Is single fraction the future of stereotactic body radiation therapy (SBRT)? A critical appraisal of the current literature.

Stereotactic Body Radiation Therapy (SBRT) is a standard of care for many localizations but the question of the optimal fractionation remains a matter of concern. If single fraction sessions are routinely used for intracranial targets, their utilization for mobile extracranial lesions is a source of debate and apprehension. Single session treatments improve patient comfort, provide a medico-economic benefit, and have proven useful in the context of the SARS-CoV 2 pandemic. However, both technical and radiobiological uncertainties remain. Experience from intracranial radiosurgery has shown that the size of the target, its proximity to organs at risk, tumor histology, and the volume of normal tissue irradiated are all determining factors in the choice of fractionation. The literature on the use of single fraction for extracranial sites is still scarce. Only primary and secondary pulmonary tumors have been evaluated in prospective randomized trials, allowing the integration of these fractionation schemes in daily practice, for highly selected cases and in trained teams. The level of evidence for the other organs is mainly based on dose escalation or retrospective trials and calls for caution, with further studies being needed before routine use in clinical practice.

Use of an intravaginal spacer in young girls treated with brachytherapy for bladder neck rhabdomyosarcoma: Dosimetric impact for organs at risk sparing and acute tolerance.

PURPOSE: Interstitial brachytherapy is indicated as part of a conservative strategy for children with bladder and/or prostate rhabdomyosarcoma (RMS), providing high local control probability with acceptable functional results. Vaginal and/or rectal complications were however reported, due to the close proximity to the implanted volume. We investigated the dosimetric impact of a vaginal spacer in terms of rectal and vaginal doses. METHODS AND PATIENTS: Medical records of 12 consecutive female patients with bladder neck RMS, median age 32 months (range: 1.3-6 years), were reviewed. Five patients were treated prior to 2017 without a vaginal spacer and seven patients treated after 2017 had their brachytherapy delivered with a vaginal spacer placed at time of implant. RESULTS: Minimal doses delivered to the most exposed 2cm3, 1cm3, and 0.5cm3 of the rectum were all statistically significantly lower among patients treated with a vaginal spacer, as compared to those treated without a spacer. Median rectal D2cm3 was 22GyEQD2 versus 38GyEQD2 (P=0.02), D1cm3 was 29GyEQD2 versus 51GyEQD2 (P=0.013), and D0.5cm3 was 32GyEQD2 versus 61GyEQD2 (P=0.017), with and without the vaginal spacer, respectively. The posterior vaginal wall D0.5cm3 dose was also significantly decreased, with median D0.5cm3 of 92GyEQD2 versus 54GyEQD2 (P<0.0001), with and without the spacer, respectively. Acute tolerance was excellent in all patients, with no need for replanning and no acute complication. CONCLUSIONS: The use of vaginal spacers in brachytherapy of female pediatric patients with bladder neck RMS resulted in significantly decreased doses to the rectum and the posterior vaginal wall. Though the clinical impact of such dose reduction remains undemonstrated, routine utilization of a vaginal spacer could be a method to decrease long-term morbidity in these patients.

Pre- or postoperative radiotherapy for soft tissue sarcomas.

Sarcomas are rare tumours arising from mesenchymal tissue. A multimodal management in an expert centre combining surgery and radiotherapy is the current standard of care for localized soft-tissue sarcomas of the extremities, to enable limb-sparing strategies. The delivery of pre- radiotherapy or postoperative radiotherapy offers similar local control and survival rates but the toxicity profile is quite different: preoperative radiotherapy increases the risk of wound complications and postoperative radiotherapy affects long-term functional outcomes. While postoperative radiotherapy has long been the rule, especially in Europe, technical improvements with image-guided- and intensity-modulated radiotherapy associated with a better management of postoperative wounds has tended to change practices with more frequent preoperative radiotherapy. More recently the possibilities of a hypofractionated regimen or potentiation by nanoparticles to increase the therapeutic index plead in favour of a preoperative delivery of radiotherapy. The aim of this paper is to report pros and cons of pre- and post-operative radiotherapy for soft-tissue sarcomas.

