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Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecular mechanisms underlying intestinal repair following TNF blockade during IBD remain elusive. Using a novel humanized model of experimental colitis, we demonstrate that TNF interfered with the tissue repair program via induction of a soluble natural antagonist of IL-22 (IL-22Ra2; IL-22BP) in the colon and abrogated IL-22/STAT3-mediated mucosal repair during colitis. Furthermore, membrane-bound TNF expressed by T cells perpetuated colonic inflammation, while soluble TNF produced by epithelial cells (IECs) induced IL-22BP expression in colonic dendritic cells (DCs) and dampened IL-22-driven restitution of colonic epithelial functions. Finally, TNF induced IL-22BP expression in human monocyte-derived DCs and levels of IL22-BP correlated with TNF in sera of IBD patients. Thus, our data can explain how anti-TNF therapy induces mucosal healing by increasing IL-22 availability and implicates new therapeutic opportunities for IBD.

Purpose According to ASTRO and ESTRO guidelines, external beam Partial Breast Irradiation (PBI) is a valid option for early-stage Breast Cancer patients. Nevertheless, there is lack of consensus about the best treatment schedule. METHODS We retrospectively analysed data of female patients treated at our institution from 2013 to 2022 with adjuvant “one-week" partial breast irradiation. Clinical Target Volume (CTV) was an isotropic expansion of 15 mm from the tumour bed (identified as the breast tissue between surgical clips). The treatment schedule was 30 Gy delivered with VMAT in 5 daily fractions. The primary endpoint was Local Control (LC). Disease Free Survival (DFS), Overall Survival (OS) and safety were secondary endpoints. RESULTS Three hundred eighty-one patients with a median age of 69 (33 – 91) years were included in the study. One hundred ninety-two (50.4%) of the cases were left-sided breast; 360 (94.5%) were invasive ductal carcinomas, 368 (96.6%) were G1 or 2, and 378 (99.2%), were Luminal-like. After a median follow-up of 28 (6 – 104) months, 7 patients (2.0%) developed a local recurrence, of which two were “In field”. Three-year LC, DFS and OS actuarial rates were 97.5% (95% C.I. 96.2% – 98.8%), 95.7% (95% C.I. 94.2% - 97.2%), and 96.9% (95% C.I. 95.7% – 98.1%) respectively. No ≥ grade 3 acute/late toxicities were reported. 10 (2.9%) patients experienced grade 2 late toxicities. Five (1.5%) patients reported late cardiac major events, although 4 of them were treated on the right breast. Three (0.9%) late pulmonary toxicities were detected. One hundred-eight (30.8%) patients reported fat necrosis. Good or Excellent cosmetic evaluation following the Harvard Scale was reported in 252 (96.9%) cases by the physicians while in 241 (89.2%) cases by the patients. CONCLUSION “One-week” PBI is effective and safe, and this schedule is a valid option for highly selected early breast cancer patients.

Oncological treatments are changing rapidly due to the advent of several targeted anticancer drugs and regimens. The primary new area of research in oncological medicine is the implementation of a combination of novel therapies and standard care. In this scenario, radioimmunotherapy is one of the most promising fields, as proven by the exponential growth of publications in this context during the last decade. This review provides an overview of the synergistic use of radiotherapy and immunotherapy and addresses questions like the importance of this subject, aspects clinicians look for in patients to administer this combined therapy, individuals who would benefit the most from this treatment, how to achieve abscopal effect and when does radio-immunotherapy become standard clinical practice. Answers to these queries generate further issues that need to be addressed and solved. The abscopal and bystander effects are not utopia, rather physiological phenomena that occur in our bodies. Nevertheless, substantial evidence regarding the combination of radioimmunotherapy is lacking. In conclusion, joining forces and finding answers to all these open questions is of paramount importance.

Background. “Ariadne’s thread” is a psycho-educational intervention designed by the Clinical Psychology Unit of an Italian Comprehensive Cancer Center and aimed at promoting empowerment in patients with metastatic breast cancer. It consists of 8 online meetings led by a psycho-oncologist where informational parts discussed by all the doctors that care these patients alternate with moments of stress management. Aim. This case study aims to investigate: 1) the feasibility of the "Ariadne's thread" intervention; 2) the satisfaction and perception of efficacy of the pilot intervention by the participants. Method. We used a mixed method in which 1) it was detected: the number of acceptance to the intervention both of patients and professionals, the number of help requests by patients and the number of requests of date changing by the professionals; 2) semi-structured interviews to the professionals who participated at the intervention were conducted; 3) 2 focus groups with the patients were conducted and a questionnaire was submitted to each of them. Results. The intervention is sustainable for the organisation, professionals and patients point of view. In particular, the patients declare the perception of efficacy in many aspects: improvement of the relation with the doctors, acceptance of their illness, learning of a relaxing technique, possibility to look at the world with trust and hope, etc. The questionnaires show an improvement of empowerment and the satisfaction with the intervention. Conclusion. Even though other research are needed, the results are promising.

Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice.This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations.An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders.Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine.

To explore breast cancer patient’s perspective on future genetic testing for prediction of toxicity after breast radiotherapy (RT). The study involved patient enrolled in the Italian branch of the REQUITE project conducted at the National Cancer Institute in Milan. Semi-structured interviews were conducted within one month from the end of radiotherapy treatment by two radiation oncologists and a radiotherapy technician previously trained by a clinical psychologist with experience in the oncology field. Semi-structured interviews are characterized by a set of pre-defined questions and developed ad hoc by researchers in Leicester within the REQUITE project. The interview questions investigated interest in undergoing the genetic test and expectations on its usefulness and disadvantages. Eighteen interviews were conducted and analysed. Forty-five initial codes were combined into nine themes which were then clustered in two main macro-areas (i) Opportunities and (ii) Challenges. Overall, all patients understand the aim of the genetic test and considered its intrinsic opportunity to make the physician more confident with the treatment. Regarding side effects, most of patients felt prepared to RT but not without fear. Many women considered important to have the largest and reliable information, also about negative experiences. Prevailing emotions were anxiety and fear but not connected to genetic test’s result. A genetic test could be an opportunity because generate knowledge and give patients a dynamic role in the decision-making approach. Prediction of single patient radiosensitivity before RT could prompt suggestion to entail a more and more tailored radiation treatment in the era of personalized approach.

Introduction The potential advantages of oncoplastic breast conserving surgery (BCS) have not been validated in robust studies that constitute high levels of evidence, despite oncoplastic techniques being widely adopted around the globe. There is hence the need to define the precise role of oncoplastic BCS in the treatment of early breast cancer, with consensual recommendations for clinical practice. Methods A panel of world-renowned breast specialists was convened to evaluate evidence, express personal viewpoints and establish recommendations for the use of oncoplastic BCS as primary treatment of unifocal early stage breast cancers using the GRADE approach. Results According to the results of the systematic review of literature, the panelists were asked to comment on the recommendation for use of oncoplastic BCS for treatment of operable breast cancer that is suitable for breast conserving surgery, with the GRADE approach. Based on the voting outcome, the following recommendation emerged as a consensus statement: Oncoplastic breast conserving surgery should be recommended versus standard breast conserving surgery for the treatment of operable breast cancer in adult women who are suitable candidates for breast conserving surgery (with very low certainty of evidence). Discussion This review has revealed a low level of evidence for most of the important outcomes in oncoplastic surgery with lack of any randomized data and absence of standard tools for evaluation of clinical outcomes and especially patients’ values. Despite areas of controversy, about one-third (36%) of panel members expressed a strong recommendation in support of oncoplastic BCS. Presumably, this reflects a synthesis of views on the relative complexity of these techniques, associated complications, impact on quality of life and costs.

Human gamma delta T cells (γδ-T cells) are non-conventional T lymphocytes expressing a TCR heterodimer comprised of gamma (γ) and delta (δ) chains. They constitute an essential part of the innate immune system playing a pivotal role at the front line of the host's defense against pathogens. γδ-T cells have received particular attention as they exert multiple functions under non-infectious settings, most notably in carcinogenesis, where they can initiate a potent HLA-independent anti-tumor activity. Owing to these attributes, γδ-T cells appear to be a promising target for designing cell-based anti-cancer immunotherapies. For such strategies - which involve manipulation of γδ-T cells, e.g. by activation, tumor-targeting, or genetic modification - accurate and quantitative cell-counting tools are indispensable. The gold standard for immune cell quantification to date is still flow cytometry (FCM), although this technology is associated with demanding sample logistics as it requires suspensions of viable cells and presents challenges to standardization amongst different sites, cytometers and operators. In recent years, a huge body of evidence has been accumulated demonstrating epigenetic qPCR (Epiontis ID®) as a powerful and FCM-equivalent methodology for cell quantification and immune monitoring, which is not affected with such limitations. Here we present a DNA methylation-specific, real-time PCR-based assay for the precise quantification of γδ-T cells in blood, tissues and formalin fixed and paraffin embedded (FFPE) samples. The qPCR assay targets a differentially methylated region in the gene encoding the constant region of the T cell receptor gamma chain (TRGC2). This marker region was shown being entirely unmethylated in γδ-T cells, but appearing fully methylated in conventional CD4+ and CD8+ T cells, in CD56+ NK and CD19+ B cells, in CD14+ monocytes and CD15+ granulocytes. Validation of the assay according to ICH guidelines and ISO17025 standards demonstrated a robust performance and stability, linear measurements in the operational range (between 0% and 100% methylation), a definite target cell type specificity and a good correlation to paralleled flow cytometric analyses. The intra- and inter-assay precision is below 15% and 20%, respectively and the lower limit of quantification, above where standard precision of measurements can be achieved, lies at 74 unmethylated target molecules. Cell type-specificity was shown using blood from heathy donors, the applicability in cancerous samples still has to be confirmed.In summary the epigenetic, γδ-T cell-specific assay posted here may represent a useful tool for immune monitoring in clinical settings assisting the development of innovative γδ-T cell-based immunotherapies. Citation Format: Sven Olek, Udo Baron, Isabell Janack, Kati Bourquain, Stefan Kärst, Deborah Phippard, Laura Lozza, Ciro Novaes Lino Rosa. Epigenetic monitoring of gamma delta T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2187.

