Impact of COVID-19 on patient-doctor interaction in a complex radiation therapy facility.

PURPOSE: In the last months, Italy faced a COVID-19 emergency and implemented preventive measures in order to protect patients and healthcare providers from a disease outbreak. The pandemic control strategies impacted patient experience directly. Questionnaires evaluating patients reported measures (PREMs) may assess critical issues and represent a helpful tool to measure the patient perception of healthcare service. Our aim was to prospectively assess patient satisfaction about doctor-patient interaction in a high-volume radiation therapy and oncology center during the COVID-19 pandemic. METHODS: Cancer patients receiving either systemic and/or radiation treatment underwent a survey. Two validated questionnaires (EORTC QLQ-C30, FACIT-TS-G version 1) and 14 specific questions evaluating patients' perception of COVID-19 measures were administered. RESULTS: One hundred twenty-five patients admitted to our department from 1-30 April 2020 completed the questionnaires. The majority (66.4%) of patients were women and the most common disease was breast cancer (40%). The average Global Health Status (GHS) of EORTC QLQ-C30 was 61.67. Emotional functioning, social, and cognitive domains obtained scores of 75.48, 80.13, and 84.67, respectively. FACIT-TS-G results revealed 120 patients rated the treatments effective and 108 patients thought the side effects were the same as expected or better. Most (89.6%) rated their treatment good, very good, or excellent. Concerning COVID-19-related questions, patients reported overall very good level of information. CONCLUSIONS: Despite the introduction of strict COVID-19 control measures, there was a high level of cancer outpatient satisfaction. The satisfaction levels may influence compliance, continuity of treatments, and patient-doctor communication, impacting the quality of clinical care in the next phases of the pandemic.

Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer.

PURPOSE: Tumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer. METHODS: A xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively). RESULTS: Tumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion. CONCLUSIONS: Activity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.

Stereotactic Re-irradiation in Recurrent Prostate Cancer after Previous Postoperative or Definitive Radiotherapy: Long-term Results after a Median Follow-up of 4 Years.

AIMS: In 2018, we published early results from a cohort of patients treated with stereotactic body radiotherapy (SBRT) after previous radiotherapy with definitive or postoperative intent. We sought to provide extended follow-up of this cohort to confirm the safety and efficacy of this approach in a real-world scenario. MATERIALS AND METHODS: Fifty patients affected by local relapse after previous definitive or postoperative radiotherapy were treated with SBRT. Treatment provided a total dose of 30 Gy in five fractions. Data about biochemical relapse-free survival (BRFS) and metastasis-free survival (MFS), together with adverse events, were analysed. Toxicity was reported according to Common Terminology Criteria for Adverse Events (CTCAE) score v.4.03. RESULTS: After a median follow-up of 48.2 months, the median BRFS was 43 months. A Gleason score >7 and concomitant androgen deprivation therapy were shown to be predictors of the worst BRFS (hazard ratio 2.42, 95% confidence interval 1.09-5.41, P = 0.02; hazard ratio 2.83, 95% confidence interval 1.17-6.8, P = 0.02, respectively). The median MFS was not reached; concomitant androgen deprivation therapy was confirmed to be predictive of the worst MFS (hazard ratio 4.75, 95% confidence interval 1.52-14.8, P = 0.007). Late grade 1 and 2 rectal and bladder toxicity occurred in three (6%) and 13 (26%) patients, respectively. One patient experienced both grade 3 acute and chronic bladder toxicity. CONCLUSION: Salvage SBRT re-irradiation after previous postoperative or definitive radiotherapy for local prostate cancer recurrence confirmed promising results in terms of oncological outcomes and the safety of this approach.

Pattern of Recurrence After Stereotactic Radiotherapy in Prostate Cancer Patients With Nodal Pelvic Relapse. A Multi-Institutional Retrospective Analysis.