[How to manage a rectal cancer with synchronous liver metastases? A question of strategy]. / Comment traiter un cancer du rectum avec métastases hépatiques synchrones ? Une question de stratégie thérapeutique.

The prognosis of patients with rectal cancer and synchronous liver metastasis has improved thanks to chemotherapy and rectal and liver surgery progresses. However, there is no consensus about optimal management and practices remain heterogeneous. A curative treatment may be considered for 20 to 30% of patients with complete resection of metastasis and primary tumor after induction chemotherapy. To this end, a primary optimal evaluation by a multidisciplinary board including hepatic and colorectal surgeons is crucial. The therapeutic strategy associates chemotherapy, radiotherapy, hepatic and rectal surgery. The most threatening site guides the sequence of treatments. If hepatic resectability is uncertain, a "liver first" strategy associating induction chemotherapy and hepatic surgery is preferred. In non-resectable metastatic cases, chemotherapies with targeted therapies might lead to secondary resection for 30% of patients (conversion). This has changed our practice and triggers reconsidering resectability after chemotherapy. When metastases remain non-resectable, additional treatment focusing on primary tumor should control pelvic symptoms otherwise hardly impacting quality of life. Rectal surgery, short-course radiotherapy (5×5Gy), conformational long-course chemoradiotherapy or intensity-modulated radiation therapy with dose escalation are options discussed in this review.

Endovascular treatment of popliteal artery aneurysms: preliminary results.

PURPOSE: Popliteal artery aneurysms (PAAs) are a rare condition with an incidence <0.1%. The objective of this study was to evaluate the effectiveness of endovascular treatment of PAA with a covered stent-graft. MATERIALS AND METHODS: Between January 2009 and July 2010, ten patients (nine men and one woman, mean age 69 ± 12 years) with PAA were treated by endovascular placement of a heparin-coated stent-graft. All procedures were evaluated in terms of technical success, patency at 1, 6 and 12 months as assessed by colour Doppler ultrasound, complications, procedure duration and length of postoperative hospital stay. RESULTS: We obtained 100% technical success, with no peri- or postprocedural complications. Average duration of the procedure was 40 min, and mean hospital stay was 3 days. Primary and secondary patency rates at 1, 6 and 12 months were 100% and 100%, 90% and 100%, and 90% and 100%, respectively. Only one case of endoleak occurred. DISCUSSION: In keeping with the literature, our study demonstrates the effectiveness of endovascular repair of PAA, with short- and mid-term patency rates comparable to those of open surgery. Larger series and longer follow-up periods are needed to confirm these preliminary results.

[Endovascular treatment of abdominal aortic aneurysms: 6 years of experience at a single centre]. / Trattamento endovascolare di aneurismi dell'aorta addominale: esperienza monocentrica di sei anni.

PURPOSE: We sought to assess the effectiveness of endovascular abdominal aortic aneurysm (AAA) repair (EVAR) through a retrospective review of 6 years' experience at a single centre. MATERIALS AND METHODS: From April 2005 to August 2011, 222 patients affected by abdominal aortic aneurysms underwent EVAR. We evaluated primary technical success, postprocedural mortality, intraprocedural and postprocedural complications with contrast-enhanced computed tomography (CT) and contrast-enhanced ultrasound (US) follow-up at 1, 6 and 12 months and annually thereafter. RESULTS: The procedures were elective in 75.7% and urgent due to symptomatic or ruptured aneurysm in 24.3%. Technical success was 98.6%; three patients (1.4%) required conversion to open surgery. Postoperative mortality rate was 24% for urgent and 2.3% for elective procedures. During a mean follow-up period of 29.6 months, no cases of stent-graft migration were observed; the overall incidence of endoleaks was 27% (60/222) and comprised four type I (1.8%) and one type III (0.45%), all treated by stent-graft extension, and 55 type 2 (24.8%), eight of which (14.5%) were treated by percutaneous injection of thrombin. In 10/222 cases (4.5%), thrombotic occlusion of the iliac extension was detected, which was successfully treated by transcatheter intra-arterial thrombolysis. One patient developed stent-graft infection requiring surgical explantation. Average hospital stay was 4 days, and average time in intensive care was 2 days. CONCLUSIONS: Consistent with the literature data, our study confirms the safety and long-term efficacy of EVAR for treating AAA.

