Moderate hypofractionation and simultaneous integrated boost by helical tomotherapy in prostate cancer: monoinstitutional report of acute tolerability assessment with different toxicity scales.

INTRODUCTION: Based on radiobiology evidence, hypofractionated radiotherapy has the potential of improving treatment outcome in prostate cancer patients. In this study, we evaluated the safety, in terms of acutetoxicity, of using moderate hypofractionated radiotherapy delivered with Helical Tomotherapy (HT) to treat prostate cancer patients. MATERIALS AND METHODS: Between December 2012 and April 2014, 42 consecutive patients were treated with hypofractionated radiotherapy using HT. All patients received 70 Gy in 28 fractions to PTV1, which included the prostate. In the intermediate risk group, 61.6 Gy were delivered to PTV2, which included the seminal vesicles. In high risk patients, the pelvic nodes were added (PTV3) and received 50.4 Gy. Acute toxicity was recorded prospectively with RTOG and Common Terminology Criteria for Adverse Events 3.0, retrospectively with CTCAE 4.0. Expanded Prostate Cancer Index Composite (EPIC) was measured at baseline and 3 months after end of treatment, to investigate health related quality of life with regards to bladder and gastrointestinal function. RESULTS: Acute toxicity was acceptable, independently from the system used to score side effects. Moderate genitourinary toxicity was more frequent than gastrointestinal toxicity. No correlation between acute side effects and patients' characteristics or physical dose parameters was registered. EPIC evaluation showed a negligible difference in urinary and bowel function post-treatment, that did not reach statistical significance. CONCLUSIONS: Our experience confirms the safety of moderate hypofractionation delivered with HT in prostate cancer patients with low, intermediate and high risk.

Organ sparing and clinical outcome with step-and-shoot IMRT for head and neck cancer: a mono-institutional experience.

PURPOSE: Intensity-modulated radiotherapy has been suggested as the technique of choice for locally advanced head and neck cancer patients. In the last decade, most radiotherapy departments have focused their efforts in programs to implement this technique. We report our experience for parotid gland and constrictor muscle sparing with intensity-modulated radiotherapy in head and neck cancer using a step-and-shoot technique. METHODS: Thirty-four consecutive patients with squamous cell carcinoma of the nasopharynx, oropharynx and larynx treated between June 2008 and June 2011 were retrospectively evaluated. A simultaneous integrated boost was adopted to treat different volumes in 30 fractions over 6 weeks. Priority as organs at risk was given to the parotid glands as well as the constrictor muscle of the pharynx in 53 % (n = 18). Dysphagia and xerostomia were evaluated according to RTOG/EORTC scale at 6, 12 and 24 months. Outcomes were analysed using Kaplan-Meier curves. RESULTS: The median follow-up was 43 months. The 5-year overall survival was 70 %, and local control was 94 %. Grade 2 dysphagia and xerostomia at 6, 12 and 24 months were as follows: 26 % (n = 9), 23 % (n = 8), 23 % (n = 8) and 21 % (n = 7), 12 % (n = 4), 12 % (n = 4), respectively. No grade 3 or 4 toxicity was found. Ordinal logistic regression analysis demonstrated that hyposalivation was the main predictive factor for late dysphagia. CONCLUSION: Excellent loco-regional results were achieved with acceptable acute and late toxicities. The low rate of late dysphagia was related to parotid gland sparing; we did not observe a correlation between late dysphagia and dose to pharyngeal constrictors.

Role of ustekinumab in treatment of ulcerative colitis: a narrative review.

The therapeutic armamentarium for gastroenterologists in treating ulcerative colitis (UC) has been rapidly growing since the introduction of monoclonal antibodies directed against anti-TNFs. Ustekinumab is a monoclonal antibody binding the shared p40 subunit of IL-12 and IL-23, and the inhibition of these two cytokines, implicated in host response to microbial pathogens, has demonstrated clinical efficacy in different immune-mediated diseases, including moderate-to-severe UC. This narrative review summarizes the newest clinical evidence regarding the efficacy, effectiveness and safety of ustekinumab in moderate-to-severe UC, including specific situations (pregnancy, breastfeeding, elderly/pediatric populations, extraintestinal manifestations, acute severe UC, pouchitis and dual biological therapy). Finally, positioning is discussed in light of the existing evidence.

