTS: Thirty-five miRs were identified to be TNBC related, out of which 21 were downregulated, 13 upregulated, and 2 had a double-side expression in this cancer. Expression modulation of many of these miRs is radiosensitizing, among which miR-7, -27a, -34a, -122, and let-7 are most studied, still only in experimental models. The miRs reported as most influencing/reflecting TNBC response to IR are miR-7, -27a, -155, -205, -211, and -221, whereas miR-21, -33a, -139-5p, and -210 are associated with TNBC patient outcome after RT. CONCLUSION: miRs are emerging biomarkers and radiosensitizers in TNBC, worth further investigation. Dynamic assessment of circulating miRs could improve monitoring and TNBC RT efficacy, which are of particular interest in the neoadjuvant and the high-risk patients' settings.

Curative intent Stereotactic Ablative Radiation Therapy (SABR) for treatment of lung oligometastases from head and neck squamous cell carcinoma (HNSCC): a multi-institutional retrospective study.

OBJECTIVES: The aim of this retrospective study was to assess outcomes of SABR for metachronous isolated lung oligometastases from HNSCC. METHODS: For patients who developed isolated, 1 or 2 lungs lesions (<5cm) consistent with metastases from HNSCC, the indication of SABR was validated in a multidisciplinary tumor board. All patients were monitored by CT or PET CT after SABR (Stereotactic Ablative Body Radiation) for HNSCC. RESULTS: Between November 2007 and February 2018, 52 patients were treated with SABR for metachronous lung metastases. The median time from the treatment of the primary HNSCC to the development of lung metastases was 18 months (3-93). The cohort's median age was 65.5 years old (50-83). The vast majority (94.2%) received 60 Gy in three fractions. Forty-one patients (78.5%) presented a solitary lung metastasis, while 11 patients (21.5%) had two lung metastases. With a median follow-up of 45.3 months, crude local and metastatic control rates were 74 and 38%, respectively. 1 year and 2 year Overall Survival (OS) were 85.8 and 65.9%, respectively. The median OS was 46.8 months. About one-fourth of patients were retreated by SABR for distant pulmonary recurrence. The treatment was well tolerated with only one patient who reported ≥ grade 3 toxicity (1.9%). CONCLUSION: In selected metastatic HNSCC patients, early detection and treatment of lung metastases with SABR is effective and safe. Prospective studies are required to validate this potential shift. ADVANCES IN KNOWLEDGE: Patients with oligometastases and controlled primary HNSCC seem to benefit from metastasis directed therapies.

Radiation Therapy Delivery Challenges in Older Patients During Coronavirus Disease 2019 Pandemic.

PURPOSE: The management of older patients in radiation therapy (RT) departments has been challenging in the context of the Coronavirus Disease 2019 (COVID-19) outbreak. We report our experience of RT adapted schedules or strategy changes in older patients during the COVID-19 pandemic. METHODS AND MATERIALS: Patients aged ≥75 years were recruited during weekly chart rounds. All were potentially eligible for a specific intervention to reduce the frequency of patients' visits to the hospital. The effect of deferring radiation and hypofractionation of RT schedules was assessed in terms of the number of courses initially planned and replanned during the lockdown. RESULTS: Twenty patients were identified during the official lockdown in France (March 17 to May 11). Median age was 78 years (75-95 years). Most patients were male (n = 12, 60%) being treated in the postoperative setting (n = 17, 85%). RT was delayed in 11 cases (55%) with hormonal therapy prescribed in 10 cases (50%). Altered RT fractionation was proposed for 5 cases (25%); combinations of altered fractionation and deferral of radiation were applied in 3 cases (15%). The number of radiation courses initially planned and replanned according to the pandemic context: 563 and 197, respectively (-62%; P < .001). None presented recurrence when RT was initiated, and no patient developed symptomatic COVID-19 infection. CONCLUSIONS: In the context of the COVID-19 outbreak, individual risk-based radiation therapy seems to be safe. Systematic screening of patients for COVID-19 before starting radiation therapy is mandatory. In our department the oncogeriatrics expertise availability for daily practice was of great use during the pandemic. Other prospective studies are needed to validate such strategies in case of resurgence of similar outbreaks.

Hemostatic radiotherapy for bladder cancer-related hematuria in patients unfit for surgery: is there any impact of fractionation schedule?