AIMS: Currently, when nodal pelvic oligorecurrent disease is detected, no standard treatment option is recommended. One possible salvage option is nodal stereotactic body radiotherapy (SBRT). Here we analysed recurrence patterns after nodal SBRT in patients affected by pelvic oligometastatic relapse after radical prostatectomy, and androgen deprivation therapy (ADT)-free survival in this population. MATERIALS AND METHODS: Data on 93 patients consecutively treated in five different institutions for pelvic oligorecurrent disease were reviewed. Inclusion criteria were biochemical recurrence after radical prostatectomy and imaging showing three or fewer metachronous lymphoadenopathies under aortic bifurcation. Patients underwent SBRT on all sites of disease. Concomitant ADT was allowed. RESULTS: After a median follow-up of 20 months (interquartile range 11-41), 57 patients had post-SBRT radiological evidence of relapse, for a median disease-free survival (DFS) of 15 months (95% confidence interval 9-24). Concomitant ADT was administered in 20 patients (21.5%). Overall, eight (8.6%), 21 (22.6%) and 28 (30.1%) patients had prostate bed only, pelvic nodal or distant relapse, respectively. The median ADT-free survival was not reached. Concomitant ADT, International Society for Urologic Pathology pattern at diagnosis < or ≥3, time to relapse ≤ or >12 months, prostate-specific antigen at recurrence < or ≥1.10 ng/ml and prostate-specific membrane antigen staging were not significantly associated with DFS. After relapse, 42 patients (45.2%) received a second SBRT course. CONCLUSION: Nodal SBRT yielded encouraging DFS and ADT-free survival in this population. Only a minority of patients developed prostate bed recurrence, suggesting that local treatment may be safely avoided. A consistent percentage of patients could be managed with a second SBRT course.

Stereotactic Body Radiation Therapy in the Management of Oligometastatic and Oligoprogressive Bladder Cancer and Other Urothelial Malignancies.

AIMS: Bladder cancer represents the most common type of urothelial carcinoma, with a median overall survival of 12.5-15 months in the case of metastatic disease. We evaluated the role of stereotactic body radiation therapy (SBRT) in the management oligometastatic urothelial cancer. MATERIALS AND METHODS: Data on patients with a maximum of five metastases were collected from three institutions. Concomitant systemic therapy was allowed. End points were the local control of treated metastases, distant progression-free survival (PFS), overall PFS and overall survival. RESULTS: Data for 82 lesions and 61 patients were included. The primary tumour was located in the bladder in 82% of patients, followed by kidney pelvis (11.5%). The most common treated site was lung (40.2%). Twenty-nine (47.5%) and 14 (23%) patients received systemic therapy before and during SBRT, respectively. The median BED10 value was 78.7 Gy. The median follow-up was 17.2 months. Rates of local control at 1 and 2 years were 92% and 88.9%, respectively, with correlation with systemic therapy before SBRT (hazard ratio 2.62, P = 0.034). Overall PFS at 1 and 2 years was 47.9% and 38.1%, respectively. The number of metastases was a predictive factor (hazard ratio 2.65, P = 0.008). The median overall survival was 25.6 months. Total dose (hazard ratio 0.93, P = 0.003) and BED10 (hazard ratio 0.97, P = 0.006) were correlated with overall survival. No grade ≥2 adverse events were reported. CONCLUSIONS: SBRT represents an effective and safe treatment in metastatic urothelial carcinoma. Prospective randomised trials are necessary to better evaluate the benefit on delaying the onset of new systemic therapies.

Radiotherapy is effective in the management of rare penile metastases: Two case reports.

Penile metastasization is an uncommon condition, mostly derived from primitive advanced abdominal cancers, with disabling symptoms. Palliative treatment, in reason of poor prognosis patients, is frequently surgical with destructive management. We report two cases of penile metastasis, from primitive prostatic adenocarcinoma and primitive urothelial carcinoma, effectively managed with radiation treatment at our institution. A three-dimensional conformal radiation therapy with 42Gy to the planning target volume in 14 fractions was delivered. Radiation treatment was safely delivered, with low toxicity profile and achieved adequate symptoms control without compromising genitourinary functions. Radiation therapy should be considered in management of rare penile metastases.

Postoperative radiotherapy after upfront radical prostatectomy: debated issues at a turning point-a survey exploring management trends on behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology).