Immunosuppressive Interleukin (IL)-10 production by pro-inflammatory CD4(+) T cells is a central self-regulatory function to limit aberrant inflammation. Still, the molecular mediators controlling IL-10 expression in human CD4(+) T cells are largely undefined. Here, we identify a Notch/STAT3 signaling-module as a universal molecular switch to induce IL-10 expression across human naïve and major effector CD4(+) T cell subsets. IL-10 induction was transient, jointly controlled by the transcription factors Blimp-1/c-Maf and accompanied by upregulation of several co-inhibitory receptors, including LAG-3, CD49b, PD-1, TIM-3 and TIGIT. Consistent with a protective role of IL-10 in inflammatory bowel diseases (IBD), effector CD4(+) T cells from Crohn's disease patients were defective in Notch/STAT3-induced IL-10 production and skewed towards an inflammatory Th1/17 cell phenotype. Collectively, our data identify a Notch/STAT3-Blimp-1/c-Maf axis as a common anti-inflammatory pathway in human CD4(+) T cells, which is defective in IBD and thus may represent an attractive therapeutic target.

Background This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing and treating acute radiation dermatitis (ARD) in Head and Neck Cancer (HNC) and Breast Cancer (BC) patients undergoing radiotherapy (RT). Methods Eligible HNC and BC patients were randomized 1:1 to receive Xonrid® + SOC or SOC during RT. Patients were instructed to apply Xonrid® on the irradiated area three times daily, starting on the first day of RT and until 2 weeks after RT completion or until the development of grade ≥ 3 skin toxicity. The primary endpoint was to evaluate the proportion of patients who developed an ARD grade Results Eighty patients (40 for each cancer site) were enrolled between June 2017 and July 2018. Groups were well balanced for population characteristics. All BC patients underwent 3-Dimensional Conformal RT (3D-CRT) whereas HNC patients underwent Volumetric-Modulated Arc Therapy (VMAT). At week 5 the proportion of BC patients who did not exhibit G2 ARD was higher in Xonrid® + SOC group (p = 0.091). In the same group the onset time of G2 ARD was significantly longer than in SOC-alone group (p Conclusion Despite the failure to achieve the primary endpoint, this study suggests that Xonrid® may represent a valid medical device in the prevention and treatment of ARD at least in BC patients, delaying time to develop skin toxicity and reducing the proportion of patients who experienced G2 ARD during RT treatment and 2 weeks later. Trial registration The study was approved by the Ethical Committee of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT 52/14 - NCT02261181). Registered on ClinicalTrial.gov on 21st August 2017.

Introduction: Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice. Method: This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group. We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology ( www.sign.ac.uk ). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations. Results: An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered. Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation). Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders. Conclusions: Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine.

Immunosuppressive Interleukin (IL)-10 production by pro-inflammatory CD4

AIM: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). MATERIALS AND METHODS: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). RESULTS: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. CONCLUSIONS: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models. ispartof: RADIOTHERAPY AND ONCOLOGY vol:159 pages:241-248 ispartof: location:Ireland status: published

The purpose of this study was to evaluate the impact of breast size on acute and late side effects in breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). In this study we analyzed patients over 50 years with a diagnosis of early BC, candidate for Hypo-RT after conservative surgery. Acute and late skin toxicities were evaluated in accordance with the RTOG scale. Multivariable logistic analysis was performed using dosimetric/anatomical factors resulted associated with toxicity outcome in univariable analysis. Among patients treated between 2009 and 2015, 425 had at least 5 years of follow-up. At RT end, acute skin toxicity ≥ G2 and edema ≥ G2 occurred in 88 (20.7%) and 4 (0.9%) patients, respectively. The multivariable analysis showed association of skin toxicity with boost administration (p

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine‐1‐phosphate (S1P). Unlike peptidoglycan sensing via the leucine‐rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF‐κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues., Intracellular pattern recognition receptors NOD1/2, best known as sensor of bacterial peptidoglycans, can also be directly activated by signaling lipid sphingosine‐1‐phosphate accumulating upon perturbed cellular homeostasis, thus linking general stress to inflammatory responses.