Th1, Th2, Th17 and regulatory T cell pattern in psoriatic patients: modulation of cytokines and gene targets induced by etanercept treatment and correlation with clinical response.

BACKGROUND: Psoriasis is sustained by pro-inflammatory CD4+ T helper cells mainly belonging to the Th1, Th17 and Th22 lineage. OBJECTIVE: To identify whether treatment with the anti-tumour-necrosis-factor antagonist etanercept is able to induce significant modulations in transcription factor and cytokine mRNA gene expressions related to the different T cell immune response polarization (Th1, Th2, Th17 and regulatory T cells, Treg and to correlate them with clinical response. METHODS: The study population included 19 psoriasis patients treated with etanercept and 19 healthy subjects. Blood samples were collected at baseline and every 4 weeks during treatment. Taqman quantitative real-time polymerase chain reaction was applied to analyse the expression of: Stat-4, T-bet, IL-12p35 and IFN-γ (Th1-related); GATA-3, IL-4 (Th2-related); Stat-3, RORγt, IL-23p19 (Th17-related); Foxp3, IL-2 (Treg-related). Flow cytometry was applied to analyse CD4+CD25+(bright)Foxp3+ cells in peripheral blood. RESULTS: Upregulation of Th1 and Th17 and downregulation of Treg subsets was found at baseline. The response to etanercept could be associated with a significant reversal of the Th1/Th17 activation, and a concomitant upregulation of Th2 and Treg subsets. CONCLUSION: Our data may contribute to a better understanding of the mechanisms underlying the achievement of clinical response in psoriasis and could be helpful for the identification of early predictive markers of response.

Combined measurement of serum DNA and urine VP1 messenger RNA in monitoring BK virus replication in kidney graft recipients.

Evaluation of BK virus replication is a fundamental tool in the monitoring of renal transplant recipients. Herein, we investigated the role of urine VP1 messenger RNA (mRNA) quantification and combined measurement of serum DNA and urine VP1 mRNA in 428 kidney allograft recipients. BK viremia and viruria were detected in 24 (5.6%) and 54 (12.6%) patients, respectively. A diagnosis of BKV-associated nephropathy (BKVAN) was established in 2 patients, both within the first year posttransplantation. Based on urine VP1 mRNA measurement, BKV replication was observed in 10 (2.1%) patients, 2 of whom displayed BKVAN. Urine VP1 mRNA was detected in all cases in association with viremia except 5 and in all cases with viruria. No difference among VP1 mRNA levels was noted between the 2 BKVAN patients and the highest values in patients without BKVAN. The urine VP1 mRNA result by analysis using the operating characteristics was not superior to viremia, despite the improvement obtained with the combined measurement of viremia (cut-off, 16,000 copies/mL) and urine VP1 mRNA (>10,000 copies/10(3) cells). In conclusion, VP1 mRNA measurements may complement viremia and viruria to monitor BKV replication, although its use is limited by its technical complexity in comparison with DNA detection.

Prevalence and clinical impact of polyomaviruses KI and WU in lung transplant recipients.