PURPOSE: The optimal schedule for palliative external beam radiotherapy (EBRT) in patients with bladder tumors with hematuria unfit for surgery remains undefined. This study aimed to assess the clinical hemostatic efficacy and safety of two EBRT hypofractionated schedules. METHODS: From February 2008 to October 2017, 31 patients were referred to our department for palliative hemostatic bladder irradiation. EBRT consisted of two schedules: "continuous" treatment (CRT) was delivered following consecutive 3-10 weekdays (3-6Gy/fraction (fr), to a total dose of 18-30Gy) (n=14); the "discontinuous" schedule (DRT) consisted of 23Gy in 4fr (6.5Gy/fr on days 1 and 3, followed by 5Gy/fr on days 15 and 17; n=12). The primary endpoint was the rate of hemostatic control (HC) at the end of the radiation course. Other endpoints included mid-term HC, toxicities and overall survival. Comparative analyses were performed by exact Fisher test with a cut-off of 0.05 for statistical significance. RESULTS: The rate of HC at the end of EBRT was 92% (n=24) with no differences between CRT and DRT (100% vs 86%; p=0.48). The median follow-up was 6 months, HC was achieved in 15/26 (58%) patients at the last follow-up, without meaningful differences between CRT and DRT (50% vs 67%; p=0.45). Three and two patients developed acute grade ≤2 diarrhea in CRT and DRT groups, respectively. CONCLUSION: Our study suggests that both hypofractionated "continuous" and "discontinuous" EBRT are well tolerated and represent acceptable schedules for patients with limited life expectancy. DRT schedule could be preferred for departments' organization to increase the slots for the treatment of other referred patients for radiotherapy.

Axillary nodal irradiation practice in the sentinel lymph node biopsy era: Comparison of the contemporary available 3D and IMRT techniques.

OBJECTIVE: Our study aimed to compare regional node coverage and doses to the organ at risk (OAR) using conventional technique (CT) vs "AMAROS" (AT) vs intensity-modulated radiation therapy (IMRT) techniques in patients receiving regional nodal irradiation (RNI) for breast cancer (BC). METHODS: We included 30 consecutive patients with BC who received RNI including axillary nodes. Two independent and blinded dosimetric RNI plans were generated for all patients. For target volume coverage, we analyzed the V95%, the D95%, the mean and the minimal dose within the nodal station. For hotspots within nodal target volume, we used the V105%, the V108% and the maximal doses. For OAR, lung V20, mean lung and heart doses, the maximal dose to the brachial plexus and the axillary-lateral thoracic vessel junction region were compared between the three techniques. RESULTS: Target volume coverage and hotspots: Mean V95% in stations I, II, III and IV were 35.8% and 75% respectively with CV, 22.59 and 59.9% respectively with AT technique and 45.58 and 99.6% respectively with IMRT with statistically significant differences (p < 0.001). Mean V105% (cc) in axillary and supraclavicular stations were 21.3 and 6.4 respectively with CV, 1.2 and 0.02 respectively with AT technique and 0.5 and 0.4 respectively with IMRT with statistically significant differences (p < 0.001)..OARs: The mean ipsilateral lung V20 was 16.9%, 16.4 and 13.3% with CT, AT and IMRT respectively. The mean heart dose (Gy) was 0.3, 0.2 and 0.2 with CT, AT and IMRT respectively. The maximal dose to the plexus brachial (Gy) was 50.3, 46.3 and 47.3 with CT, AT and IMRT respectively. The maximal dose to the axillary-lateral thoracic vessel junction (Gy) was 52.3, 47.3 and 47.6 with CT, AT and IMRT respectively. The differences were statistically significant for all OAR (p < 0.001). CONCLUSION: AT is a valuable technique for RNI including axilla in patients with limited sentinel lymph node biopsy involvement without additional axillary lymph node dissection since it decreases hotspots in the target volume and lowers the radiation exposure of the OAR. For more advanced tumors or patients who did not respond to primary systemic therapy, CT or IMRT should be considered because of their better coverage of the potentially residual nodal disease. IMRT combines several advantages of offering high conformal plans, limited hotspots and protection of main OAR. The clinical impact of these dosimetric differences need to be addressed. ADVANCES IN KNOWLEDGE: This study is to our knowledge the first to compare conventional three-dimensional and IMRT techniques for regional nodal irradiation for each nodal station in breast cancer in a context of increasing utilization of axillary irradiation.

Primary extranodal lymphoma of the glands. Literature review and options for best practice in 2019.