OBJECTIVES: Postoperative prostate cancer patients are a heterogeneous population, and many prognostic factors (e.g., local staging, PSA kinetics, margin status, histopathological features) may influence their clinical management. In this complex scenario, univocal recommendations are often lacking. For these reasons, the present survey was developed by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) to collect the opinion of Italian radiation oncologists and delineate a representation of current clinical practice in our country. METHODS: A questionnaire was administered online to AIRO (Italian Association of Radiotherapy and Clinical Oncology) members registered in 2020 with a clinical interest in uro-oncological disease. RESULTS: Sixty-one per cent of AIRO members answered the proposed survey. Explored topics included career and expertise, indications to adjuvant RT, additional imaging in biochemical recurrence setting, use of salvage radiotherapy (SRT), management of clinically evident locoregional recurrence and future considerations. CONCLUSIONS: Overall, good level of agreement was found between participants for most of the topics. Most debated issues regarded, as expected, implementation of new imaging methods in this setting. Notably, trend in favour of early SRT vs. immediate adjuvant RT was underlined, and preference for global evaluation rather than isolated risk factors for RT indications was noticed.

Toxicity after moderately hypofractionated versus conventionally fractionated prostate radiotherapy: A systematic review and meta-analysis of the current literature.

BACKGROUND: Moderately hypofractionated radiotherapy (RT) currently represents the standard RT approach for all prostate cancer (PCa) risk categories. We performed a systematic review and meta-analysis of available literature, focusing on acute and late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) of moderate hypofractionation for localized PCa. MATERIALS AND METHODS: Literature search was performed and two independent reviewers selected the records according to the following Population (P) Intervention (I) Comparator (C) and Outcomes (O) (PICO) question: "In patients affected by localized PCa (P), moderately hypofractionated RT (defined as a treatment schedule providing a single dose per fraction of 3-4.5 Gy) (I) can be considered equivalent to conventionally fractionated RT (C) in terms of G > 2 GI and GU acute and late adverse events (O)?". Bias assessment was performed using Cochrane Cochrane Collaboration's Tool for Assessing Risk of Bias. RESULTS: Thirteen records were identified and a meta-analysis was performed. Risk of acute GI and GU > 2 adverse events in the moderately hypofractionated arm was increased by 9.8 % (95 %CI 4.8 %-14.7 %; I2 = 57 %) and 1.5 % (95 % CI -1.5 %-4.4 %; I2 = 0%), respectively. DISCUSSION: Overall, majority of trials included in our meta-analysis suggested that moderately hypofractionated RT is equivalent, in terms of GI and GU adverse events, to conventional fractionation. Pooled analysis showed a trend to increased GI toxicity after hypofractionated treatment, but this might be related to dose escalation rather than hypofractionation.

Stereotactic ablative radiotherapy in castration-resistant prostate cancer patients with oligoprogression during androgen receptor-targeted therapy.

OBJECTIVES: To report outcomes of stereotactic body radiotherapy (SBRT) in metastatic castration-resistant prostate cancer (mCRPC) patients with oligoprogression (≤ 5 metastases) during first-line treatment with androgen receptor-targeted therapy (ARTT). PATIENTS AND METHODS: Retrospective multi-institutional analysis of mCRPC patients treated with SBRT to oligoprogressive lesions during ARTT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Survival analysis was performed using the Kaplan-Meier method, univariate and multivariate analysis (MVA) were performed. RESULTS: Data from 34 patients were analyzed. Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively. At MVA, factors associated with worse NEST-free survival and r-PFS were polymetastatic burden at diagnosis of metastatic hormone-sensitive disease (hazard ratio [HR] 3.66, p = 0.009; HR 3.03, p = 0.034), PSA ≤ 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSADT ≤ 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037). Polymetastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029). No patient developed acute or late grade ≥ 2 toxicity. CONCLUSION: Our results suggest that SBRT in oligoprogressive mCPRC is safe, effective and seems to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression. Prospective trials are needed.

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275).

In our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC- patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL- patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.

Detection rate, pattern of relapse and influence on therapeutic decision of PSMA PET/CT in patients affected by biochemical recurrence after radical prostatectomy, a retrospective case series.