The newly discovered polyomaviruses KI and WU (KIV and WUV) were isolated from secretions of patients with respiratory symptoms as well as in blood, spleen, lymphoid tissues, and stools, especially in immunocompromised conditions. The aim of this work was to evaluate the prevalence of KIV and WUV in bronchoalveolar lavage (BAL) from lung transplant recipients. We also examined potential correlations between these viruses and occurrences of pneumonia, acute respiratory insufficiency, or other acute respiratory conditions and acute rejection episodes. Discharge diagnosis was based on the International Classification of Diseases-Italian version 2002, based on the 9th-revision clinical modification. A rejection episode was diagnosed by transbronchial lung biopsy in accordance with the 2007 International Society for Heart and Lung Transplantation Working Formulation. Overall, we analyzed 53 BALs obtained from 24 transplant recipients. Positive polymerase chain reaction results were observed in 6 samples (11.3%) from 6 patients (25%), versus 7 samples (13.2%) from 7 patients (29.2%) for KIV and WUV, respectively. Regarding the diagnosis of pneumonia, the prevalence was 22.2% and 33.3% for KIV and WUV, respectively. In cases of acute respiratory insufficiency or other acute respiratory conditions, 2 out of 9 samples were positive for KIV (22.2%) and 4 out of 9 for WUV (44.4%). An Acute rejection episode (ARE) was diagnosed in 7 instances among 6 lung transplant patients: The corresponding BAL specimens showed positive results for KIV in 3 out of 7 (42.8%) cases with ARE vs 3 out of 46 (6.5%) without an ARE (P < .05), and for WUV in 3 out of 7 (42.8%) vs 4 out of 46 (8.7%) (P < .05), respectively. Although the small number of specimens limits the statistical analysis, our results showed a higher prevalence of WUV compared with KIV. The compromised pulmonary environment in the lung allograft may cause reactivation of these viruses. Their roles in this context need to be further evaluated.

Prevalence of polyomaviruses BK, JC, SV40, KI, and WU in non-malignant tonsil specimens.

AIM: The recently described polyomaviruses KI and WU have been detected in respiratory samples, stools, tonsils, and blood, particularly in immunocompromised conditions, although little is known about tissue tropism. Herein we investigated the occurrence of KIV and WUV in non-malignant tonsillar specimens by Real-time quantitative PCR; the presence of polyomaviruses BK, JC and SV40-DNA was also evaluated. METHODS: Twenty-nine non-malignant tonsil specimens obtained from children and adults admitted for tonsillectomy were prospectively studied. Real-time quantitative TaqMan PCR for polyomaviruses KI, WU, BK, JC, and SV40 were performed. RESULTS: KI-DNA was positive in 2/29 tonsillar specimens (6.9%), while BK- DNA, JC-DNA, SV-40 DNA, and WU-DNA sequences were not identified. CONCLUSION: Few studies have investigated the prevalence of polyomaviruses in tonsil specimens, with varying results, and data are particularly scant as regards the newly discovered KIV and WUV. Two major questions remain to be definitely answered at this regard: the possibility that human tonsils represent the initial site of infection and/or a latency site and the biological and clinical meaning of KIV and WUV in different contexts and groups of patients, in that it is not clear whether they are simple bystanders or play a role in tonsil disease.

MRI post-vertebroplasty.

PURPOSE: Percutaneous vertebroplasty (PVP), first described by Hervè Deramond in 1984, is an interventional procedure for the treatment of aggressive vertebral angioma. The aim of this study was to evaluate magnetic resonance imaging (MRI) patterns in the affected vertebrae before and after vertebroplasty by determining changes in signal intensity and size and distribution of bone cement within the vertebra at follow-up carried out at 1 week, 6 months and 12 months. MATERIALS AND METHODS: Fourteen patients were examined using MRI, for a total of 41 treated vertebrae; MRI was performed with a 0.5-Tesla (T) superconductive magnet (SIGNA GE). RESULTS: MRI patterns following vertebroplasty are mainly characterised by the signal produced by the areas surrounding the cement and by the cement itself. There is little effect on the size of the treated vertebra. Acrylic cement appears as an intraspongy focal area of T1 and T2 hypointensity that is mostly oval (34%) or rounded (26.8%); this appearance tends to become stable 6 months after treatment. The area surrounding the cement appears hypointense on T1 and hyperintense on T2, a likely expression of bone marrow oedema; this signal alteration tends to disappear gradually. CONCLUSIONS: In pre- and post-vertebroplasty imaging, MRI is regarded as the reference standard for correct evaluation of both container and content. Awareness of cement changes over time and of the reaction of the surrounding bone tissue is crucial for correct assessment of post-vertebroplasty images.

Association of Children with Heart Disease in the World: 10-year experience.

