Modulation of tumor-associated macrophage activity with radiation therapy: a systematic review.

OBJECTIVE: Tumor-associated macrophages (TAMs) are the most represented cells of the immune system in the tumor microenvironment (TME). Besides its effects on cancer cells, radiation therapy (RT) can alter TME composition. With this systematic review, we provide a better understanding on how RT can regulate macrophage characterization, namely the M1 antitumor and the M2 protumor polarization, with the aim of describing new effective RT models and exploration of the possibility of integrating radiation with other available therapies. METHODS: A systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was carried out in PubMed, Google Scholar, and Scopus. Articles from January 2000 to April 2020 which focus on the role of M1 and M2 macrophages in the response to RT were identified. RESULTS: Of the 304 selected articles, 29 qualitative summary papers were included in our analysis (16 focusing on administration of RT and concomitant systemic molecules, and 13 reporting on RT alone). Based on dose intensity, irradiation was classified into low (low-dose irradiation, LDI; corresponding to less than 1 Gy), moderate (moderate-dose irradiation, MDI; between 1 and 10 Gy), and high (high-dose irradiation, HDI; greater than 10 Gy). While HDI seems to be responsible for induced angiogenesis and accelerated tumor growth through early M2-polarized TAM infiltration, MDI stimulates phagocytosis and local LDI may represent a valid treatment option for possible combination with cancer immunotherapeutic agents. CONCLUSION: TAMs seem to have an ambivalent role on the efficacy of cancer treatment. Radiation therapy, which exerts its main antitumor activity via cell killing, can in turn interfere with TAM characterization through different modalities. The plasticity of TAMs makes them an attractive target for anticancer therapies and more research should be conducted to explore this potential therapeutic strategy.

Pleomorphic Xanthoastrocytoma: a single institution retrospective analysis and a review of the literature.

BACKGROUND:  Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade brain tumor. To date, limited studies have analyzed factors affecting survival outcomes and defined the therapeutic strategy. The aim of this retrospective analysis was to investigate the clinicopathologic characteristics of PXA and identify factors associated with outcomes. METHODS:  We retrospectively analyzed a cohort of 16 adult and children patients with PXA who underwent primary resection from 1997 to 2019, referred to our Radiation Oncology Unit and to Meyer's Paediatric Hospital. We also reviewed the relevant literature. RESULTS:  All patients underwent primary surgical resection; 10 patients received adjuvant radiation treatment course, ranging from DTF 54 to 64 Gy; 8 of them received, in addition, concurrent adjuvant chemotherapy; 6 patients underwent only radiological follow-up. After a median follow up was 60 months: median OS was 34.9 months (95% CI 30-218), 1-year OS 87%, 5-years OS 50%, 10-years OS 50%; median PFS 24.4 months (95% CI 13-156), 1-year PFS 80%, 5-years PFS 33%, 10-years PFS 33%. A chi-square test showed a significant association between OS and recurrent disease (p = 0.002) and with chemotherapy adjuvant treatment (p = 0.049). A borderline statistical significant association was instead recognized with BRAF mutation (p = 0.058). CONCLUSIONS: Despite our analysis did not reveal a strong prognostic or predictive factor able to address pleomorphic xanthoastrocytoma management; however, in selected patients could be considered the addition of adjuvant radiation chemotherapy treatment after adequate neurosurgical primary resection. Furthermore, recurrent disease evidenced a detrimental impact on survival.

Study protocol and preliminary results from a mono-centric cohort within a trial testing stereotactic body radiotherapy and abiraterone (ARTO-NCT03449719).