The objective was to explore whether epigenetic immune cell counting can advance efficiency and quality of diagnostic and immune monitoring related to COVID-19. Application areas were monitoring disease course, therapeutic clinical development, and measurements of SARS-CoV2 vaccine responses. Immune cell type specific epigenetic assays have been developed over the last decade. They are primarily used in therapeutic clinical research in oncology and autoimmune disease. Due to the high sample stability and low amount requirements for epigenetic measurements and available assay portfolio for key immune cell populations relevant in COVID-19, the method promised to be useful and practical in the pandemic setting. Epigenetic immunophenotyping using whole blood of hospitalized Covid19 patients was applied and CD3, CD4, CD8 and regulatory T cell populations, NK cells, naïve and memory B cells were quantified, and measurement results show to predict mild or severe COVID-19 disease courses. Furthermore, nasopharyngeal swab and saliva samples were applied demonstrating that epigenetic immune monitoring can measure immune cell content in such non-invasive sample types. Due to the low sample volume and handling requirements and availability of 35 assays for relevant immune cell populations, epigenetic immune monitoring is suitable for therapeutic COVID-19 clinical trials. Another possibility for sample collection is single drops of capillary blood deposited on filter paper (dried blood spots), which have been collected pre and post SARS-CoV2 booster vaccinations in healthy subjects. Such measurements revealed vaccine response for example in changes of cell populations epigenetically active in the markers CCR7 and TIGIT.

Randomized trials confirmed the efficacy and the safety of hypofractionated whole breast irradiation (HF-WBI) in patients with early-stage breast cancer. However, the role of HF-WBI in patients with DCIS after breast conserving surgery has not yet been clearly established in prospective randomized trials. The aim of this study was to evaluate if HF-WBI can be considered comparable to conventionally fractionated (CF)-WBI in DCIS patients. The analysis included DCIS patients from four Italian centers treated with CF-WBI 50 Gy/25 fractions or HFRT 40.5 Gy/15 fractions, without tumor bed boost. A propensity score matching (PSM) analysis was performed using a logistic regression that considered age, grading, presence of necrosis, resection margin status and adjuvant endocrine therapy. Five hundred twenty-seven patients was included (367 in the CF-WBI-group and 160 in the HR-WBI group). After 1:1 matching, 101 patients were allocated to the CF-WBI-group and 104 to the HF-WBI group. No correlation was observed between the type of RT schedule and LRFS (HR 1.68, 95% CI 0.82–3.45; p = 0.152). After PSM, no statistical difference was observed between the two RT group (HR 1.11, 95% CI 0.40–3.04; p = 0.833), with 3- and 5-years LRFS rates of 100% and 97.9% for CF-WBI and 95.6% and 94% for HF-WBI. A short course of radiation therapy seems to be comparable to CF-WBI in terms of clinical outcomes. These data support the use of hypofractionated schedules in DCIS patients, but considering the remaining uncertainties.

Introduction Although the need for axillary lymph node dissection (AD) is decreasing in breast cancer patients, it remains necessary in some cases. Axillary reverse mapping (ARM) enables the detection of upper extremity lymphatic drainage that may be spared during selective axillary dissection (SAD) so as to reduce the risk of lymphedema. The ability of the ARM-SAD procedure to reduce the incidence of lymphedema is being tested in an ongoing randomized trial. Crossover between arm drainage and breast drainage is well documented in the axilla, however, and whether the procedure is oncologically safe remains controversial. We aim to assess the axillary failure rate when a few nodes draining the upper arm are being spared by the ARM-SAD. Methods We report oncological outcomes, and axillary failure in particular, in the first 100 consecutive axillary node-positive patients treated with ARM-SAD as part of a pilot study and a randomized trial. Results A median of 18 (IQR 14–22) axillary nodes were excised per patient. During the follow-up (median 51 months, IQR 34–91), 11 patients experienced a treatment failure, but only one - treated with neoadjuvant chemotherapy - developed overt axillary disease as a first (and isolated) event. The crude rate of axillary failure was 1.36% (95% CI: 0.19–9.63) with an estimated 5-year crude cumulative incidence of 1.85% (95% CI: 0–5.47%). Conclusions The axillary failure rate was low in our patients and did not exceed rates reported in the literature after standard AD, thus indicating that the ARM-SAD procedure is oncologically safe.