Thousands of children live in developing countries with untreated but correctable congenital heart disease (CHD), and most of them will die simple because they live in poor countries that do not have suitable medical/surgical facilities. The aim of the Association of Children with Heart Disease in the World is to support the operatory and teaching activities of a group of voluntary doctors engaged in the management of children with CHD in developing countries. Since 1992, the association has obtained 160 grants for foreign doctors who have been trained in our hospitals; performed 75 missions abroad, with more than 2150 cases evaluated and 404 cardiac operations performed; obtained millions of dollars worth of donated medical equipment; and constructed two cardiac surgery departments in Syria and Cameroon. Many efforts have been made, but much more can be done as we attain more experience and develop better coordination and collaboration between the international groups engaged in this emerging social need.

Coronary heart disease in smokers: vitamin C restores coronary microcirculatory function.

BACKGROUND: Coronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. METHODS AND RESULTS: We used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects (P:<0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects. CONCLUSIONS: The present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.

Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations.

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.

Increased risk of secondary leukemia after single-agent treatment with etoposide for Langerhans' cell histiocytosis.

The study evaluated 139 patients diagnosed with Langerhans' cell histiocytosis (LCH) and enrolled in any protocol of the Italian Association of Pediatric Hematology/Oncology since 1982. Treatment was etoposide (VP-16) only in 50 patients, VP-16 and other drugs with an already established leukemogenic effect in 17 patients, only drugs with leukemogenic effect in 6 patients, other drugs in 35 patients, and surgery only in 31 patients. Median length of follow-up after diagnosis was 65 months (range, 1 to 126 months) for a total of 742.5 person-years at risk (PYRs). Three cases of acute myelogenous leukemia (AML) were reported; only 0.0044 case was expected. The standard incidence ratio (SIR) of AML in this cohort was 680.5 [95% confidence interval (CI), 140.2-1988.5], and the incidence rate per 1000 PYRs was 4.0 (95% CI, 0.8-11.8). For the subgroup treated with single-agent VP-16, the SIR after treatment was 2270.0 (95% CI, 275-8199), and the incidence rate after treatment was 14.7 (95% CI, 1.8-42.8). The study confirms a higher risk of leukemia after LCH and supports the hypothesis of an association between treatment-related acute nonlymphocytic leukemia and single-agent treatment with VP-16.

Lactate dehydrogenase isoenzyme patterns in blood cells from histiocytosis X children.

To find a clinical assay for histiocytosis X (HX) diagnosis, measurements were made of both activity and isoenzyme distribution of lactate dehydrogenase (LDH; EC 1.1.1.27) from the blood cells of 6 acute phase and 9 remission patients. A significant increase in the LDH activity measured in the monocytes and lymphocytes isolated from the blood of the acute phase patients was found. The increased activity was due to an enhancement of the normal pattern of LDH isoenzymes in these cells and not to a change in isoenzyme distribution. No increase was found in monocyte LDH isoenzymes from the patients in remission.

Langerhans cell histiocytosis in childhood: results from the Italian Cooperative AIEOP-CNR-H.X '83 study.

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients.

Angioimmunoblastic lymphadenopathy with dysproteinemia: report of a case in infancy with review of literature.

A case of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) in infancy is reported. The disease had a mild onset with generalized lymphadenopathy, hepatosplenomegaly, thrombocytopenia, polyclonal hypergammaglobulinemia, and T-cell deficiency. The AILD course lasted more than 100 months, alternating clinical remission to recurrent relapses. Hepatitis B viral infection suddenly evolving to hepatic failure was the cause of death. From a rapid survey of the present knowledge, the nosology, immunological features, and therapy of AILD are discussed and a possible presumptive pathogenetic pathway is proposed.

Etoposide in recurrent childhood Langerhans' cell histiocytosis: an Italian cooperative study.

Eighteen evaluable children with recurrent Langerhans' cell histiocytosis (LCH) which was resistant to standard therapy, were treated with etoposide (VP 16-213), 200 mg/m2/day for 3 days every 3 weeks, to study the efficacy and toxicity of this drug. Complete and partial responses were demonstrated in 15 patients (83.3%). Only one of the 12 children achieving a complete remission has relapsed. No dose-limiting major toxicities were registered. Although etoposide might be an effective treatment in recurrent LCH which needs a chemotherapeutic approach, it is emphasized that this drug must be used carefully.