BACKGROUND: ARTO trial was designed to evaluate the difference in terms of outcomes between patients affected by oligo metastatic castrate resistant prostate cancer (mCRPC) treated with Abiraterone acetate and randomized to receive or not SBRT on all sites of disease. Here, we present a preliminary analysis conducted on patients enrolled at promoting institution. OBJECTIVE: To present a preliminary overview about population features, clinical outcomes, adverse events, quality of life and explorative translational research. DESIGN, SETTING, AND PARTICIPANTS: ARTO (NCT03449719) is a phase II trial including patients affected by oligo mCRPC, randomized to receive standard of care (GnRH agonist or antagonist plus abiraterone acetate 1000 mg and oral prednisone 10 mg daily) with or without SBRT on all metastatic sites of disease. All subjects have < 3 bone or nodal metastases. All patients are treated in I line mCRPC setting, no previous lines of treatment for mCRPC are allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data about a mono-centric cohort of 42 patients enrolled are presented in the current analysis, with focus on baseline population features, PSA drop at 3 months, biochemical response, and quality of life outcomes. Descriptive statistics regarding translational research are also presented. RESULTS AND LIMITATION: Significant difference in terms of PSA drop at three months was not detected (p = 0.68). Biochemical response (PSA reduction > 50%) was reported in 73.7 versus 76.5% of patients in control vs SBRT arm, respectively (p = 0.84). All patients are alive. Progression occurred in 1 versus 0 patients in the control versus SBRT arm, respectively. After 3 months, an average decrease of 13 points in terms of Global Health Score was reported for the overall population. However, complete recovery was noticed at 6 months. Circulating tumor cells detection rate was 40%. CONCLUSIONS: SBRT + Abiraterone treatment was safe and well tolerated, non-significant trend in terms of PSA drop and biochemical response at 3 months was detected in SBRT arm. Interestingly, CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients.

Bevacizumab in recurrent high-grade glioma: a single institution retrospective analysis on 92 patients.

BACKGROUND: High-grade gliomas are among the most aggressive central nervous system primary tumors, with a high risk of recurrence and a poor prognosis. Re-operation, re-irradiation, chemotherapy are options in this setting. No-best therapy has been established. Bevacizumab was approved on the basis of two Phase 2 trials that evaluated its efficacy in patients with recurrent glioblastoma. MATERIALS AND METHODS: We have retrospectively review data of patients with high-grade glioma treated at our institution that undergone radiological or histological progression after at least one systemic treatment for recurrent disease. Bevacizumab was administered alone or in combination with chemotherapy until disease progression or unacceptable toxicity. Bevacizumab regimen was analyzed to assess PFS and OS. Histological, molecular and clinical features of the entire cohort were collected. RESULTS: We reviewed data from 92 patients, treated from April 2009 to November 2019, with histologically confirmed diagnosis of high-grade gliomas and recurrent disease. A PFS of 55.2%, 22.9% and 9.6% was observed at 6, 12 and 24 months, respectively. Performance status, age at diagnosis (< 65 or > 65 ys.) and use of corticosteroids during bevacizumab therapy were strongly associated with PFS. The OS was 74.9% at 6 months, 31.7% at 12 months, 10.1% at 24 months. In our cohort, 51.1% were long-term responders (PFS > 6 months). Globally, bevacizumab treatment was well tolerated. CONCLUSION: Our analysis confirms the efficacy of bevacizumab in recurrent high-grade glioma patients with an acceptable toxicity profile, in keeping with its known safety in the literature.

Axillary Management in Breast Cancer Patients Undergoing Upfront Surgery: Results from a Nationwide Survey on Behalf of the Clinical Oncology Breast Cancer Group (COBCG) and the Breast Cancer Study Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