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.

To assess the impact of age, comorbidities and endocrine therapy (ET) in older breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). From June 2009 to December 2017, we enrolled in this study 735 ER-positive BC patients (stage pT1–T2, pNx–1, M0 and age ≥ 65 years) receiving hypo-RT and followed them until September 2019. Baseline comorbidities included in the hypertension-augmented Charlson Comorbidity Index were retrospectively retrieved. Logistic regression model estimated adjusted-odds ratios (ORs) of ET prescription in relation to baseline patient and tumor characteristics. Competing risk analysis estimated 5-year cumulative incidence function (CIF) of ET discontinuation due to side effects (with BC progression or death as competing events), and its effect on locoregional recurrence (LRR) and distant metastasis (DM) (with death as competing event). ET has been prescribed in 89% patients. In multivariable analysis, the odds of ET prescription was significantly reduced in older patients (≥ 80 years, OR 0.08, 95% CI 0.03–0.20) and significantly increased in patients with moderate comorbidity. Patients ≥ 80 years discontinued the prescribed therapy earlier and more frequently than younger (65–69 years) patients (p = 0.060). Five-year CIF of LLR, DM and death from causes other that BC were 1.7%, 2.2% and 7.5%, respectively. Patients who discontinued ET had higher chance of LRR (p = 0.004). ET use did not impact on OS in any of the analyzed groups. In older patients, ET did not show a benefit in terms of overall survival. Further studies focusing on tailored treatment approaches are warranted to offer the best care in terms of adjuvant treatment to these patients.

Background - Physical distancing for COVID-19 led to decreased in-person patient follow up assessments and delayed imaging appointments. Herein we describe for the first time the impact of delays in diagnostic investigations of patients with an history of early-stage breast cancer (BC) in the largest public cancer center of Lombardy, the Italian region most affected by the pandemic. Methods - This single-institution retrospective study included three observational periods. The first pandemic peak period (March-April 2020) corresponding to the interruption of follow up imaging; the post-peak period (May-December 2020); the pre-pandemic period represented by the five previous years (January 2015- December 2019) as control. The flow of diagnostic activities was compared among the different years. Moreover, the number and characteristics of recurrent BC cases (rBC) diagnosed in the post-peak period were compared to the figures observed in pre-pandemic years, when imaging was regularly carried out, using descriptive statistics. A further comparison was performed between the characteristics of scheduled and delayed rBC diagnosed after the first peak. Results - During the first pandemic peak, diagnostic investigations declined by 81.2% (from 1032 in January-February to 194 in March-April), a drop which was not identified in the same period of the pre-pandemic years, before rebounding to 1065 in May-June, 832 July-August (reflecting the summer physiological drop), 1334 September-October, and 879 November-December. The average number of rBC cases of 16 (range 12-25) in March-April of the pre-pandemic period declined to a value as low as 4 during the first pandemic peak. Thereafter, the number of rBC cases began a steady increase, until reaching a total of 27 in September-October 2020, almost doubling the mean of 14.8 (range 11-21) achieved in the corresponding months of 2015-2019. As a result, the absolute number of rBC cases was 76 in 2020 and on average 78.4 (range 70 - 95) in pre-pandemic years, and the rBC proportion of 1.42% (76/5336; 95% exact confidence interval, CI: 1.12-1.78%) in 2020 was slightly higher than the average proportion of 1.26% of the five previous years, though the latter being well included in the CI of the 2020 proportion. No difference in primary tumor presentation and age at initial diagnosis was found among recurrent patients before and after the pandemic. Of the rBC cases reported during 2020, 10 were from 513 patients with postponed follow up who were finally diagnosed between September-December. As compared to patients on schedule, delayed rBC cases did not present with ductal carcinoma in situ, and reported a median tumor size of 18 mm (range 4.3-90 mm), which was 20% higher than the median of 15 mm (3.1-34) observed for scheduled patients. Distribution of luminal-like, triple negative and HER2-overexpressing BC subtypes among evaluable rBC cases was 75%, 12.5%, 12.5% in scheduled and 66%, 11% and 22% in delayed cases, respectively. Conclusions - Our data showed a slight decrease in the absolute number of rBC during 2020 despite a rebound of examinations, and an increased size of invasive recurrence following the 2-month stop of the first pandemic peak. The full impact of the COVID-19 pandemic on recurrent cancer diagnosis will be known when national population-based data become available in the coming years. Citation Format: Serena Di Cosimo, Catherine Depretto, Rosalba Miceli, Paolo Baili, Silva Ljevar, Milena Sant, Claudio Ferranti, Secondo Folli, Massimiliano Gennaro, Filippo G de Braud, Claudio Vernieri, Maria Carmen De Santis, Laura Lozza, Andrea Vingiani, Giancarlo Pruneri, Giovanni Apolone, Alfonso Marchianò, Gianfranco P Scaperrotta. The impact of COVID-19 on diagnosis of recurrent breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-01-12.