Ustekinumab (UST) is a biological drug that has been recently licensed as a novel therapy for ulcerative colitis, one of the two main conditions that constitute inflammatory bowel diseases. UST has been previously successfully used in psoriasis and psoriatic arthritis, two conditions in which dysregulation of the immune system causes inflammation in the skin and joints, and Crohn's disease, a type of inflammatory bowel disease. This led to great interest in the use of UST for treating patients with moderate and severe ulcerative colitis. UST is administered with a weight-based intravenous infusion followed by subcutaneous administration every 8 weeks, which can be performed at home and is effective in reducing symptoms of the disease with a particularly favorable safety profile. These features make UST a suitable option for treating especially elderly and frail patients, as well as patients who did not benefit or had side effects with other biological therapies and patients who also suffer from psoriasis or psoriatic arthritis.

Severe Activity of Inflammatory Bowel Disease is a Risk Factor for Severe COVID-19.

BACKGROUND: Data from the first wave of the coronavirus disease 2019 (COVID-19) pandemic suggested that patients with inflammatory bowel disease (IBD) are not at higher risk of being infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population and that a worse prognosis is not associated with immunomodulatory drugs, with the possible exception of systemic steroids. METHODS: This retrospective, observational study included consecutive IBD patients from the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) cohort who had a SARS-CoV-2 infection diagnosis (polymerase chain reaction-confirmed presence of the viral genome in a nasopharyngeal swab) during the second COVID-19 pandemic wave (September 2020 to December 2020). Data regarding demographics, IBD features and treatments, and comorbidities were analyzed in correlation with COVID-19 clinical outcomes. RESULTS: Data on 122 patients (mean age, 43.9 ±â€…16.7 years; males, 50.0%; Crohn's disease, 62.3%; ulcerative colitis, 37.7%) were reported. Twelve patients developed COVID-19-related pneumonia (9.8%), 4 (3.3%) required respiratory assistance (nonmechanical ventilation or orotracheal intubation), and 4 died (case fatality rate, 3.3%). In a multivariable analysis, age (odds ratio [OR], 1.034; 95% CI, 1.006-1.147; P = .032) and severe IBD activity (OR, 13.465; 95% CI, 1.104-164.182; P = .042) were independent predictors of COVID-19-related pneumonia, while severe IBD activity (OR, 15.359; 95% CI, 1.320-178.677; P = .030) was the only independent predictor of severe COVID-19, a composite endpoint defined as the need for respiratory assistance or death. A trend towards a protective role of tumor necrosis factor α inhibitors on pneumonia development was reported (P = .076). CONCLUSIONS: In this cohort of patients with IBD and SARS-CoV-2 infection, severe IBD activity was the only independent risk factor for severe COVID-19.

This retrospective, observational study on patients with inflammatory bowel disease and severe acute respiratory syndrome coronavirus 2 infection showed that severe inflammatory bowel disease activity was the only independent risk factor for severe coronavirus disease 2019.

Reduced humoral response to two doses of COVID-19 vaccine in patients with inflammatory bowel disease: Data from ESCAPE-IBD, an IG-IBD study.

BACKGROUND: Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy. AIMS: To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) METHODS: Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs). RESULTS: 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p<0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p<0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0-4.1]; p<0.001). CONCLUSIONS: Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258).

Safety, hesitancy of coronavirus disease 2019 vaccination and pandemic burden in patients with inflammatory bowel disease: data of a national study (ESCAPE-IBD).

BACKGROUND AND AIMS: The purpose of this study was to present data on the safety of anti- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of inflammatory bowel disease (IBD) patients of an ongoing multicenter study (ESCAPE-IBD) sponsored by the Italian Group for the study of Inflammatory Bowel Disease (ClinicalTrials.gov Identifier: NCT04769258). METHODS: Anti-SARS-CoV-2 vaccination was administrated to 809 IBD patients. Interviews were conducted to report adverse events related to vaccination. Of these 809, 346 patients were surveyed on the pandemic burden and the main reason for hesitancy in coronavirus disease 2019 vaccination. The chi-square test was used to compare categorical variables. Logistic regression was used to assess the relationship between disease-related characteristics and the onset of adverse events. RESULTS: About 45% of patients had at least one side effect, following the first dose (10%), the second (15%), and both doses (19%). All the adverse events were mild and lasted only a few days. Logistic regression analysis revealed that female sex ( P  < 0.001), younger age ( P  = 0.001), seroconversion ( P  = 0.002), and comorbidity ( P  < 0.001) were significantly associated with adverse events. The survey showed that the main concerns were the possibility of adverse event (33%). Almost all patients (99%) felt safer having been vaccinated at their IBD reference center. CONCLUSION: The vaccine reactions experienced in IBD patients were mostly self-limited. We found high acceptance and good safety of SARS-CoV-2 vaccination in our cohort.