BACKGROUND: We assessed the current practice concerning the axillary management of breast cancer (BC) patients undergoing upfront surgery among radiation oncologists (ROs) practising in Italy. METHODS: An online survey via SurveyMonkey (including 21 questions) was distributed amongst ROs in Italy through personal contacts and the Italian Association for Radiotherapy and Clinical Oncology (AIRO) network from August to September 2022. We particularly focused on the emerging omission of axillary lymph node dissection (ALND) in the presence of 1-2 sentinel node-positive patients and the consequent change in the role of regional nodal irradiation (RNI). RESULTS: A total of 101/195 (51% response rate) Italian Radiotherapy Cancer Care Centres answered the survey. With respect to patients with 1-2 sentinel node-positive, the relative proportion of respondents that offer patients ALND a) always, b) only in selected cases, and c) never was 37.6%, 60.4%, and 2.0%, respectively, with no significant geographical (North vs. Centre-South Italy; p = 0.92) or institutional (Academic vs. non-Academic; p = 0.49) differences. Radiation therapy indications varied widely in patients who did not undergo ALND. Among these, about a third of the respondents (17/56, 30.4%) stated that RNI was constantly performed. On the other hand, half of the respondents offered RNI in selected cases, stating that an unfavourable biologic tumour profile and extracapsular nodal extension were considered drivers of their decision. CONCLUSIONS: Results of the present survey show the variability of axillary management offered in clinical practice for BC patients undergoing conserving surgery upfront in Italy. Analysis of these attitudes may trigger the modification of some clinical approaches through multidisciplinary collaboration and create the background for future clinical investigations.

Choline PET/CT in recurrent prostate cancer.

Purpose: Biochemical recurrence (BR) occurs in up to 40% of patients with prostate cancer (PCa) treated with primary radical prostatectomy (RP). Choline PET/CT may show, in a single-step examination, the site of tumor recurrence earlier than traditional imaging methods, particularly at low prostate-specific antigen (PSA) levels, thus influencing subsequent treatment. Methods/patients: Patients with recurrent and non-metastatic prostate cancer (nmPCa), who were assessed with choline PET/CT, were included in the analysis. Based on imaging results, the following therapeutic strategies were chosen: radiotherapy to the prostatic bed, androgen deprivation therapy (ADT), and chemotherapy or stereotactic body radiotherapy (SBRT) to either the pelvic lymph nodes or distant metastases. We assessed the impact of age, PSA levels, Gleason score (GS), and adjuvant therapy on oncological outcomes. Results: Data from 410 consecutive nmPCa patients with BR who underwent RP as primary treatment were analyzed. One hundred seventy-six (42.9%) patients had a negative choline PET/CT, and 234 (57.1%) patients resulted positive. In the multivariate analysis, only chemotherapy and PSA at recurrence were significant independent prognostic factors on overall survival (OS). In the PET-positive subgroup, the number of relapses, PSA post-prostatectomy, and chemotherapy impacted on OS. PSA (post-surgery and at recurrence) affected progression-free survival (PFS) in the univariate analysis. In the multivariate analysis, GS, the number of relapse sites, and PSA (post-surgery and at recurrence) were significant prognostic factors for disease-free survival (DFS). Conclusion: Choline PET/CT provides better accuracy than conventional imaging for the assessment of nmPCa with BR after prostatectomy, thereby enabling salvage strategies and improving quality of life.

Psychological Distress in Healthcare Workers During the Covid-19 Pandemic: Development and Validation of the Italian Version of the Healthcare Workers Emergency Distress Questionnaire (HEDQ).

Objective: The COVID-19 pandemic has presented unprecedented challenges for health systems as it has proven to be an extraordinary emergency. Exposure to such chronic stress can have detrimental effects on the psychophysical well-being of healthcare workers, with possible manifestation of stress-related symptoms. The present study aimed to develop and validate the Healthcare Workers Emergency Distress Questionnaire (HEDQ), a self-report screening questionnaire with the purpose of identifying the healthcare workers at risk for psychological and moral distress, and PTSD-related symptoms during emergencies. Method: The HEDQ was administered to 250 healthcare workers of the AULSS 3 Serenissima and 47 citizens from the general population in Venice (Italy) during the health emergency period (from April to June 2020). In the second administration (from August to September 2020), data were collected from 101 of the 250 healthcare workers who had participated in the first administration. To test for the convergent validity, the Depression Anxiety Stress Scale (DASS-21) was also administered. Results: Exploratory and hierarchical confirmatory factor analyses validated the 21-item structure of the questionnaire. Internal consistency, and factorial and convergent validity were good. Moreover, the HEDQ discriminated between those who worked in COVID-19 hospital units and those who did not (including the general population), showing good known-group validity. The two-month temporal stability of the questionnaire was excellent. The HEDQ scale scores significantly decreased from the first to the second administration, thus supporting that the tool is a measure of acute stress in healthcare workers. Conclusions: Our results provide support for the use of the HEDQ as a brief, multidimensional measure of emergency-related stress reactions in healthcare workers. Consequently, the HEDQ can be considered a useful instrument supporting clinical activity to identify those who may be more easily affected by stress reactions in the event of atypically high levels of risk exposure during crises.