AIMS: 68Ga-Prostate-specific membrane antigen (PSMA) PET/CT is widely used in patients with biochemical recurrence (BCR) after radical prostatectomy. We collected data about patients staged with PSMA PET/CT after BCR (PSA < 1 ng/ml) in four different institutes. Impact of baseline features (Gleason score, risk classification, PSA at recurrence, PSA doubling time and time to recurrence) was explored to understand predictive factors of (PSMA) PET/CT positivity. Impact of restaging on following treatment approaches was reported. RESULTS: 92 patients were included. PSMA PET/CT detection rate was 56.5% and low-volume disease (≤ 3 non-visceral lesions) was detected in 52.2% of patients. After positive scan, 13.5% of patients still lies on observation, ADT alone was administered in 30.8% of cases, Stereotactic body RT (SBRT) alone was delivered to 44.2% of patients and 11.5% of patients underwent concomitant SBRT and ADT. Seven patients underwent conventional salvage prostate bed RT. Chi-squared test showed a higher rate of positive PSMA PET/CT for patients with Gleason score > 7 (p = 0.004) and TTR < 29.5 months (p = 0.003). CONCLUSIONS: PSMA PET/CT showed a high detection rate. This influenced clinical management in a significant percentage of patients, allowing treatment tailoring on the basis of imaging.

Stereotactic radiotherapy in oligoprogressive and oligorecurrent urothelial cancer patients: A retrospective experience.

Urothelial cancer is one of the most common malignancies; after relapse or disease progression available therapeutic options are limited. We analyze efficacy and toxicity of local treatment on metastases using stereotactic body radiation therapy (SBRT) in selected patients with oligometastatic disease from urothelial cancer. A significant percentage of treated lesions achieved local control, with a promising overall response rate. OBJECTIVES: to analyze efficacy and toxicity of local treatment on metastases using stereotactic body radiation therapy (SBRT) in selected patients with oligometastatic disease from urothelial cancer. MATERIALS AND METHODS: Data from clinical records of 19 patients treated in our institution since May 2011 to October 2017 with SBRT for oligometastatic/oligoprogressive urothelial carcinoma were retrospectively collected. Clinical outcomes in terms of local control (LC), response rate, symptoms control, progression free and overall survival (PFS and OS), and adverse events were analyzed and reported. RESULTS: Nineteen patients were treated on 25 metastatic lesions; 5 of them received treatment on multiple sites. After an average follow up of 11.5 months, LC was achieved in 17 lesions (68%) and there was no local recurrence in lesions with complete or partial response. OS was 13.8 months. Adverse events were reported only in 3 patients (5 overall events). No late toxicity was reported. CONCLUSIONS: An approach consisting in SBRT for local treatment of oligometastatic or persistent disease can be effective and safe in selected patients. Prospective studies are needed, to find correct selection criteria and optimal dose and fractionation.

Benefit of ablative versus palliative-only radiotherapy in combination with nivolumab in patients affected by metastatic kidney and lung cancer.

PURPOSE: Here, we present the results from a retrospective analysis, with the purpose of evaluating the safety and feasibility of nivolumab and radiotherapy (RT) concomitant association in metastatic kidney and lung cancer patients. MATERIALS AND METHODS: From August 2015 until September 2017, we retrospectively observed 20 patients with metastatic lung and renal cell carcinoma who had been initiated therapy with nivolumab and underwent concomitant RT. RT was administered either as an ablative therapy in the oligometastatic/oligoprogressive setting or as palliative-only treatment for symptomatic patients. Data on progression-free and overall survival (PFS and OS), treatment response and adverse events were collected and reported. Comparison between palliative-only and ablative treatments was performed. RESULTS: PFS and OS were 7 and 12.5 months in the entire population, respectively. Oligoprogressive patients treated with ablative intent, compared to patients undergoing RT with palliative-only intent, had statistically longer PFS (11.5 vs 5.2 months, HR 0.42, CI 0.18-0.98, p 0.03) and OS (17.9 vs 10.31 months, HR 0.41 CI 0.16-1.02, p 0.04). Considering only patients treated with ablative intent, 87.5% showed response to treatment, and complete response was reported in 37.5% of cases. Adverse G2-G3 related to combination treatment were reported as follows: 1 gastrointestinal (nausea), 4 breakthrough pain. CONCLUSIONS: Our data showed significant advantage for oligoprogressive patients treated with RT during nivolumab therapy. No safety alert emerged. These results underline the potential synergistic effects of RT and Immune therapy combination. Our analysis prompts further prospective studies exploring the benefit of integrated treatment strategies.