Primary extranodal non-Hodgkin's lymphomas (EN-NHL) are a heterogeneous group of malignancies that involve numerous entities with significant difference in terms of tumor site locations, prognostic factors, biology expression, and therapeutic options. In the literature, many EN-NHL types were reported from limited series which only allowed narrow views for elucidating prognostic factors and defining the role of loco-regional therapies in the era of new systemic and biologically targeted therapies. The Rare Cancer Network (RCN), an international multidisciplinary consortium, has published a number of reports on several EN-NHL sites which included many gland locations. In this review, we will focus on the recent literature for a selected number of EN-NHL types in both exocrine and endocrine gland locations. We aim to provide renewed and clear messages for the best practice in 2019 for diagnosis, histopathology, treatments, and also their prognostic implications. We believe that better understanding of molecular and genetic characteristics of these particular diseases is crucial for an appropriate management in the era of personalized treatment developments.

Ionizing radiation-induced cellular senescence promotes tissue fibrosis after radiotherapy. A review.

Ionizing radiation-exposure induces a variety of cellular reactions, such as senescence and apoptosis. Senescence is a permanent arrest state of the cell division, which can be beneficial or detrimental for normal tissue via an inflammatory response and senescence-associated secretion phenotype. Damage to healthy cells and their microenvironment is considered as an important source of early and late complications with an increased risk of morbidity in patients after radiotherapy (RT). In addition, the benefit/risk ratio may depend on the radiation technique/dose used for cancer eradication and the irradiated volume of healthy tissues. For radiation-induced fibrosis risk, the knowledge of mechanisms and potential prevention has become a crucial point to determining radiation parameters and patients' intrinsic radiosensitivity. This review summarizes our understanding of ionizing radiation-induced senescent cell in fibrogenesis. This mechanism may provide new insights for therapeutic modalities for better risk/benefit ratios after RT in the new era of personalized treatments.

[Radiation therapy in patients with inflammatory bowel disease. A review]. / Radiothérapie et maladies inflammatoires chroniques de l'intestin : revue de la littérature.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are multifactorial diseases characterized by a chronic intestinal inflammation. Abdominal and pelvic irradiation can result in acute or chronic digestive toxicity. A few old studies on small population samples have suggested an increase of gastro-intestinal toxicities in patients with IBD in case of irradiation. Nevertheless, the physiopathology is unknown. More recent studies, including new irradiation techniques, have shown less toxicity events in these patients with IBD. There are no recommendations for irradiation in patients with IBD. This review aims to report recent data on this topic and discuss them regarding radiation parameters.

The Henri Mondor Procedure of Morbidity and Mortality Review Meetings: Prospective Registration of Clinical, Dosimetric, and Individual Radiosensitivity Data of Patients With Severe Radiation Toxicity.

PURPOSE: After radiation therapy (RT), various radiation-induced toxicities can develop in about one-fourth of patients. An international interest in using morbidity and mortality rates to monitor the quality of care and integrate morbidity and mortality review (MMR) meetings into organizations' governance processes has arisen. We report the first results of patients included in our MMR procedure that included biological assays for individual intrinsic radiosensitivity (IIRS). METHODS AND MATERIALS: Twenty-three patients were prospectively included in the MMR database. Twenty-two were evaluable for IIRS. Prostate (n=10) and breast (n=8) cancers were the most frequent disease types. The total dose delivered, determined according to the type of disease, ranged from 30 to 74 Gy. Our MMR procedure requires strict criteria: patients with unresolved toxicity of grade 3 or higher with availability of clinical (photographic) data, IIRS results obtained from skin biopsy assays, treatment modalities, and follow-up data. The RT technique and dosimetry were reviewed. RESULTS: Our prospective registration of toxicities showed mainly rectitis, occurring in 7 cases, and skin toxicities, occurring in 9. Of the 7 patients with rectitis, 5 received 66 Gy of post-prostatectomy RT with V50 (rectum volume receiving 50 Gy) ranging from 45% to 75% and a mean maximal dose of 66.5 Gy. For dermatitis and cystitis, the mean maximal doses were in the range of classical constraints without any overdosage or dose heterogeneity. No errors were found in the review of treatment planning and positioning. Conversely, all the patients were considered biologically as radiosensitive with genomic instability and ATM (ataxia telangiectasia mutated)-dependent DNA double-strand break repair impairments. CONCLUSIONS: The MMR review of files allowed clear answers for patients on the relationship between clinical events and their IIRS. Our procedure has allowed education of all our staff to monitor, identify, and document clinical, physical, and biological aspects of radiation-induced toxicities. Thus we recommend the introduction of the MMR procedure in RT departments.