Effectiveness and safety of an on-demand ferric carboxymaltose infusion strategy in patients with inflammatory bowel disease: a real world experience.

BACKGROUND: We evaluated an on-demand ferric carboxymaltose (FCM) infusion strategy in inflammatory bowel disease (IBD) patients with iron deficiency anemia (IDA). AIMS: The primary outcome was the response rate to single or multiple FCM infusions after 12 months. Secondary outcomes were the response rate to a single FCM infusion after 3 months and the FCM safety profile. METHODS: We retrospectively included 185 IBD patients who received at least one FCM infusion of 500 mg, between 2015 and 2018. FCM was administered to patients with Hb ≤10 g/dL and hypoferritinemia and repeated according to the physician's assessment. Complete response (CR) was defined as Hb ≥12 g/dL (≥13 g/dL for men) or Hb increase ≥2 g/dL. Partial response (PR) was defined as an Hb increase between 1 and 2 g/dL. A univariate analysis was performed at 3 and 12 months. RESULTS: After 12 months, the response rate was 75.1% (CR, 48.6%; PR, 26.4%; mean number of FCM infusions, 1.7 ± 1.1). In total 169/185 patients received a single FCM infusion during the first 3 months and 79.2% achieved response (CR, 56.8%; PR, 22.4%). At univariate analysis, no variable was associated with response. No adverse events were reported. CONCLUSIONS: An on-demand strategy was effective and well-tolerated in treating IDA in IBD patients.

Effect of breast-duct anatomy and wound-healing responses on local tumour recurrence after primary surgery for early breast cancer.

Despite the improvement in outcome for women with early breast cancer undergoing breast conservation surgery and radiotherapy, there are significant gaps in our understanding of local tumour relapse. In this Personal View, we propose two hypotheses: early-onset changes in breast-duct anatomy limit the degree of intraductal spread and explain much of the substantial age-related difference in risk of local tumour relapse; and wound-healing proteins stimulate the growth of cancer cells left behind after surgery. These mechanisms help to explain why generous surgical margins offer no greater protection against local tumour relapse than narrow margins after complete microscopic tumour excision.

Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld?

Rates of local tumour relapse after breast conservation treatment in women with early breast cancer are falling. Explanations for this decline are considered in this review including advances in breast cancer management and aging of the breast cancer population. Breast surgery has become more standardised following publication of practice guidelines and is mostly carried out by specialist surgeons. Systemic therapies (hormonal therapy and chemotherapy) are now more effective and are recommended to a higher proportion of patients than ever before. Radiotherapy techniques have also improved. The contributions of each factor are difficult to quantify precisely, but all are likely to be relevant. In order to identify a subgroup of women that might safely be spared radiotherapy, several factors are analysed, including the prognostic significance for local relapse of tumour characteristics (pathologic data, gene-expression profiles), patient characteristics and life expectancy (age and comorbidities).

Accelerated partial breast irradiation trials: diversity in rationale and design.

Seven randomised trials are currently testing accelerated partial breast irradiation against whole breast radiotherapy after breast conservation surgery. The trials are varied in the techniques used to deliver partial breast radiotherapy, reflecting the range of opportunities offered by advanced brachytherapy and teletherapy modalities. Dose schedules also vary between trials, but the most important point of difference between them reflects alternative concepts of clinical and planning target volumes. These are based mainly on the spatial pattern of relapse in retrospective and prospective studies, which report the majority of first local relapses close to the primary tumour site, and on the assumption that radiotherapy does not prevent the development of new primary tumours developing elsewhere in the breast. However, the pattern of ipsilateral breast tumour relapse is not accurately defined in the clinical literature and does not correspond closely to pathological findings. In addition, published data are consistent with a significant reduction in the rate of other quadrant relapse after whole breast radiotherapy. Regardless of the biological model of local tumour relapse and responsiveness to radiation, the ongoing trials will generate level I evidence for or against accelerated partial breast irradiation, provided patients are followed up long enough before the first reporting of results.

Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials.