Stereotactic body radiation therapy (SBRT) on renal cell carcinoma, an overview of technical aspects, biological rationale and current literature.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is characterized by the delivery of high doses of ionizing radiation in few fractions. It is highly effective in achieving local control, and, due to the high biological effective dose administered, it seems to overcome the radioresistance of renal cell carcinoma (RCC). Thus, SBRT could constitute a treatment option for the management of localized RCC in patients who are not surgical candidates. In this paper, we report an overview about data from the current evidence about SBRT in patients affected by localized RCC. MATERIALS AND METHODS: A non-systematic review was performed, including data from both retrospective and prospective studies focusing on the use of SBRT for localized RCC and its biological rationale. Furthermore, ongoing trials on this issue are reported. CONCLUSION: Currently, SBRT might be considered a treatment alternative in inoperable patients affected by primary RCC. Currently, dose-escalation to 48 Gy in 3-4 fractions are effective and well tolerated. Emerging role of immune therapies in RCC patients warrant further studies to explore interactions between SBRT and immune response.

Robotic Stereotactic Retreatment for Biochemical Control in Previously Irradiated Patients Affected by Recurrent Prostate Cancer.

AIMS: Robotic stereotactic body radiotherapy (rSBRT) to local recurrences emerged as a valuable option for exclusive local failure after prior external beam radiation therapy (EBRT) for localised prostate cancer. The aim of this study was to assess the efficacy and safety of rSBRT in patients experiencing locally recurrent prostate cancer after prior definitive or postoperative radiotherapy using the Cyberknife. MATERIALS AND METHODS: Data from 50 patients were retrospectively reviewed. Local recurrence was assessed by 18F-choline positron emission tomography and pelvic magnetic resonance imaging; a dose of 30 Gy was delivered in five fractions. Prostate-specific antigen (PSA) was assessed at 2 months, 6 months and every 4 months thereafter. Toxicity was assessed according to CTCAE v.4.03. RESULTS: All patients received prior EBRT. The median EQD2 total dose was 74 Gy (60-80 Gy). Eleven patients were receiving androgen deprivation after prior biochemical failure. At 6 months, 41 patients showed a median PSA decline of -77.1% (14.3-99.3%), whereas nine patients experienced a median PSA elevation of +58.7% (0-2300.0%). Biochemical relapse-free survival (BRFS) was 80.0%. Impaired BRFS was correlated with the high-risk category at diagnosis (P = 0.014, hazard ratio 5.61) and ongoing androgen deprivation (P = 0.025, hazard ratio 2.98). Neither clinical variables nor dosimetric parameters were found to be predictive for toxicity. CONCLUSION: Focal rSBRT can achieve durable remission in locally relapsing patients and systemic treatment can be postponed with acceptable toxicity. Accurate patient selection is mandatory to maximise disease control.

Gamma Knife Radiosurgery in the management of single and multiple brain metastases.

OBJECTIVES: To evaluate the efficacy and safety of Gamma Knife Radiosurgery (GKRS) in the treatment of single and multiple brain metastases. PATIENTS AND METHODS: From October 2012 to June 2014 106 patients were treated with Radiosurgery (RS) for brain metastases at University of Florence. 77 out of 106 patients had a radiological follow up and their data were analyzed. The target was defined as the enhancing lesion. The prescription dose was defined depending on tumor volume and tumor location. Each patient performed an MRI one month after GKRS for the first three months and every 3 months thereafter. Overall survival was calculated from the day of RS until death. Local recurrence (LR) was defined as radiologic growth of the irradiated lesion, while distant brain recurrence (DBR) was the evidence of brain lesion outside the previous irradiated field. Both the LR and DBR were calculated from the RS till the day of radiological evidence of relapse. The correlations within patient and disease characteristics and the outcomes of survival and disease control were analyzed. RESULTS: Mean follow up was 7.2 ± 4.8 months (range: 2.4-22.8 months). At the time of analysis 21 patients (27.3%) were dead. The overall survival (OS) at 1 year was 74%. On univariate Cox Regression analysis female gender (p=0.043, HR: 0.391, 95% CI: 0.157-0.972) and age >65 years (p=0.003 HR: 4.623, 95% CI: 1.687-12.663) were predictive for survival. On multivariate analysis, age older than 65 years (p=0.005HR: 4.254, 95% CI: 1.544-11.721) was confirmed as associated with worsened overall survival. 19 patients (24.7%) had recurrence in the radiosurgery field. The median time to local failure was 4.8 ± 2.0 months (range: 1.8-9.4 months) from GKRS. On Cox Regression univariate analysis, the only factor associated with higher risk of local failure was a number of treated lesions more than 4 (p=0.015, HR: 3.813, 95% CI: 1.298-11.202), no significant parameters were found at the multivariate analysis. The median time to develop distant brain failure was 6 ± 4.32 months (range: 1.08-21.6 months). Median distant brain control was 74% at 1 year. None of the factors analyzed was statistically significant for the distant brain relapse. The radiosurgery treatment was well tolerated. One patient treated for seven metastases developed seizures 8h after GKRS, he was treated with steroids and anticonvulsants. One patient had radiologic evidence of radionecrosis without any neurological symptoms. CONCLUSIONS: In well-performing patients with stable systemic disease radiosurgery can be performed as an exclusive treatment for brain metastases. Younger patients could have a greater benefit from the RS, on the other hand our finding confirm no correlation between the survival outcome and the number of lesions treated.