Use of an alfa-lipoic, Methylsulfonylmethane, Boswellia serrata and Bromelain dietary supplement (OPERA®) for aromatase inhibitors-related arthralgia management (AIA): a prospective phase II trial (NCT04161833).

Aromatase Inhibitors (AIs) are recommended for the adjuvant treatment of hormone receptor positive breast cancer in both high-risk pre-menopausal and post-menopausal population; arthralgia is the main cause of discontinuation of therapy and affects up to 25% of population on AI treatment. The objective of the study was to prospectively evaluate OPERA® (GAMFARMA srl, Milan, Italy), a new dietary supplement where α-Lipoic acid, Boswellia serrata, Methylsulfonylmethane and Bromelain are combined in a single hard-gelatin capsule to be taken once a day. Fifty-three patients with arthralgia (NCI-CTCAE v4.0 grade ≥ 1) occurring during AI therapy were enrolled. All patients received OPERA® from enrollment (T0) up to sixth months (T3). Patients' AI-related arthralgia was evaluated every two months with VAS Scale, PRAI questionnaire, and CTCAE scale. Primary endpoint was the number of patients with symptom resolution (G0) at T3 if compared to T0, according to CTCAE and VAS scale. Secondary endpoints were decrease in arthralgia intensity measured with PRAI score at T3 compared to baseline, safety of OPERA® and rate of AI interruption. Treatment with OPERA® supplement was overall well tolerated; no relevant toxicities related to OPERA® intake were reported. Seven subjects (13.2%) were not included in the final analysis because of consent withdrawal. 46 participants were eligible for final analysis. According to CTCAE scale, 10 out of 46 patients reported symptoms resolution at 6-month follow-up from the time of enrollment T0 (p = 0.0009). According to VAS score, 5 patients reported complete resolution of symptoms at T3 if compared to baseline starting situation T0 (p = 0.0222). Analysis of PRAI score showed a significant reduction in arthralgia-related pain perceived (p = 0.0001). OPERA® was able to reduce the intensity of arthralgia related to AI therapy. Randomized, double-blind studies are warranted to confirm the effectiveness of this dietary supplement.

Regorafenib in glioblastoma recurrence: A case report.

GBM (glioblastoma multiforme) is the most common and aggressive brain tumor. To date, treatment options for glioblastoma recurrence are lacking. Recently, REGOMA trial showed the superiority of regorafenib to lomustine in patients with first glioblastoma recurrence. We report an excellent response to three months treatment with regorafenib, in a patient who presented a rapid progression after the end of post operative radio-chemotherapy and after only one cycle of adjuvant TMZ (Temozolomide).

Re-irradiation for oligoprogression under Nivolumab in recurrent head and neck squamous cell carcinoma: A case report.

Immune checkpoint inhibitors (ICIs) represent a recently introduced class of agents active in head and neck squamous cell carcinoma (HNSCC). For a subgroup of patients with recurrent or metastatic disease, long-term benefit can be achieved: maintaining a sustained response to immunotherapy is therefore a critical factor for its efficacy at an individual level. In analogy to targeted agents, a limited pattern of progression, or "oligoprogression", can occur. For locally recurrent HNSCC, the potential biologic interplay between the efficacy of ICIs and the design of radiation fields chosen for primary treatment is currently unknown. Here, we report on a patient who presented two subsequent oligoprogressions successfully treated with re-irradiation without interrupting Nivolumab. Both oligoprogressive lesions developed in previously unirradiated areas. We hypothesize the existence of a synergistic effect with optimal spatial cooperation between ICIs and re-irradiation for oligoprogressive disease under immunotherapy.