Spying on bacterial signals Many bacteria produce small molecules for monitoring population density and thus regulating their collective behavior, a process termed quorum sensing. Pathogens like Pseudomonas aeruginosa , which complicates cystic fibrosis disease, produce different quorum-sensing ligands at different stages of infection. Moura-Alves et al. used experiments in human cells, zebrafish, and mice to show that a host organism can eavesdrop on these bacterial conversations. A host sensor responds differentially to bacterial quorum-sensing molecules to activate or repress different response pathways. The ability to “listen in” on bacterial signaling provides the host with the capacity to fine-tune physiologically costly immune responses. Science , this issue p. eaaw1629

To report acute toxicities in breast cancer (BC) patients (pts) recruited in a prospective trial and treated with accelerated partial-breast irradiation (APBI) using Volumetric Modulated Arc Therapy (VMAT) delivered with a hypofractionated schedule. From March 2014 to June 2019, pts with early-stage BC (Stage I), who underwent breast conservative surgery (BCS), were recruited in a prospective study started at the National Cancer Institute of Milan. Pts received APBI with a hypofractionated schedule of 30 Gy in five daily fractions. Radiotherapy treatment (RT) was delivered using VMAT. Acute toxicity was assessed according to RTOG/EORTC criteria at the end of RT. Between March 2014 and June 2019, 151 pts were enrolled in this study. 79 Pts had right-side and 72 had left-side breast cancer. Median age was 69 (range 43–92). All pts presented with pathological stage IA BC, molecular classification was Luminal A in 128/151 (85%) and Luminal B in 23/151 (15%) cases. Acute toxicity, assessed at the end of RT, consisted of G1 erythema in 37/151 (24. 5%) pts and skin toxicities higher than G1, did not occur. Fibrosis G1 and G2 were reported in 41/151 (27. 1%) pts and in 2/151 pts (1. 3%), respectively. Edema G1 occurred in 8/151 (5. 3%) pts and asthenia G1 occurred in 1/151 (0. 6%) pts. APBI with VMAT proved to be feasible and can be a valid alternative treatment option after BCS in selected early breast cancer pts according to ASTRO guidelines. A longer follow-up is needed to assess late toxicity.

International audience; As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes. The skin acts as an important first barrier of the body, which is constantly exposed to diverse environmental and mechanical insults, such as pollution, infection, injury and radiation, amongst others 1. Additionally, the application of cosmetics and other agents can have a major impact on skin homeostasis 1. Among the most widely used skin dyes, are the extracts of Lawsonia inermis, commonly known as Henna 2. In traditional medicine, Henna has been widely used to treat bacterial and fungal infections, inflammation, cancer and various skin pathologies 3 , but the underlying mechanisms remain insufficiently understood. Major side effects of Henna preparations are caused by the additive para-phenylenediamine (PPD) that has been associated with allergic contact dermatitis 4,5. As natural product, Henna comprises a mixture of numerous compounds most of which are poorly characterized opeN There are amendments to this paper

The purpose of this study was to examine the impact of trastuzumab on acute skin and cardiac toxicity in patients with breast cancer treated with chemotherapy with or without trastuzumab and adjuvant whole breast hypofractionated radiotherapy (hypo-RT).The study was conducted on 727 patients treated from April 2009 to October 2016. Patients received 42.4 Gy in 16 daily fractions (2.65 Gy per fraction). A boost was only administered in cases with grade (G) 3 primary tumor and close or positive margins. Acute and late toxicity was assessed prospectively during and after hypo-RT, based on the Radiation Therapy Oncology Group scale. Multivariable logistic regression models were used to examine the onset of acute skin toxicity (≥ G2) in the whole study population, and the impact of trastuzumab on the onset of acute skin (≥ G2) or cardiac toxicity in the subgroup of 176 patients given chemotherapy.A total of 176 patients received chemotherapy with anthracycline and taxane, and 51 (29%) of them were also treated with trastuzumab. Acute G1, G2, and G3 skin toxicity occurred, respectively, in 56.8%, 27.3%, and 1.1% of the patients given chemotherapy alone, and in 64.7%, 19.6%, and 0% of those given trastuzumab as well. Among the patients given chemotherapy, left ventricular ejection fraction (LVEF) toxicity developed with a severity of G1 (LVEF 60%-50%) in 12 (6.8%) patients, G2 (LVEF 50%-40%) in 2 (1.1%) patients, and G3 (LVEF 40%) in 1 (0.6%) patient. Among the patients also given trastuzumab, 7 (13.7%) patients had G1 LVEF toxicity, and 1 (2%) patient had G2 LVEF toxicity. We found that patients given trastuzumab were at higher risk of cardiac toxicity ≥ G1 (odds ratio, 4.3; P = .01), and at lower risk of acute skin toxicity ≥ G2 (odds ratio, 0.4; P = .03) than patients given chemotherapy alone.This analysis showed that trastuzumab with adjuvant hypo-RT for patients with breast cancer was generally well-tolerated in routine clinical practice. A longer follow-up will be necessary to assess late cardiac toxicity.

Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer. This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result. Mean pathological tumor size was 10.5 mm (±4.3, range 3–18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107–213; range:56–325) with a median PTV isodose prescription of 86.0% (IQR 85.0–88.5; range:82–94). The median PTV was 88.1 cm3 (IQR 63.8–108.6; range:32.3–238.8). The median breast V100 and V50 was 0.6 (IQR 0.1–1.5; range:0–13) and 18.6 (IQR 13.1–21.7; range:7.5–37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7–27.6; range 22.3–29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients’ evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer. These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results. The present study is registered at Clinicaltrial.gov ( NCT02896322 ). Retrospectively egistered August 4, 2016.

Complete response (CR) in metastatic breast cancer (MBC) is rare. This study aims at analyzing the characteristics and outcome of MBC patients achieving CR. We performed a cross-sectional analysis of clinical data from a consecutive series of MBC patients admitted at the Division of Medical Oncology of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, achieving CR following treatment for systemic disease and with at least 2 years of follow-up. Seventy-six MBC patients with CR were identified during a calendar year. 47 patients (61.8%) achieved CR more than once, for a total of 123 cases. Median age at MBC diagnosis was 56 years (range 30–76). 52 patients (68.4%) presented with recurrent disease, 24 (31.6%) with de novo metastatic disease. The majority of patients (80.3%) had hormone receptor (HR) positive and 26 (34.2%) had HER2 overexpressing MBC. 54 patients (71.1%) had only one site of metastatic disease. 33 patients (43.4%) received a local approach as part of their treatment and 67 (54.5%) achieved CR during maintenance therapy. CRs were durable, as after a median follow-up of 8.3 years (interquartile range 5.8–11.0 years) 42 patients (55.3%) were alive with no evidence of disease. Durable CRs can occur after systemic therapy alone or after combined systemic and local treatments. Most cases presented CR in the presence of limited disease spreading, not necessarily on first-line therapy. Our study highlights the crucial role of multidisciplinary approach to MBC and the benefit of maintenance treatment.

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity. ispartof: RADIOTHERAPY AND ONCOLOGY vol:138 pages:59-67 ispartof: location:Ireland status: published

Background:Ductal carcinoma in situ (DCIS) is considered a morphologic precursor of invasive cancer and is often treated with adjuvant whole-breast irradiation and endocrine therapy, as if it were an invasive cancer. Our aim was to provide further support for treatment de-escalation or enrollment of such patients in active surveillance trials.Methods:We retrospectively analyzed data on patients with conservatively treated primary DCIS subsequently diagnosed with ipsilateral invasive breast cancer (IBC) at 2 comprehensive breast cancer centers. From their merged databases, we identified 50 cases with full details on tumor grade, hormone receptor expression, and HER2 amplification, for both the primary DCIS and the corresponding IBC, and we assessed the similarities and differences between the two.Results:Distributions of hormone receptors were similar in primary DCIS and IBC, while high-grade and HER2-positive status was less common in IBC than in primary DCIS. The positivity for estrogen receptors (ER) and well-differentiated or moderately differentiated morphology in the primary DCIS persisted in 90% of the matching IBC. Changes in progesterone receptor expression were slightly more common than those in ER expression. Overall consistency for the luminal-like receptors subtype was found in 90% of cases.Conclusion:The high consistency between the features of primary DCIS and those of subsequent IBC (in the rare but not negligible cases of local failure) should be borne in mind when considering the therapeutic options. Treatment de-escalation and accrual of patients for active surveillance trials could be appropriate for luminal-like precursors.