BACKGROUND AND PURPOSE: Adjuvant lymphatic radiotherapy (LNRT) is recommended for selected axillary node positive women with early breast cancer. We investigated whether hypofractionated LNRT is safe combined with similarly-hypofractionated breast/chest wall radiotherapy (RT). MATERIAL AND METHODS: The Standardisation of Breast Radiotherapy (START) pilot, A and B trials randomised women with early breast cancer to schedules of 2.67-3.3 Gy versus 2.0 Gy fractions (control). RT adverse effects were assessed by patients using the EORTC QLQ-BR23 and protocol-specific questions, and by physicians. Rates of arm/shoulder effects were compared between schedules for patients given LNRT. RESULTS: 864/5861 (14.7%) patients received LNRT (385 START-pilot, 318 START-A, 161 START-B). Prevalences of moderate/marked arm/shoulder effects were low up to 10 years. There were no significant differences between the hypofractionated and control groups for patient- and physician-assessed symptoms in START-A or START-B. In START-pilot, adverse effect rates were higher after 13 fractions of 3.3 Gy, consistent with effects reported in the breast/chest wall (significant for shoulder stiffness, HR 3.07, 95%CI 1.62-5.83, p = 0.001). CONCLUSIONS: The START trial results suggest that appropriately-dosed hypofractionated LNRT is safe in the long-term, according to patient and physician-assessed arm and shoulder symptoms. These findings are consistent with those reported after the same schedules delivered to the breast/chest wall.

Helical Tomotherapy® is a Safe and Feasible Technique for Total Scalp Irradiation.

Angiosarcoma of the scalp is a rare aggressive tumor that affects elderly patients. Chemoradiation is the treatment of choice for multicentric and extensive disease. The shape of the scalp represents a dosimetric challenge in terms of achieving a homogeneous concave dose distribution with coverage of the entire target volume and an acceptable organs-at-risk sparing. We report a case of an 81-year-old man with a multifocal angiosarcoma of the scalp treated with Helical TomoTherapy® (Accuray Inc., Sunnyvale, CA, USA) intensity modulated radiotherapy. This technique allows precise and daily verifiable coverage of the target keeping the dose to the organs at risk within the constraints.

Differential sensitivity of Glioma stem cells to Aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics.

Glioma stem-cell-like cells are considered to be responsible for treatment resistance and tumour recurrence following chemo-radiation in glioblastoma patients, but specific targets by which to kill the cancer stem cell population remain elusive. A characteristic feature of stem cells is their ability to undergo both symmetric and asymmetric cell divisions. In this study we have analysed specific features of glioma stem cell mitosis. We found that glioma stem cells appear to be highly prone to undergo aberrant cell division and polyploidization. Moreover, we discovered a pronounced change in the dynamic of mitotic centrosome maturation in these cells. Accordingly, glioma stem cell survival appeared to be strongly dependent on Aurora A activity. Unlike differentiated cells, glioma stem cells responded to moderate Aurora A inhibition with spindle defects, polyploidization and a dramatic increase in cellular senescence, and were selectively sensitive to Aurora A and Plk1 inhibitor treatment. Our study proposes inhibition of centrosomal kinases as a novel strategy to selectively target glioma stem cells.

Radioresistance of glioma stem cells: intrinsic characteristic or property of the 'microenvironment-stem cell unit'?

There is increasing evidence that glioblastoma possess 'stem-like' cells, low concentrations of which can initiate a tumour. It has been proposed that these cells are radioresistant, and that this property contributes to the poor treatment outcomes of these tumours. In this paper we propose that radioresistance is not simply an intrinsic characteristic of glioma stem cells but a result of interactions between these cells and microenvironmental factors, i.e. the 'microenvironment - stem cell unit'. The critical role of the microenvironment, along with glioma stem cells, is supported directly or indirectly by the following observations: glioma stem cells have been shown to reside preferentially in specific niches, the characteristics of which are known to influence cellular responses to radiation; radiation modifies environmental factors; and, contrarily to the consistency of clinical data, in vitro experiments have reported a wide variety in the radiation response of these cells. The paper, therefore, focuses on the interaction between tumour stem cells and the microenvironment, analyzing how its various elements (endothelial cells, extracellular matrix, cytokines, nitric oxide, oxygen levels) are affected by radiation and how these might influence the response of tumour stem cells to radiation. Finally, we summarize the ongoing debate on the optimal culture conditions for glioma stem cells and the difficulties in designing assays that reliably characterize their radiation response.