Accelerated Partial-Breast Irradiation Compared With Whole-Breast Irradiation for Early Breast Cancer: Long-Term Results of the Randomized Phase III APBI-IMRT-Florence Trial.

PURPOSE: To report the long-term results of external-beam accelerated partial-breast irradiation (APBI) intensity-modulated radiation therapy (IMRT) Florence phase III trial comparing whole-breast irradiation (WBI) to APBI in early-stage breast cancer. PATIENTS AND METHODS: The primary end point was to determine the 5-year difference in ipsilateral breast tumor recurrence (IBTR) between 30 Gy in 5 once-daily fractions (APBI arm) and 50 Gy in 25 fractions with a tumor bed boost (WBI arm) after breast-conserving surgery. RESULTS: Five hundred twenty patients, more than 90% of whom had characteristics associated with low recurrence risk, were randomly assigned (WBI, n = 260; APBI, n = 260) between 2005 and 2013. Median follow-up was 10.7 years. The 10-year cumulative incidence of IBTR was 2.5% (n = 6) in the WBI and 3.7% (n = 9) in the APBI arm (hazard ratio [HR], 1.56; 95% CI, 0.55 to 4.37; P = .40). Overall survival at 10 years was 91.9% in both arms (HR, 0.95; 95% CI, 0.50 to 1.79; P = .86). Breast cancer-specific survival at 10 years was 96.7% in the WBI and 97.8% in the APBI arm (HR, 0.65; 95% CI, 0.21 to 1.99; P = .45). The APBI arm showed significantly less acute toxicity (P = .0001) and late toxicity (P = .0001) and improved cosmetic outcome as evaluated by both physician (P = .0001) and patient (P = .0001). CONCLUSION: The 10-year cumulative IBTR incidence in early breast cancer treated with external APBI using IMRT technique in 5 once-daily fractions is low and not different from that after WBI. Acute and late treatment-related toxicity and cosmesis outcomes were significantly in favor of APBI.

Patterns of Care and Survival in Elderly Patients With Locally Advanced Soft Tissue Sarcoma.

OBJECTIVES: The aim of this study was to analyze patterns of care in elderly soft tissue sarcoma (STS) patients and their impact on clinical outcome and treatment-related toxicity. MATERIALS AND METHODS: We retrospectively collected data of >65-year-old patients diagnosed with locally advanced STS between 1991 and 2017 in a single institution. RESULTS: The study included 111 patients: 105 (94.6%) patients underwent surgery, associated with preoperative (n=19, 17.1%) or postoperative radiotherapy (n=72, 64.8%). Anthracycline-based chemotherapy was prescribed in 41.4% of patients (n=46). Acute grade ≥3 postoperative radiotherapy-related radiation dermatitis and all grades of chemotherapy-induced neutropenia were significantly correlated to age >80 years (P=0.02) and >70 years (P=0.045), respectively. The mean follow-up was 4.1 years (range, 0.1 to 17.7). Three-year and 5-year local recurrence-free survival were 80.3% and 75.7%, respectively; neither treatment-related nor patient-related characteristics affected local recurrence. Three-year and 5-year distant relapse-free survival were 59.6% and 44.6%, respectively. On multivariate Cox regression, undifferentiated pleomorphic sarcoma histology and Charlson Comorbidity Index >7 were independent factors associated with distant relapse-free survival (P=0.026 and P=0.0001). Overall survival was 62% and 46.6% at 3 and 5 years, respectively. On multivariate Cox regression, surgery and Charlson Comorbidity Index <7 were independent factors associated with overall survival (P=0.006 and P=0.0001). CONCLUSIONS: In this study, elderly STS patients receiving a tailored treatment encompassing surgery, radiotherapy, and/or chemotherapy obtained an improved outcome, although caution is advised because of increased toxicity in relation to age. Comorbidities should be considered to offer the best treatment option to this frail patient population.