Tuberculosis is caused by Mycobacterium tuberculosis, and the increasing emergence of multidrug-resistant strains renders current treatment options ineffective. Although new antimycobacterial drugs are urgently required, their successful development often relies on complete understanding of the metabolic pathways—e.g., cholesterol assimilation—that are critical for persistence and for pathogenesis of M. tuberculosis. In this regard, mycofactocin (MFT) function appears to be important because its biosynthesis genes are predicted to be essential for M. tuberculosis in vitro growth in cholesterol. In determining the metabolic basis of this genetic requirement, our results unexpectedly revealed the essential function of MFT in ethanol metabolism. The metabolic dysfunction thereof was found to affect the mycobacterial growth in cholesterol which is solubilized by ethanol. This knowledge is fundamental in recognizing the bona fide function of MFT, which likely resembles the pyrroloquinoline quinone-dependent ethanol oxidation in acetic acid bacteria exploited for industrial production of vinegar., Mycofactocin (MFT) belongs to the class of ribosomally synthesized and posttranslationally modified peptides conserved in many Actinobacteria. Mycobacterium tuberculosis assimilates cholesterol during chronic infection, and its in vitro growth in the presence of cholesterol requires most of the MFT biosynthesis genes (mftA, mftB, mftC, mftD, mftE, and mftF), although the reasons for this requirement remain unclear. To identify the function of MFT, we characterized MFT biosynthesis mutants constructed in Mycobacterium smegmatis, M. marinum, and M. tuberculosis. We found that the growth deficit of mft deletion mutants in medium containing cholesterol—a phenotypic basis for gene essentiality prediction—depends on ethanol, a solvent used to solubilize cholesterol. Furthermore, functionality of MFT was strictly required for growth of free-living mycobacteria in ethanol and other primary alcohols. Among other genes encoding predicted MFT-associated dehydrogenases, MSMEG_6242 was indispensable for M. smegmatis ethanol assimilation, suggesting that it is a candidate catalytic interactor with MFT. Despite being a poor growth substrate, ethanol treatment resulted in a reductive cellular state with NADH accumulation in M. tuberculosis. During ethanol treatment, mftC mutant expressed the transcriptional signatures that are characteristic of respirational dysfunction and a redox-imbalanced cellular state. Counterintuitively, there were no differences in cellular bioenergetics and redox parameters in mftC mutant cells treated with ethanol. Therefore, further understanding of the function of MFT in ethanol metabolism is required to identify the cause of growth retardation of MFT mutants in cholesterol. Nevertheless, our results establish the physiological role of MFT and also provide new insights into the specific functions of MFT homologs in other actinobacterial systems.

Human immune system mice are highly valuable for in vivo dissection of human immune responses. Although they were employed for analyzing tuberculosis (TB) disease, there is little data on the spatial organization and cellular composition of human immune cells in TB granuloma pathology in this model. We demonstrate that human immune system mice, generated by transplanted human fetal liver derived hematopoietic stem cells develop a continuum of pulmonary lesions upon Mycobacterium tuberculosis aerosol infection. In particular, caseous necrotic granulomas, which contribute to prolonged TB treatment time, developed, and had cellular phenotypic spatial-organization similar to TB patients. By comparing two recommended drug regimens, we confirmed observations made in clinical settings: Adding Moxifloxacin to a classical chemotherapy regimen had no beneficial effects on bacterial eradication. We consider this model instrumental for deeper understanding of human specific features of TB pathogenesis and of particular value for the pre-clinical drug development pipeline.

BACKGROUND AND PURPOSE Breast-conserving surgery (BCS) and whole breast radiation (RT) with or without endocrine therapy (ET) represent the standard of care for ductal carcinoma in situ (DCIS). The use of adjuvant treatments after surgery is still controversial in this setting. We performed a retrospective multicenter analysis on a series of DCIS patients treated with BCS and adjuvant RT. MATERIALS AND METHODS We collected clinical data from nine Italian centers on 1072 women having a diagnosis of DCIS and treated between 1997 and 2012. We reported on the 5- and 10-year local recurrence (LR) rates, overall survival, and breast cancer specific survival (BCSS) employing the Kaplan-Meier method. RESULTS At a median follow-up of 8.4 years, 67 LR (6.3%) and 47 deaths (4.4%) were observed. LR rates at 5 and 10 years were 3.4% and 7.6%, respectively. BCSS rates at 5 and 10 years were 99.7% and 99.1%, respectively. At univariate regression analysis, postmenopausal state (p = 0.009), estrogen receptor (ER) (p = 0.0001) and progesterone receptor (p = 0.018) positivity and ET (p = 0.006) were inversely correlated with LR. Final surgical margins (FSM) status