Circulating levels of tumour necrosis factor-alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis.

An immunologic pathogenesis for amyotrophic lateral sclerosis (ALS) has been recently proposed. We tested the whole tumour necrosis factor (TNF) system in the serum of 51 ALS patients at different stages of the disease and 36 healthy controls. Antigenic TNF-alpha and its soluble receptors (sTNF-Rs), measured by ELISA, were significantly higher in ALS patients than in healthy controls. However, biologically active TNF-alpha, corresponding to the sTNF-Rs-unbound trimeric TNFalpha molecule and assayed by its cytotoxic activity on a sensitive cell line, was similar between ALS patients and healthy controls. Neither antigenic TNF-alpha, bioactive TNF-alpha nor sTNF-Rs correlated with disease severity, disease duration, or weight loss. In conclusion, we reported an activation of the TNF system in ALS. The role of this activation in the pathogenesis of the disease remains elusive.

Left atrial function: bridge to central and hormonal determinants of exercise capacity in patients with chronic heart failure.

UNLABELLED: The stroke volume response to exercise is a critical determinant in meeting peripheral metabolic demands in patients with chronic hear failure. The Left atrium, by its position, is important in coupling right and left ventricles, to left preload reserve and to modulate sympathetic activity. We performed this study to investigate the relationship between exercise capacity and diastolic and systolic left atrium function in patients with chronic heart failure. METHODS: We considered 128 consecutive patients with severe chronic heart failure (EF < 35%) due to ischemic or idiopathic dilated cardiomyopathy. Cardiac output, right atrial pressure, pulmonary artery pressures and mean pulmonary wedge pressure (A, X, V, Y wedge pressures) were determined during right cardiac catheterization. By Echocardiography evaluation, we measured atrial pressures and volume during early and late left atrial systolic filling and we calculated left atrial chamber stiffness by this equation P = A*eKV1. (P = left atrial pressure; A = elastic constant (mmHg*ml); e = the base of the natural logarithm; V1 = left atrial volume (ml); K = left atrial chamber stiffness constant (ml-1) = ln (V/X)/(maximal--minimal left atrial volumes)). All patients performed cardiopulmonary exercise test with modified Noughton protocol. Plasma norepinephrine and Atrial natriuretic factor levels were determined. RESULTS: Maximal and minimal left atrial volumes were inversely related to oxygen consumption (r = -.44, p < .001; r = -.61, p < .001). At rest, no differences were found in plasma norepinephrine concentrations (309 +/- 152 pg/ml vs 309 +/- 394 pg/ml; p = ns) and systemic vascular resistance (1706 +/- 435 vs 1771 +/- 524 dynes/cm sec-5; p = ns) in patients with large or normal left atrial volumes. During exercise the chronotropic response increased less in patients with large atrial volumes (56 +/- 13 vs 45 +/- 14; p = .001). The left atrial chamber stiffness constant was inversely related to peak oxygen consumption and exercise time. Patients with different chamber stiffness showed statistical difference in peak VO2 (16 +/- 4 vs 11 +/- 3 ml/kg/min; p = .0001). Left atrial ejection fraction was directly related to peak oxygen consumption (r = 0.55), but the most strongly correlation was with atrial filling fraction (r = .67). CONCLUSIONS: This study demonstrates a strong relationship between left atrial function and exercise capacity in patients with chronic heart failure.